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Advanced Drug Delivery Reviews
Journal Prestige (SJR): 4.09
Citation Impact (citeScore): 13
Number of Followers: 152  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0169-409X
Published by Elsevier Homepage  [3163 journals]
  • Triggering antitumoural drug release and gene expression by magnetic
    • Abstract: Publication date: Available online 17 October 2018Source: Advanced Drug Delivery ReviewsAuthor(s): María Moros, Javier Idiago-López, Laura Asín, Eduardo Moreno-Antolín, Lilianne Beola, Valeria Grazú, Raluca M. Fratila, Lucía Gutiérrez, Jesús Martínez de la Fuente Magnetic nanoparticles (MNPs) are promising tools for a wide array of biomedical applications. One of their most outstanding properties is the ability to generate heat when exposed to alternating magnetic fields, usually exploited in magnetic hyperthermia therapy of cancer. In this contribution, we provide a critical review of the use of MNPs and magnetic hyperthermia as drug release and gene expression triggers for cancer therapy. Several strategies for the release of chemotherapeutic drugs from thermo-responsive matrices are discussed, providing representative examples of their application at different levels (from proof of concept to in vivo applications). The potential of magnetic hyperthermia to promote in situ expression of therapeutic genes using vectors that contain heat-responsive promoters is also reviewed in the context of cancer gene therapy.Graphical abstractUnlabelled Image
  • Pharmacokinetics, pharmacodynamics and safety of aptamers
    • Abstract: Publication date: Available online 12 October 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Katarina D. Kovacevic, James C. Gilbert, Bernd Jilma Aptamers are synthetic molecules structured as single-stranded DNA or RNA oligonucleotides that can be designed to mimic the functional properties of monoclonal antibodies. They bind to the target molecules (typically soluble or cell-bound proteins) with high affinity (with picomolar to low nanomolar range) and specificity, and therefore can be an alternative to therapeutic antibodies or peptide ligands. This paper reviews published data regarding pharmacokinetics, pharmacodynamics and safety of aptamers from preclinical and clinical studies. Aptamers have been developed for the treatment of a variety of diseases, including cancer, macular degeneration, cardiovascular disease, diabetes and anaemia of chronic diseases. There are several preclinical studies with unmodified aptamers, but the vast majority of aptamer trials in humans have been conducted with modified aptamers, because unmodified aptamers demonstrate metabolic instability, as well as rapid renal filtration and elimination. Various strategies have been developed to improve the pharmacokinetic profile of aptamers. Aside from chemical modification of nucleotides in order to stabilize them against nuclease degradation, the main modification to extend the half-life is pegylation. Therefore, the process of pegylation as well as its benefits and possible shortcomings will briefly be discussed.Graphical abstractUnlabelled Image
  • Advances on non-invasive physically triggered Nucleic Acid delivery from
    • Abstract: Publication date: Available online 12 October 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Hai Doan Do, Brice Martin Couillaud, Bich-Thuy Doan, Yohann Corvis, Nathalie Mignet Nucleic acids (NAs) have been considered as promising therapeutic agents for various types of diseases. However, their clinical applications still face many limitations due to their charge, high molecular weight, instability in biological environment and low levels of transfection. To overcome these drawbacks, therapeutic NAs should be carried in a stable nanocarrier, which can be viral or non-viral vectors, and released at specific target site. Various controllable gene release strategies are currently being evaluated with interesting results. Endogenous stimuli-responsive systems, for example pH-, redox reaction-, enzymatic-triggered approaches have been widely studied based on the physiological differences between pathological and normal tissues. Meanwhile, exogenous triggered release strategies require the use of externally non-invasive physical triggering signals such as light, heat, magnetic field and ultrasound. Compared to internal triggered strategies, external triggered gene release is time and site specifically controllable through active management of outside stimuli. The signal induces changes in the stability of the delivery system or some specific reactions which lead to endosomal escape and/or gene release. In the present review, the mechanisms and examples of exogenous triggered gene release approaches are detailed. Challenges and perspectives of such gene delivery systems are also discussed.Graphical abstractUnlabelled Image
  • Light-Responsive Nanomedicine for Biophotonic Imaging and Targeted Therapy
    • Abstract: Publication date: Available online 12 October 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Jihwan Son, Gawon Yi, Jihye Yoo, Changhee Park, Heebeom Koo, Hak Soo Choi Nanoparticles (NPs) play a key role in nanomedicine in multimodal imaging, drug delivery and targeted therapy of human diseases. Consequently, due to the attractive properties of NPs including high stability, high payload, multifunctionality, design flexibility, and efficient delivery to target tissues, nanomedicine employs various types of NPs to enhance targeting and treatment efficacy. In this review, we primarily focus on light-responsive materials, such as fluorophores, photosensitizers, semiconducting polymers, carbon structures, gold particles, quantum dots, and upconversion crystals, for their biomedical applications. Armed with these nanomaterials, NPs represent a growing potential in biophotonic imaging (luminescence, photoacoustic, surface enhanced Raman scattering, and optical coherence tomography) as well as targeted therapy (photodynamic therapy, photothermal therapy, and light-responsive drug release).Graphical abstractUnlabelled Image
  • External Stimulus Responsive Inorganic Nanomaterials for Cancer
    • Abstract: Publication date: Available online 12 October 2018Source: Advanced Drug Delivery ReviewsAuthor(s): M. Sheikh Mohamed, Srivani Veeranarayanan, Toru Maekawa, D. Sakthi Kumar Cancer is a highly intelligent system of cells, that works together with the body to thrive and subsequently overwhelm the host in order for its survival. Therefore, treatment regimens should be equally competent to outsmart these cells. Unfortunately, it is not the case with current therapeutic practices, the reason why it is still one of the most deadly adversaries and an imposing challenge to healthcare practitioners and researchers alike. With rapid nanotechnological interventions in the medical arena, the amalgamation of diagnostic and therapeutic functionalities into a single platform, theranostics provides a never before experienced hope of enhancing diagnostic accuracy and therapeutic efficiency. Additionally, the ability of these nanotheranostic agents to perform their actions on-demand, i.e. can be controlled by external stimulus such as light, magnetic field, sound waves and radiation has cemented their position as next generation anti-cancer candidates. Numerous reports exist of such stimuli-responsive theranostic nanomaterials against cancer, but few have broken through to clinical trials, let alone clinical practice. This review sheds light on the pros and cons of a few such theranostic nanomaterials, especially inorganic nanomaterials which do not require any additional chemical moieties to initiate the stimulus. The review will primarily focus on preclinical and clinical trial approved theranostic agents alone, describing their success or failure in the respective stages.Graphical abstractUnlabelled Image
  • Thermoresponsive polymer nanocarriers for biomedical applications
    • Abstract: Publication date: Available online 11 October 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Alexandre Bordat, Tanguy Boissenot, Julien Nicolas, Nicolas Tsapis Polymer nanocarriers allow drug encapsulation leading to fragile molecule protection from early degradation/metabolization, increased solubility of poorly soluble drugs and improved plasmatic half-life. However, efficiently controlling the drug release from nanocarriers is still challenging. Thermoresponsive polymers exhibiting either a lower critical solubility temperature (LCST) or an upper critical solubility temperature (UCST) in aqueous medium may be the key to build spatially and temporally controlled drug delivery systems. In this review, we provide an overview of LCST and UCST polymers used as building blocks for thermoresponsive nanocarriers for biomedical applications. Recent nanocarriers based on thermoresponsive polymer exhibiting unprecedented features useful for biomedical applications are also discussed. While LCST nanocarriers have been studied for over two decades, UCST nanocarriers have recently emerged and already show great potential for effective thermoresponsive drug release.Graphical abstractUnlabelled Image
  • Remotely controlled opening of delivery vehicles and release of cargo by
           external triggers
    • Abstract: Publication date: Available online 11 October 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Dingcheng Zhu, Sathi Roy, Ziyao Liu, Horst Weller, Wolfgang Parak, Neus Feliu Tremendous efforts have been devoted to the development of future nanomedicines that can be specifically designed to incorporate responsive elements that undergo modification in structural properties upon external triggers. One potential use of such stimuli-responsive materials is to release encapsulated cargo upon excitation by an external trigger. Today, such stimuli-response materials allow for spatial and temporal tunability, which enables the controlled delivery of compounds in a specific and dose-dependent manner. This potentially is of great interest for medicine (e.g. allowing for remotely controlled drug delivery to cells, etc.). Among the different external exogenous and endogenous stimuli used to control the desired release, light and magnetic fields offer interesting possibilities, allowing defined, real time control of intracellular releases. In this review we highlight the use of stimuli-responsive controlled release systems that are able to respond to light and magnetic field triggers for controlling the release of encapsulated cargo inside cells. We discuss established approaches and technologies and describe prominent examples. Special attention is devoted towards polymer capsules and polymer vesicles as containers for encapsulated cargo molecules. The advantages and disadvantages of this methodology in both, in vitro and in vivo models are discussed. An overview of challenges associate with the successful translation of those stimuli-responsive materials towards future applications in the direction of potential clinical use is given.Graphical abstractRelease of encapsulated molecular cargo upon (external) triggers.Unlabelled Image
  • The potential for remodelling the tumour vasculature in glioblastoma
    • Abstract: Publication date: Available online 9 October 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Caterina Brighi, Simon Puttick, Stephen Rose, Andrew K. Whittaker Despite significant improvements in the clinical management of glioblastoma, poor delivery of systemic therapies to the entire population of tumour cells remains one of the biggest challenges in the achievement of more effective treatments. On the one hand, the abnormal and dysfunctional tumour vascular network largely limits blood perfusion, resulting in an inhomogeneous delivery of drugs to the tumour. On the other hand, the presence of an intact blood-brain barrier (BBB) in certain regions of the tumour prevents chemotherapeutic drugs from permeating through the tumour vessels and reaching the diseased cells. In this review we analyse in detail the implications of the presence of a dysfunctional vascular network and the impenetrable BBB on drug transport. We discuss advantages and limitations of the currently available strategies for remodelling the tumour vasculature aiming to ameliorate the above mentioned limitations. Finally we review research methods for visualising vascular dysfunction and highlight the power of DCE- and DSC-MRI imaging to assess changes in blood perfusion and BBB permeability.Graphical abstractUnlabelled Image
  • Animal models for analysis of immunological responses to nanomaterials:
           Challenges and considerations
    • Abstract: Publication date: Available online 29 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): William C. Zamboni, Janos Szebeni, Serguei V. Kozlov, Andrew T. Lucas, Joseph A. Piscitelli, Marina A. Dobrovolskaia Nanotechnology provides many solutions to improve conventional drug delivery and has a unique niche in the areas related to the specific targeting of the immune system, such as immunotherapies and vaccines. Preclinical studies in this field rely heavily on the combination of in vitro and in vivo methods to assess the safety and efficacy of nanotechnology platforms, nanoparticle-formulated drugs, and vaccines. While certain types of toxicities can be evaluated in vitro and good in vitro–in vivo correlation has been demonstrated for such tests, animal studies are still needed to address complex biological questions and, therefore, provide a unique contribution to establishing nanoparticle safety and efficacy profiles. The genetic, metabolic, mechanistic, and phenotypic diversity of currently available animal models often complicates both the animal choice and the interpretation of the results. This review summarizes current knowledge about differences in the immune system function and immunological responses of animals commonly used in preclinical studies of nanomaterials. We discuss challenges, highlight current gaps, and propose recommendations for animal model selection to streamline preclinical analysis of nanotechnology formulations.Graphical abstractUnlabelled Image
  • Aptamer-guided nanomedicines for anticancer drug delivery
    • Abstract: Publication date: Available online 27 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Walhan Alshaer, Hervé Hillaireau, Elias Fattal Aptamers are versatile nucleic acid-based macromolecules characterized by their high affinity and specificity to a specific target. Taking advantage of such binding properties, several aptamers have been selected to bind tumor biomarkers and have been used as targeting ligands for the functionalization of nanomedicines. Different functionalization methods have been used to link aptamers to the surface drug nanocarriers. The pre-clinical data of such nanomedicines overall show an enhanced and selective delivery of therapeutic payloads to cancer cells, thereby accelerating steps towards more effective therapeutic systems. This review describes the current advances in the use of aptamers as targeting moieties for the delivery of therapeutic and imaging agents to tumors by conjugation to organic and inorganic nanocarriers.Graphical abstractUnlabelled Image
  • Therapeutic strategies for enhancing angiogenesis in wound healing
    • Abstract: Publication date: Available online 26 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Austin P. Veith, Kayla Henderson, Adrianne Spencer, Andrew D. Sligar, Aaron B. Baker The enhancement of wound healing has been a goal of medical practitioners for thousands of years. The development of chronic, non-healing wounds is a persistent medical problem that drives patient morbidity and increases healthcare costs. A key aspect of many non-healing wounds is the reduced presence of vessel growth through the process of angiogenesis. This review surveys the creation of new treatments for healing cutaneous wounds through therapeutic angiogenesis. In particular, we discuss the challenges and advancement that have been made in delivering biologic, pharmaceutical and cell-based therapies as enhancers of wound vascularity and healing.Graphical abstractUnlabelled Image
  • Utilizing microphysiological systems and induced pluripotent stem cells
           for disease modeling: a case study for blood brain barrier research in a
           pharmaceutical setting
    • Abstract: Publication date: Available online 22 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Kristin M. Fabre, Louise Delsing, Ryan Hicks, Nicola Colclough, Damian Crowther, Lorna Ewart Microphysiological systems (MPS) may be able to provide the pharmaceutical industry models that can reflect human physiological responses to improve drug discovery and translational outcomes. With lack of efficacy being the primary cause for drug attrition, developing MPS disease models would help researchers identify novel targets, study mechanisms in more physiologically-relevant depth, screen for novel biomarkers and test/optimize various therapeutics (small molecules, nanoparticles and biologics). Furthermore, with advances in inducible pluripotent stem cell technology (iPSC), pharmaceutical companies can access cells from patients to help recreate specific disease phenotypes in MPS platforms. Combining iPSC and MPS technologies will contribute to our understanding of the complexities of neurodegenerative diseases and of the blood brain barrier (BBB) leading to development of enhanced therapeutics.Graphical abstractUnlabelled Image
  • Novel targets for delaying aging: The importance of the liver and advances
           in drug delivery
    • Abstract: Publication date: Available online 21 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Nicholas J. Hunt, Peter A.G. McCourt, David G. Le Couteur, Victoria C. Cogger Age-related changes in liver function have a significant impact on systemic aging and susceptibility to age-related diseases. Nutrient sensing pathways have emerged as important targets for the development of drugs that delay aging and the onset age-related diseases. This supports a central role for the hepatic regulation of metabolism in the association between nutrition and aging. Recently, a role for liver sinusoidal endothelial cells (LSECs) in the relationship between aging and metabolism has also been proposed. Age-related loss of fenestrations within LSECs impairs the transfer of substrates (such as lipoproteins and insulin) between sinusoidal blood and hepatocytes, resulting in post-prandial hyperlipidemia and insulin resistance. Targeted drug delivery methods such as nanoparticles and quantum dots will facilitate the direct delivery of drugs that regulate fenestrations in LSECs, providing an innovative approach to ameliorating age-related diseases and increasing healthspan.Graphical abstractUnlabelled Image
  • Micromotors for drug delivery in vivo: The road ahead
    • Abstract: Publication date: Available online 17 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sarvesh Kumar Srivastava, Gael Clergeaud, Thomas L. Andresen, Anja Boisen Autonomously propelled/externally guided micromotors overcome current drug delivery challenges by providing (a) higher drug loading capacity, (b) localized delivery (less toxicity), (c) enhanced tissue penetration and (d) active maneuvering in vivo. These microscale drug delivery systems can exploit biological fluids as well as exogenous stimuli, like light-NIR, ultrasound and magnetic fields (or a combination of these) towards propulsion/drug release. Ability of these wireless drug carriers towards localized targeting and controlled drug release, makes them a lucrative candidate for drug administration in complex microenvironments (like solid tumors or gastrointestinal tract). In this report, we discuss these microscale drug delivery systems for their therapeutic benefits under in vivo setting and provide a design-application rationale towards greater clinical significance.Graphical abstractUnlabelled Image
  • The effect of Low- and High-Penetration Light on Localized Cancer Therapy
    • Abstract: Publication date: Available online 12 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Daniel F. Costa, Lívia P. Mendes, Vladimir P. Torchilin The design of a delivery system allowing targeted and controlled drug release has been considered one of the main strategies used to provide individualized cancer therapy, to improve survival statistics, and to enhance quality-of-life. External stimuli including low- and high-penetration light have been shown to have the ability to turn drug delivery on and off in a non-invasive remotely-controlled fashion. The success of this approach has been closely related to the development of a variety of drug delivery systems – from photosensitive liposomes to gold nanocages – and relies on multiple mechanisms of drug release activation. In this review, we make reference to the two extremes of the light spectrum and their potential as triggers for the delivery of antitumor drugs, along with the most recent achievements in preclinical trials and the challenges to an efficient translation of this technology to the clinical setting.Graphical abstractUnlabelled Image
  • Challenges and innovations of drug delivery in older age
    • Abstract: Publication date: Available online 11 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Muhammad Suleman Khan, Michael S. Roberts Both drug delivery performance and various age-related physical, mental and physiological changes can affect their effectiveness and safety in elderly patients. The many drug delivery systems developed over the years include recent novel transdermal, nasal, pulmonary and orally disintegrating tablet delivery systems that provide consistent, precise, timely and more targeted absorption. Certain drug delivery systems may be associated with suboptimal outcomes in the elderly because of the nature of drug present, a lack of appreciation of the impact of age-related changes in drug absorption, distribution and clearance on their pharmacokinetics, the limited availability of pharmacokinetic, safety and clinical data. Polypharmacy, patient morbidity and poor adherence can also contribute to sub-optimal drug delivery systems outcomes in older people. The development of drug delivery systems for the elderly is a poorly realised opportunity, with each system having specific advantages and limitations. A key challenge is to provide the innovation that best meets the specific physiological, psychological and multiple drug requirements of individual elderly patients.Graphical abstractUnlabelled Image
  • Editorial: Drug Nanoparticles and Nano-Cocrystals: From Production and
           Characterization to Clinical Translation
    • Abstract: Publication date: June 2018Source: Advanced Drug Delivery Reviews, Volume 131Author(s): Alejandro Sosnik, Stefan Mühlebach
  • Editorial board members
    • Abstract: Publication date: June 2018Source: Advanced Drug Delivery Reviews, Volume 131Author(s):
  • Limiting angiogenesis to modulate scar formation
    • Abstract: Publication date: Available online 3 March 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Stefanie Korntner, Christine Lehner, Renate Gehwolf, Andrea Wagner, Moritz Grütz, Nadja Kunkel, Herbert Tempfer, Andreas Traweger Angiogenesis, the process of new blood vessel formation from existing blood vessels, is a key aspect of virtually every repair process. During wound healing an extensive, but immature and leaky vascular plexus forms which is subsequently reduced by regression of non-functional vessels. More recent studies indicate that uncontrolled vessel growth or impaired vessel regression as a consequence of an excessive inflammatory response can impair wound healing, resulting in scarring and dysfunction. However, in order to elucidate targetable factors to promote functional tissue regeneration we need to understand the molecular and cellular underpinnings of physiological angiogenesis, ranging from induction to resolution of blood vessels. Especially for avascular tissues (e.g. cornea, tendon, ligament, cartilage, etc.), limiting rather than boosting vessel growth during wound repair potentially is beneficial to restore full tissue function and may result in favourable long-term healing outcomes.Graphical abstractUnlabelled Image
  • Fluorescence anisotropy imaging in drug discovery
    • Abstract: Publication date: Available online 2 February 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Claudio Vinegoni, Paolo Fumene Feruglio, Ignacy Gryczynski, Ralph Mazitschek, Ralph Weissleder Non-invasive measurement of drug-target engagement can provide critical insights in the molecular pharmacology of small molecule drugs. Fluorescence polarization/fluorescence anisotropy measurements are commonly employed in protein/cell screening assays. However, the expansion of such measurements to the in vivo setting has proven difficult until recently. With the advent of high-resolution fluorescence anisotropy microscopy it is now possible to perform kinetic measurements of intracellular drug distribution and target engagement in commonly used mouse models. In this review we discuss the background, current advances and future perspectives in intravital fluorescence anisotropy measurements to derive pharmacokinetic and pharmacodynamic measurements in single cells and whole organs.Graphical abstractUnlabelled Image
  • Enhancing patient-level clinical data access to promote evidence-based
           practice and incentivize therapeutic innovation
    • Abstract: Publication date: Available online 31 January 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Alice Fortunato, David W. Grainger, Mohamed Abou-El-Enein Clinical trials are crucial to determining the human safety and efficacy of new therapeutic innovations. Extraordinary amounts of human experiential data are generated over the course of any clinical trial, however, much of these data is never made publicly accessible. Improved, reliable data sharing is essential to inform clinical decisions and incentivize further therapeutic improvements; this need, and the call and concept to enhance patient-level clinical trial data accessibility is not new. Several recent public and private shifts in clinical data sharing policies and procedures promise to improve access and data utility to reduce waste in research and increase efficiency of evidence synthesis. Nonetheless, pharmaceutical industry remain reluctant to share full clinical data sets at some level to protect their commercial interests and avoid misuse of their data. Here, we review the landscape of emerging regulations related to the sharing of patient level data and current clinical data access models of major pharmaceutical companies. We also summarize the different measures that could satisfy both clinical data producers and users in achieving the benefits of accessing patient-level data while mitigating any associated risks.Graphical abstractResponsible data sharing model would facilitate the access to clinical trial data to make informed decisions critical to advancing new therapeutics for patient benefit.Unlabelled Image
  • Antibody-cytokine fusion proteins: Biopharmaceuticals with
           immunomodulatory properties for cancer therapy
    • Abstract: Publication date: Available online 7 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Cornelia Hutmacher, Dario Neri Cytokines have long been used for therapeutic applications in cancer patients. Substantial side effects and unfavorable pharmacokinetics limit their application and may prevent dose escalation to therapeutically active regimens. Antibody-cytokine fusion proteins (often referred to as immunocytokines) may help localize immunomodulatory cytokine payloads to the tumor, thereby activating anticancer immune responses. A variety of formats (e.g., intact IgGs or antibody fragments), molecular targets (e.g., extracellular matrix components and cell membrane antigens) and cytokine payloads have been considered for the development of this novel class of biopharmaceuticals. This review presents the basic concepts on the design and engineering of immunocytokines, reviews their potential limitations, points out emerging opportunities and summarizes key features of preclinical and clinical-stage products.Graphical abstractUnlabelled Image
  • The potential to treat lung cancer via inhalation of repurposed drugs
    • Abstract: Publication date: Available online 4 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Wing-Hin Lee, Ching-Yee Loo, Maliheh Ghadiri, Chean-Ring Leong, Paul M. Young, Daniela Traini Lung cancer is a highly invasive and prevalent disease with ineffective first-line treatment and remains the leading cause of cancer death in men and women. Despite the improvements in diagnosis and therapy, the prognosis and outcome of lung cancer patients is still poor. This could be associated with the lack of effective first-line oncology drugs, formation of resistant tumors and non-optimal administration route. Therefore, the repurposing of existing drugs currently used for different indications and the introduction of a different method of drug administration could be investigated as an alternative to improve lung cancer therapy. This review describes the rationale and development of repositioning of drugs for lung cancer treatment with emphasis on inhalation. The review includes the current progress of repurposing non-cancer drugs, as well as current chemotherapeutics for lung malignancies via inhalation. Several potential non-cancer drugs such as statins, itraconazole and clarithromycin, that have demonstrated preclinical anti-cancer activity, are also presented. Furthermore, the potential challenges and limitations that might hamper the clinical translation of repurposed oncology drugs are described.Graphical abstractUnlabelled Image
  • Orally Inhaled Migraine Therapy: Where are we now'
    • Abstract: Publication date: Available online 4 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Kevin W. Stapleton Migraine is a debilitating disease that affects 9% of men and 19% of women worldwide with high socio-economic and personal impact. Surveys indicate that migraineurs are among the most dissatisfied with available therapeutic options, predominantly given via oral or injectable routes, citing side effects as the primary complaint. Orally inhaled therapies have the potential to offer faster onset of action with fewer side effects compared to existing therapies, yet development has stalled. Despite emerging therapies such as calcitonin gene-related peptide antagonists, there are still good opportunities for repositioning migraine drugs via the inhaled route.Graphical abstractUnlabelled Image
  • Physiologically based pharmacokinetic modelling to guide drug delivery in
           older people
    • Abstract: Publication date: Available online 4 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Manoranjenni Chetty, Trevor N. Johnson, Sebastian Polak, Farzaneh Salem, Kosuke Doki, Amin Rostami-Hodjegan Older patients are generally not included in Phase 1 clinical trials despite being the population group who use the largest number of prescription medicines. Physiologically based pharmacokinetic (PBPK) modelling provides an understanding of the absorption and disposition of drugs in older patients. In this review, PBPK models used for the prediction of absorption and exposure of drugs after parenteral, oral and transdermal administration are discussed. Comparisons between predicted drug pharmacokinetics (PK) and observed PK are presented to illustrate the accuracy of the predictions by the PBPK models and their potential use in informing clinical trial design and dosage adjustments in older patients. In addition, a case of PBPK modelling of a bioequivalence study on two controlled release products is described, where PBPK predictions reproduced the study showing bioequivalence in healthy volunteers but not in older subjects with achlorhydria, indicating further utility in prospectively identifying challenges in bioequivalence studies.Graphical abstractUnlabelled Image
  • Corrigendum to ‘Current state and challenges in developing oral
           vaccines’ [Adv. Drug Deliv. Rev. 114 (2017) 116-131]
    • Abstract: Publication date: Available online 3 September 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Julia E. Vela Ramirez, Lindsey A. Sharpe, Nicholas A. Peppas
  • Plant virus-based materials for biomedical applications: trends and
    • Abstract: Publication date: Available online 31 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sabine Eiben, Claudia Koch, Klara Altintoprak, Alexander Southan, Günter Tovar, Sabine Laschat, Ingrid M. Weiss, Christina Wege Nanomaterials composed of plant viral components are finding their way into medical technology and health care, as they offer singular properties. Precisely shaped, tailored virus nanoparticles (VNPs) with multivalent protein surfaces are efficiently loaded with functional compounds such as contrast agents and drugs, and serve as carrier templates and targeting vehicles displaying e.g. peptides and synthetic molecules. Multiple modifications enable uses including vaccination, biosensing, tissue engineering, intravital delivery and theranostics. Novel concepts exploit self-organization capacities of viral building blocks into hierarchical 2D and 3D structures, and their conversion into biocompatible, biodegradable units. High yields of VNPs and proteins can be harvested from plants after a few days so that various products have reached or are close to commercialization. The article delineates potentials and limitations of biomedical plant VNP uses, integrating perspectives of chemistry, biomaterials sciences, molecular plant virology and process engineering.Graphical abstractUnlabelled Image
  • Physically-triggered nanosystems based on two-dimensional materials for
           cancer theranostics
    • Abstract: Publication date: Available online 31 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Ding-Kun Ji, Cécilia Ménard-Moyon, Alberto Bianco There is an increasing demand to develop effective methods for treating malignant diseases to improve healthcare in our society. Stimuli-responsive nanosystems, which can respond to internal or external stimuli are promising in cancer therapy and diagnosis due to their functionality and versatility. As a newly emerging class of nanomaterials, two-dimensional (2D) nanomaterials have attracted huge interest in many different fields including biomedicine due to their unique physical and chemical properties. In the past decade, stimuli-responsive nanosystems based on 2D nanomaterials have been widely studied, showing promising applications in cancer therapy and diagnosis, including phototherapies, magnetic therapy, drug and gene delivery, and non-invasive imaging. Here, we will focus our attention on the state-of-the-art of physically-triggered nanosystems based on graphene and two-dimensional nanomaterials for cancer therapy and diagnosis. The physical triggers include light, temperature, magnetic and electric fields.Graphical abstractUnlabelled Image
  • Current and upcoming therapies to modulate skin scarring and fibrosis
    • Abstract: Publication date: Available online 30 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): João Q. Coentro, Eugenia Pugliese, Geoffrey Hanley, Michael Raghunath, Dimitrios I. Zeugolis Skin is the largest organ of the human body. Being the interface between the body and the outer environment, makes it susceptible to physical injury. To maintain life, nature has endowed skin with a fast healing response that invariably ends in the formation of scar at the wounded dermal area. In many cases, skin remodelling may be impaired, leading to local hypertrophic scars or keloids. One should also consider that the scarring process is part of the wound healing response, which always starts with inflammation. Thus, scarring can also be induced in the dermis, in the absence of an actual wound, during chronic inflammatory processes. Considering the significant portion of the population that is subject to abnormal scarring, this review critically discusses the state-of-the-art and upcoming therapies in skin scarring and fibrosis.Graphical abstractUnlabelled Image
  • Use of plant viruses and virus-like particles for the creation of novel
    • Abstract: Publication date: Available online 30 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Ina Balke, Andris Zeltins In recent decades, the development of plant virology and genetic engineering techniques has resulted in the construction of plant virus-based vaccines for protection against different infectious agents, cancers and autoimmune diseases in both humans and animals. Interaction studies between plant viruses and mammalian organisms have suggested that plant viruses and virus-like particles (VLPs) are safe and noninfectious to humans and animals. Plant viruses with introduced antigens are powerful vaccine components due to their strongly organized, repetitive spatial structure; they can elicit strong immune responses similar to those observed with infectious mammalian viruses. The analysis of published data demonstrated that at least 73 experimental vaccines, including 61 prophylactic and 12 therapeutic vaccines, have been constructed using plant viruses as a carrier structure for presentation of different antigens. This information clearly demonstrates that noninfectious viruses are also applicable as vaccine carriers. Moreover, several plant viruses have been used for platform development, and corresponding vaccines are currently being tested in human and veterinary clinical trials. This review therefore discusses the main principles of plant VLP vaccine construction, emphasizing the physical, chemical, genetic and immunological aspects. Results of the latest studies suggest that several plant virus-based vaccines will join the list of approved human and animal vaccines in the near future.Graphical abstractUnlabelled Image
  • Guest Editorial Title: Nanomedicine: past, present, and future
    • Abstract: Publication date: May 2018Source: Advanced Drug Delivery Reviews, Volume 130Author(s): James J. Moon, Steven P. Schwendeman, Anna Schwendeman
  • Aptamer-based targeted therapy
    • Abstract: Publication date: Available online 17 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Guizhi Zhu, Xiaoyuan Chen Precision medicine holds great promise to harness genetic and epigenetic cues for targeted treatment of a variety of diseases, ranging from many types of cancers, neurodegenerative diseases, to cardiovascular diseases. The proteomic profiles resulting from the unique genetic and epigenetic signatures represent a class of relatively well accessible molecular targets for both interrogation (e.g., diagnosis, prognosis) and intervention (e.g., targeted therapy) of these diseases. Aptamers are promising for such applications by specific binding with cognate disease biomarkers. Nucleic acid aptamers are a class of DNA or RNA with unique three-dimensional conformations that allow them to tightly bind with target molecules. Aptamers can be relatively easily screened, synthesized, programmably designed, and chemically modified for various biomedical applications, including targeted therapy. Aptamers can be chemically modified to resist enzymatic degradation or optimize their pharmacological behaviors, which ensured their chemical integrity and bioavailability under physiological conditions. In this review, we will focus on recent progress and discuss the challenges and opportunities in the research areas of aptamer-based targeted therapy in the forms of aptamer therapeutics or aptamer-drug conjugates (ApDCs).Graphical abstractUnlabelled Image
  • Application of aptamers for in vivo Molecular Imaging and
    • Abstract: Publication date: Available online 17 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Alix Bouvier-Müller, Frédéric Ducongé Nucleic acid aptamers are small three-dimensional structures of oligonucleotides selected to bind to a target of interest with high affinity and specificity. In vitro, aptamers already compete with antibodies to serve as imaging probes, e.g. for microscopy or flow cytometry. However, they are also increasingly used for in vivo molecular imaging. Accordingly, aptamers have been evaluated over the last twenty years in almost every imaging modality, including single photon emission computed tomography, positron emission tomography, magnetic resonance imaging, fluorescence imaging, echography, and x-ray computed tomography. This review focuses on the studies that were conducted in vivo with aptamer-based imaging probes. It also presents how aptamers have been recently used to develop new types of probes for multimodal imaging and theranostic applications.Graphical abstractUnlabelled Image
  • Therapeutic Aptamers in Discovery, Preclinical and Clinical Stages
    • Abstract: Publication date: Available online 17 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Said I. Ismail, Walhan Alshaer The aptamer field witnessed steady growth during the past 28 years as evident from the exponentially increasing number of related publications. The field is “coming of age”, but like other biomedical research areas facing a global push towards translational research to carry ideas from bench- to bedside, there is pressure to show impact for aptamers at the clinical end. Being easy-to-make, non-immunogenic, stable and high-affinity nano-ligands, aptamers are perfectly poised to move in this direction. They can specifically bind targets ranging from small molecules to complex multimeric structures, making them potentially useful in a limitless variety of therapeutic approaches. This review will summarize efforts made to accomplish the therapeutic promise of aptamers, with a focus on aptamers directly acting as therapeutic molecules, rather than those used in targeted delivery of other drugs. The review will showcase representative examples at various stages of development, covering different disease categories.Graphical abstractUnlabelled Image
  • Challenges and innovations of delivering medicines to older adults
    • Abstract: Publication date: Available online 15 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Danijela Gnjidic, Andy Husband, Adam Todd Older adults with multimorbidity, polypharmacy, and complex health needs are the major consumer of health care. Ensuring that medicines are used safely, effectively, and delivered efficiently in this population is challenging. In this context, the approach to medicines delivery should seek to overcome some of the difficulties of delivering medicines to older people, and ensure each medication is delivered by the optimal and most convenient route for the patient in question. However, this poses significant obstacles, as the development of medicines suitable for use in older populations does not often account for complex health needs, potential challenges in relation to drug disposition, safety of excipients and limitations with practical usability of dosage forms. The objective of this review is to summarise and discuss current challenges and novel approaches to delivering medications to older adults.
  • Muscle fibrosis in the soft palate: Delivery of cells, growth factors and
    • Abstract: Publication date: Available online 11 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Johannes W. Von den Hoff, Paola L. Carvajal Monroy, Edwin M. Ongkosuwito, Toin H. van Kuppevelt, Willeke F. Daamen The healing of skeletal muscle injuries after major trauma or surgical reconstruction is often complicated by the development of fibrosis leading to impaired function. Research in the field of muscle regeneration is mainly focused on the restoration of muscle mass while far less attention is paid to the prevention of fibrosis. In this review, we take as an example the reconstruction of the muscles in the soft palate of cleft palate patients. After surgical closure of the soft palate, muscle function during speech is often impaired by a shortage of muscle tissue as well as the development of fibrosis. We will give a short overview of the most common approaches to generate muscle mass and then focus on strategies to prevent fibrosis. These include anti-fibrotic strategies that have been developed for muscle and other organs by the delivery of small molecules, decorin and miRNAs. Anti-fibrotic compounds should be delivered in aligned constructs in order to obtain the organized architecture of muscle tissue. The available techniques for the preparation of aligned muscle constructs will be discussed. The combination of approaches to generate muscle mass with anti-fibrotic components in an aligned muscle construct may greatly improve the functional outcome of regenerative therapies for muscle injuries.Graphical abstractUnlabelled Image
  • Phage therapy for respiratory infections
    • Abstract: Publication date: Available online 7 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Rachel Yoon Kyung Chang, Martin Wallin, Yu Lin, Sharon Sui Yee Leung, Hui Wang, Sandra Morales, Hak-Kim Chan A respiratory infection caused by antibiotic-resistant bacteria can be life-threatening. In recent years, there has been tremendous effort put towards therapeutic application of bacteriophages (phages) as an alternative or supplementary treatment option over conventional antibiotics. Phages are natural parasitic viruses of bacteria that can kill the bacterial host, including those that are resistant to antibiotics. Inhaled phage therapy involves the development of stable phage formulations suitable for aerosol delivery followed by preclinical and clinical studies for assessment of efficacy, pharmacokinetics and safety. We presented an overview of recent advances in phage formulation for aerosol delivery and their efficacy in acute and chronic rodent lung infection models. We have reviewed and presented on the prospects of inhaled phage therapy as a complementary treatment option with current antibiotics and as a preventative means. Inhaled phage therapy has the potential to transform the prevention and treatment of bacterial respiratory infections, including those caused by antibiotic-resistant bacteria.Graphical abstractUnlabelled Image
  • Acellular and cellular approaches to improve diabetic wound healing
    • Abstract: Publication date: Available online 1 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Hongkwan Cho, Michael R. Blatchley, Elia J. Duh, Sharon Gerecht Chronic diabetic wounds represent a huge socioeconomic burden for both affected individuals and the entire healthcare system. Although the number of available treatment options as well as our understanding of wound healing mechanisms associated with diabetes has vastly improved over the past decades, there still remains a great need for additional therapeutic options. Tissue engineering and regenerative medicine approaches provide great advantages over conventional treatment options, which are mainly aimed at wound closure rather than addressing the underlying pathophysiology of diabetic wounds. Recent advances in biomaterials and stem cell research presented in this review provide novel ways to tackle different molecular and cellular culprits responsible for chronic and nonhealing wounds by delivering therapeutic agents in direct or indirect ways. Careful integration of different approaches presented in the current article could lead to the development of new therapeutic platforms that can address multiple pathophysiologic abnormalities and facilitate wound healing in patients with diabetes.Graphical abstractUnlabelled Image
  • Computational modelling of drug delivery to solid tumour: Understanding
           the interplay between chemotherapeutics and biological system for
           optimised delivery system
    • Abstract: Publication date: Available online 29 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Wenbo Zhan, Moath Alamer, Xiao Yun Xu Drug delivery to solid tumour involves multiple physiological, biochemical and biophysical processes taking place across a wide range of length and time scales. The therapeutic efficacy of anticancer drugs is influenced by the complex interplays among the intrinsic properties of tumours, biophysical aspects of drug transport and cellular uptake. Mathematical and computational modelling allows for a well-controlled study on the individual and combined effects of a wide range of parameters on drug transport and therapeutic efficacy, which would not be possible or economically viable through experimental means. A wide spectrum of mathematical models has been developed for the simulation of drug transport and delivery in solid tumours, including PK/PD-based compartmental models, microscopic and macroscopic transport models, and molecular dynamics drug loading and release models. These models have been used as a tool to identify the limiting factors and for optimal design of efficient drug delivery systems. This article gives an overview of the currently available computational models for drug transport in solid tumours, together with their applications to novel drug delivery systems, such as nanoparticle-mediated drug delivery and convection-enhanced delivery.Graphical abstractUnlabelled Image
  • Strategies to overcome the polycation dilemma in drug delivery
    • Abstract: Publication date: Available online 29 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Andreas Bernkop-Schnürch Because of polycationic auxiliary agents such as chitosan, polyethyleneimine and cell penetrating peptides as well as cationic lipids assembling to polycationic systems, drug carriers can tightly interact with cell membranes exhibiting a high-density anionic charge. Because of these interactions the cell membrane is depolarized and becomes vulnerable to various uptake mechanisms. On their way to the target site, however, the polycationic character of all these drug carriers is eliminated by polyanionic macromolecules such as mucus glycoproteins, serum proteins, proteoglycans of the extracellular matrix (ECM) and polyanionic surface substructures of non-target cells such as red blood cells. Strategies to overcome this polycation dilemma are focusing on a pH-, redox- or enzyme-triggered charge conversion at the target site. The pH-triggered systems are making use of a slight acidic environment at the target site such as in case of solid tumors, inflammatory tissue and ischemic tissue. Due to a pH shift from 7.2 to slightly acidic mainly amino substructures of polymeric excipients are protonated or shielding groups such as 2,3 dimethylmaleic acid are cleaved off unleashing the underlying cationic character. Redox-triggered systems are utilizing disulfide linkages to bulky side chains such as PEGs masking the polycationic character. Under mild reducing conditions such as in the tumor microenvironment these disulfide bonds are cleaved. Enzyme-triggered systems are targeting enzymes such as alkaline phosphatase, matrix metalloproteinases or hyaluronidase in order to eliminate anionic moieties via enzymatic cleavage resulting in a charge conversion from negative to positive. Within this review an overview about the pros and cons of these systems is provided.Graphical abstractUnlabelled Image
  • Harnessing albumin as a carrier for cancer therapies
    • Abstract: Publication date: Available online 27 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Ella N. Hoogenboezem, Craig L. Duvall Serum albumin, a natural ligand carrier that is highly concentrated and long-circulating in the blood, has shown remarkable promise as a carrier for anti-cancer agents. Albumin is able to prolong the circulation half-life of otherwise rapidly cleared drugs and, importantly, promote their accumulation within tumors. The applications for using albumin as a cancer drug carrier are broad and include both traditional cancer chemotherapeutics and new classes of biologics. Strategies for leveraging albumin for drug delivery can be classified broadly into exogenous and in situ binding formulations that utilize covalent attachment, non-covalent association, or encapsulation in albumin-based nanoparticles. These methods have shown remarkable preclinical and clinical successes that are examined in this review.Graphical abstractUnlabelled Image
  • 3D bioprinting of skin tissue: From pre-processing to final product
    • Abstract: Publication date: Available online 26 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Wei-Cheng Yan, Pooya Davoodi, S. Vijayavenkataraman, Yuan Tian, Wei Cheng Ng, Jerry Y.H. Fuh, Kim Samirah Robinson, Chi-Hwa Wang Bioprinted skin tissue has the potential for aiding drug screening, formulation development, clinical transplantation, chemical and cosmetic testing, as well as basic research. Limitations of conventional skin tissue engineering approaches have driven the development of biomimetic skin equivalent via 3D bioprinting. A key hope for bioprinting skin is the improved tissue authenticity over conventional skin equivalent construction, enabling the precise localization of multiple cell types and appendages within a construct. The printing of skin faces challenges broadly associated with general 3D bioprinting, including the selection of cell types and biomaterials, and additionally requires in vitro culture formats that allow for growth at an air-liquid interface. This paper provides a thorough review of current 3D bioprinting technologies used to engineer human skin constructs and presents the overall pipelines of designing a biomimetic artificial skin via 3D bioprinting from the design phase (i.e. pre-processing phase) through the tissue maturation phase (i.e. post-processing) and into final product evaluation for drug screening, development, and drug delivery applications.Graphical abstractUnlabelled Image
  • Stem cell-based Lung-on-Chips: The best of both worlds'
    • Abstract: Publication date: Available online 25 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Janna C. Nawroth, Riccardo Barrile, David Conegliano, Sander van Riet, Pieter S. Hiemstra, Remi Villenave Pathologies of the respiratory system such as lung infections, chronic inflammatory lung diseases, and lung cancer are among the leading causes of morbidity and mortality, killing one in six people worldwide. Development of more effective treatments is hindered by the lack of preclinical models of the human lung that can capture the disease complexity, highly heterogeneous disease phenotypes, and pharmacokinetics and pharmacodynamics observed in patients. The merger of two novel technologies, Organs-on-Chips and human stem cell engineering, has the potential to deliver such urgently needed models. Organs-on-Chips, which are microengineered bioinspired tissue systems, recapitulate the mechanochemical environment and physiological functions of human organs while concurrent advances in generating and differentiating human stem cells promise a renewable supply of patient-specific cells for personalized and precision medicine. Here, we discuss the challenges of modeling human lung pathophysiology in vitro, evaluate past and current models including Organs-on-Chips, review the current status of lung tissue modeling using human pluripotent stem cells, explore in depth how stem-cell based Lung-on-Chips may advance disease modeling and drug testing, and summarize practical consideration for the design of Lung-on-Chips for academic and industry applications.Graphical abstractUnlabelled Image
  • The quest for mechanically and biologically functional soft biomaterials
           via soft network composites
    • Abstract: Publication date: Available online 24 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Onur Bas, Elena M. De-Juan-Pardo, Isabelle Catelas, Dietmar W. Hutmacher Developing multifunctional soft biomaterials capable of addressing all of the requirements of the complex tissue regeneration process is a multifaceted problem. In order to tackle the current challenges, recent research efforts are increasingly being directed towards biomimetic design concepts that can be translated into soft biomaterials via advanced manufacturing technologies. Among those, soft network composites consisting of a continuous hydrogel matrix and a reinforcing fibrous network closely resemble native soft biological materials from the design, composition and physicochemical point of view. This article reviews soft network composite systems with a particular emphasis on the design, biomaterial and fabrication aspects within the context of soft tissue engineering and drug delivery applications.Graphical abstractUnlabelled Image
  • 3D bioprinting for cardiovascular regeneration and pharmacology
    • Abstract: Publication date: Available online 24 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Haitao Cui, Shida Miao, Timothy Esworthy, Xuan Zhou, Se-jun Lee, Chengyu Liu, Zu-xi Yu, John P. Fisher, Muhammad Mohiuddin, Lijie Grace Zhang Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Compared to traditional therapeutic strategies, three-dimensional (3D) bioprinting is one of the most advanced techniques for creating complicated cardiovascular implants with biomimetic features, which are capable of recapitulating both the native physiochemical and biomechanical characteristics of the cardiovascular system. The present review provides an overview of the cardiovascular system, as well as describes the principles of, and recent advances in, 3D bioprinting cardiovascular tissues and models. Moreover, this review will focus on the applications of 3D bioprinting technology in cardiovascular repair/regeneration and pharmacological modeling, further discussing current challenges and perspectives.Graphical abstractUnlabelled Image
  • Top-down fabrication of shape-controlled, monodisperse nanoparticles for
           biomedical applications
    • Abstract: Publication date: Available online 23 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Xinxin Fu, Jingxuan Cai, Xiang Zhang, Wen-Di Li, Haixiong Ge, Yong Hu Nanoparticles for biomedical applications are generally formed by bottom-up approaches such as self-assembly, emulsification and precipitation. But these methods usually have critical limitations in fabrication of nanoparticles with controllable morphologies and monodispersed size. Compared with bottom-up methods, top-down nanofabrication techniques offer advantages of high fidelity and high controllability. This review focuses on top-down nanofabrication techniques for engineering particles along with their biomedical applications. We present several commonly used top-down nanofabrication techniques that have the potential to fabricate nanoparticles, including photolithography, interference lithography, electron beam lithography, mold-based lithography (nanoimprint lithography and soft lithography), nanostencil lithography, and nanosphere lithography. Varieties of current and emerging applications are also covered: (i) targeting, (ii) drug and gene delivery, (iii) imaging, and (iv) therapy. Finally, a future perspective of the nanoparticles fabricated by the top-down techniques in biomedicine is also addressed.Graphical abstractUnlabelled Image
  • Battle of GLP-1 delivery technologies
    • Abstract: Publication date: Available online 21 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Minzhi Yu, Mason M. Benjamin, Santhanakrishnan Srinivasan, Emily E. Morin, Ekaterina I. Shishatskaya, Steven P. Schwendeman, Anna Schwendeman Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.Graphical abstractUnlabelled Image
  • A review on core–shell structured unimolecular nanoparticles for
           biomedical applications
    • Abstract: Publication date: Available online 20 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Guojun Chen, Yuyuan Wang, Ruosen Xie, Shaoqin Gong Polymeric unimolecular nanoparticles (NPs) exhibiting a core-shell structure and formed by a single multi-arm molecule containing only covalent bonds have attracted increasing attention for numerous biomedical applications. This unique single-molecular architecture provides the unimolecular NP with superior stability both in vitro and in vivo, a high drug loading capacity, as well as versatile surface chemistry, thereby making it a desirable nanoplatform for therapeutic and diagnostic applications. In this review, we surveyed the architecture of various types of polymeric unimolecular NPs, including water-dispersible unimolecular micelles and water-soluble unimolecular NPs used for the delivery of hydrophobic and hydrophilic agents, respectively, as well as their diverse biomedical applications. Future opportunities and challenges of unimolecular NPs were also briefly discussed.Graphical abstractUnlabelled Image
  • Electrohydrodynamic atomization and spray-drying for the production of
           pure drug nanocrystals and co-crystals
    • Abstract: Publication date: Available online 20 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Roni Sverdlov Arzi, Alejandro Sosnik In recent years, nanotechnology has offered attractive opportunities to overcome the (bio)pharmaceutical drawbacks of most drugs such as low aqueous solubility and bioavailability. Among the numerous methodologies that have been applied to improve drug performance, a special emphasis has been made on those that increase the dissolution rate and the saturation solubility by the reduction of the particle size of pure drugs to the nanoscale and the associated increase of the specific surface area. Different top-down and bottom-up methods have been implemented, each one with its own pros and cons. Over the last years, the latter that rely on the dissolution of the drug in a proper solvent and its crystallization or co-crystallization by precipitation in an anti-solvent or, conversely, by solvent evaporation have gained remarkable impulse owing to the ability to features such as size, size distribution, morphology and to control the amorphous/crystalline nature of the product. In this framework, electrohydrodynamic atomization (also called electrospraying) and spray-drying excel due to their simplicity and potential scalability. Moreover, they do not necessarily need suspension stabilizers and dry products are often produced during the formation of the nanoparticles what ensures physicochemical stability for longer times than liquid products. This review overviews the potential of these two technologies for the production of pure drug nanocrystals and co-crystals and discusses the recent technological advances and challenges for their implementation in pharmaceutical research and development.Graphical abstractUnlabelled Image
  • Tumor targeting via EPR: Strategies to enhance patient responses
    • Abstract: Publication date: Available online 19 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Susanne K. Golombek, Jan-Niklas May, Benjamin Theek, Lia Appold, Natascha Drude, Fabian Kiessling, Twan Lammers The tumor accumulation of nanomedicines relies on the enhanced permeability and retention (EPR) effect. In the last 5–10 years, it has been increasingly recognized that there is a large inter- and intra-individual heterogeneity in EPR-mediated tumor targeting, explaining the heterogeneous outcomes of clinical trials in which nanomedicine formulations have been evaluated. To address this heterogeneity, as in other areas of oncology drug development, we have to move away from a one-size-fits-all tumor targeting approach, towards methods that can be employed to individualize and improve nanomedicine treatments. To this end, efforts have to be invested in better understanding the nature, the complexity and the heterogeneity of the EPR effect, and in establishing systems and strategies to enhance, combine, bypass and image EPR-based tumor targeting. In the present manuscript, we summarize key studies in which these strategies are explored, and we discuss how these approaches can be employed to enhance patient responses.Graphical abstractUnlabelled Image
  • Supercritical carbon dioxide-based technologies for the production of drug
           nanoparticles/nanocrystals – A comprehensive review
    • Abstract: Publication date: Available online 17 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Luís Padrela, Miguel A. Rodrigues, Andreia Duarte, Ana M.A. Dias, Mara E.M. Braga, Hermínio C. de Sousa Low drug bioavailability, which is mostly a result of poor aqueous drug solubilities and of inadequate drug dissolution rates, is one of the most significant challenges that pharmaceutical companies are currently facing, since this may limit the therapeutic efficacy of marketed drugs, or even result in the discard of potential highly effective drug candidates during developmental stages. Two of the main approaches that have been implemented in recent years to overcome poor drug solubility/dissolution issues have frequently involved drug particle size reduction (i.e., micronization/nanonization) and/or the modification of some of the physicochemical and structural properties of poorly water soluble drugs. A large number of particle engineering methodologies have been developed, tested, and applied in the synthesis and control of particle size/particle-size distributions, crystallinities, and polymorphic purities of drug micro- and nano-particles/crystals. In recent years pharmaceutical processing using supercritical fluids (SCF), in general, and supercritical carbon dioxide (scCO2), in particular, have attracted a great attention from the pharmaceutical industry. This is mostly due to the several well-known advantageous technical features of these processes, as well as to other increasingly important subjects for the pharmaceutical industry, namely their “green”, sustainable, safe and “environmentally-friendly” intrinsic characteristics.In this work, it is presented a comprehensive state-of-the-art review on scCO2-based processes focused on the formation and on the control of the physicochemical, structural and morphological properties of amorphous/crystalline pure drug nanoparticles. It is presented and discussed the most relevant scCO2, scCO2-based fluids and drug physicochemical properties that are pertinent for the development of successful pharmaceutical products, namely those that are critical in the selection of an adequate scCO2-based method to produce pure drug nanoparticles/nanocrystals. scCO2-based nanoparticle formation methodologies are classified in three main families, and in terms of the most important role played by scCO2 in particle formation processes: as a solvent; as an antisolvent or a co-antisolvent; and as a “high mobility” additive (a solute, a co-solute, or a co-solvent). Specific particle formation methods belonging to each one of these families are presented, discussed and compared. Some selected amorphous/crystalline drug nanoparticles that were prepared by these methods are compiled and presented, namely those studied in the last 10–15 years. A special emphasis is given to the formation of drug cocrystals. It is also discussed the fundamental knowledge and the main mechanisms in which the scCO2-based particle formation methods rely on, as well as the current status and urgent needs in terms of reliable experimental data and of robust modeling approaches. Other addressed and discussed topics include the currently available and the most adequate physicochemical, morphological and biological characterization methods required for pure drug nanoparticles/nanocrystals, some of the current nanometrology and regulatory issues associated to the use of these methods, as well as some scale-up, post-processing and pharmaceutical regulatory subjects related to the industrial implementation of these scCO2-based processes. Finally, it is also discussed the current status of these techniques, as well as their future major perspectives and opportunities for industrial implementation in the upcoming years.Graphical abstractUnlabelled Image
  • 3D bioprinting of tissues and organs for regenerative medicine
    • Abstract: Publication date: Available online 7 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sanjairaj Vijayavenkataraman, Wei-Cheng Yan, Wen Feng Lu, Chi-Hwa Wang, Jerry Ying Hsi Fuh 3D bioprinting is a pioneering technology that enables fabrication of biomimetic, multiscale, multi-cellular tissues with highly complex tissue microenvironment, intricate cytoarchitecture, structure-function hierarchy, and tissue-specific compositional and mechanical heterogeneity. Given the huge demand for organ transplantation, coupled with limited organ donors, bioprinting is a potential technology that could solve this crisis of organ shortage by fabrication of fully-functional whole organs. Though organ bioprinting is a far-fetched goal, there has been a considerable and commendable progress in the field of bioprinting that could be used as transplantable tissues in regenerative medicine. This paper presents a first-time review of 3D bioprinting in regenerative medicine, where the current status and contemporary issues of 3D bioprinting pertaining to the eleven organ systems of the human body including skeletal, muscular, nervous, lymphatic, endocrine, reproductive, integumentary, respiratory, digestive, urinary, and circulatory systems were critically reviewed. The implications of 3D bioprinting in drug discovery, development, and delivery systems are also briefly discussed, in terms of in vitro drug testing models, and personalized medicine. While there is a substantial progress in the field of bioprinting in the recent past, there is still a long way to go to fully realize the translational potential of this technology. Computational studies for study of tissue growth or tissue fusion post-printing, improving the scalability of this technology to fabricate human-scale tissues, development of hybrid systems with integration of different bioprinting modalities, formulation of new bioinks with tuneable mechanical and rheological properties, mechanobiological studies on cell-bioink interaction, 4D bioprinting with smart (stimuli-responsive) hydrogels, and addressing the ethical, social, and regulatory issues concerning bioprinting are potential futuristic focus areas that would aid in successful clinical translation of this technology.
  • Aptamers: Uptake mechanisms and intracellular applications
    • Abstract: Publication date: Available online 6 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sorah Yoon, John J. Rossi The structural flexibility and small size of aptamers enable precise recognition of cellular elements for imaging and therapeutic applications. The process by which aptamers are taken into cells depends on their targets but is typically clathrin-mediated endocytosis or macropinocytosis. After internalization, most aptamers are transported to endosomes, lysosomes, endoplasmic reticulum, Golgi apparatus, and occasionally mitochondria and autophagosomes. Intracellular aptamers, or “intramers,” have versatile functions ranging from intracellular RNA imaging, gene regulation, and therapeutics to allosteric modulation, which we discuss in this review. Immune responses to therapeutic aptamers and the effects of G-quadruplex structure on aptamer function are also discussed.Graphical abstractUnlabelled Image
  • Bacteriophage T4 nanoparticles for vaccine delivery against infectious
    • Abstract: Publication date: Available online 6 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Pan Tao, Jingen Zhu, Marthandan Mahalingam, Himanshu Batra, Venigalla B. Rao Subunit vaccines containing one or more target antigens from pathogenic organisms represent safer alternatives to whole pathogen vaccines. However, the antigens by themselves are not sufficiently immunogenic and require additives known as adjuvants to enhance immunogenicity and protective efficacy. Assembly of the antigens into virus-like nanoparticles (VLPs) is a better approach as it allows presentation of the epitopes in a more native context. The repetitive, symmetrical, and high density display of antigens on the VLPs mimic pathogen-associated molecular patterns seen on bacteria and viruses. The antigens, thus, might be better presented to stimulate host's innate as well as adaptive immune systems thereby eliciting both humoral and cellular immune responses. Bacteriophages such as phage T4 provide excellent platforms to generate the nanoparticle vaccines. The T4 capsid containing two non-essential outer proteins Soc and Hoc allow high density array of antigen epitopes in the form of peptides, domains, full-length proteins, or even multi-subunit complexes. Co-delivery of DNAs, targeting molecules, and/or molecular adjuvants provides additional advantages. Recent studies demonstrate that the phage T4 VLPs are highly immunogenic, do not need an adjuvant, and provide complete protection against bacterial and viral pathogens. Thus, phage T4 could potentially be developed as a “universal” VLP platform to design future multivalent vaccines against complex and emerging pathogens.Graphical abstractUnlabelled Image
  • Drug delivery systems for programmed and on-demand release
    • Abstract: Publication date: Available online 6 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Pooya Davoodi, Lai Yeng Lee, Qingxing Xu, Vishnu Sunil, Yajuan Sun, Siowling Soh, Chi-Hwa Wang With the advancement in medical science and understanding the importance of biodistribution and pharmacokinetics of therapeutic agents, modern drug delivery research strives to utilize novel materials and fabrication technologies for the preparation of robust drug delivery systems to combat acute and chronic diseases. Compared to traditional drug carriers, which could only control the release of the agents in a monotonic manner, the new drug carriers are able to provide a precise control over the release time and the quantity of drug introduced into the patient's body. To achieve this goal, scientists have introduced “programmed” and “on-demand” approaches. The former provides delivery systems with a sophisticated architecture to precisely tune the release rate for a definite time period, while the latter includes systems directly controlled by an operator/practitioner, perhaps with a remote device triggering/affecting the implanted or injected drug carrier. Ideally, such devices can determine flexible release pattern and intensify the efficacy of a therapy via controlling time, duration, dosage, and location of drug release in a predictable, repeatable, and reliable manner. This review sheds light on the past and current techniques available for fabricating and remotely controlling drug delivery systems and addresses the application of new technologies (e.g. 3D printing) in this field.Graphical abstractUnlabelled Image
  • Re-epithelialization of adult skin wounds: Cellular mechanisms and
           therapeutic strategies
    • Abstract: Publication date: Available online 5 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Patricia Rousselle, Fabienne Braye, Guila Dayan Cutaneous wound healing in adult mammals is a complex multi-step process involving overlapping stages of blood clot formation, inflammation, re-epithelialization, granulation tissue formation, neovascularization, and remodelling. Re-epithelialization describes the resurfacing of a wound with new epithelium. The cellular and molecular processes involved in the initiation, maintenance, and completion of epithelialization are essential for successful wound closure. A variety of modulators are involved, including growth factors, cytokines, matrix metalloproteinases, cellular receptors, and extracellular matrix components. Here, we focus on cellular mechanisms underlying keratinocyte migration and proliferation during epidermal closure. Inability to re-epithelialize is a clear indicator of chronic non-healing wounds, which fail to proceed through the normal phases of wound healing in an orderly and timely manner. This review summarizes the current knowledge regarding the management and treatment of acute and chronic wounds, with a focus on re-epithelialization, offering some insights into novel future therapies.Graphical Unlabelled Image
  • Bioresponsive drug delivery systems in intestinal inflammation:
           State-of-the-art and future perspectives
    • Abstract: Publication date: Available online 5 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Niranjan G. Kotla, Shubhasmin Rana, Gandhi Sivaraman, Omprakash Sunnapu, Praveen K. Vemula, Abhay Pandit, Yury Rochev Oral colon-specific delivery systems emerged as the main therapeutic cargos by making a significant impact in the field of modern medicine for local drug delivery in intestinal inflammation. The site-specific delivery of therapeutics (aminosalicylates, glucocorticoids, biologics) to the ulcerative mucus tissue can provide prominent advantages in mucosal healing (MH). Attaining gut mucosal healing and anti-fibrosis are main treatment outcomes in inflammatory bowel disease (IBD). The pharmaceutical strategies that are commonly used to achieve a colon-specific drug delivery system include time, pH-dependent polymer coating, prodrug, colonic microbiota-activated delivery systems and a combination of these approaches. Amongst the different approaches reported, the use of biodegradable polysaccharide coated systems holds great promise in delivering drugs to the ulcerative regions. The present review focuses on major physiological gastro-intestinal tract challenges involved in altering the pharmacokinetics of delivery systems, pathophysiology of MH and fibrosis, reported drug-polysaccharide cargos and focusing on conventional to advanced disease responsive delivery strategies, highlighting their limitations and future perspectives in intestinal inflammation therapy.Graphical abstractUnlabelled Image
  • SEDDS: A game changing approach for the oral administration of hydrophilic
           macromolecular drugs
    • Abstract: Publication date: Available online 4 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Arshad Mahmood, Andreas Bernkop-Schnürch Since the development of self-emulsifying drug delivery systems (SEDDS) in 1980's, they attract the attention of researchers in order to confront the challenge of poor water-solubility of orally given drugs. Within recent years, SEDDS were also discovered for oral administration of hydrophilic macromolecular drugs such as peptides, proteins, polysaccharides and pDNA. Due to hydrophobic ion pairing (HIP) with oppositely charged lipophilic auxiliary agents the resulting complexes can be incorporated in the lipophilic phase of SEDDS. Depending on the solubility of the complex in the SEDDS pre-concentrate and in the release medium drug release can be adjusted on purpose by choosing more or less lipophilic auxiliary agents in appropriate quantities for HIP. Within the oily droplets formed in the GI-tract drugs are protected towards degradation by proteases and nucleases and thiol-disulfide exchange reactions with dietary proteins. The oily droplets can be made mucoadhesive or highly mucus permeating depending on their target site. Furthermore, even their cellular uptake properties can be tuned by adjusting their zeta potential or decorating them with cell penetrating peptides. The potential of SEDDS for oral administration of hydrophilic macromolecular drugs could meanwhile be demonstrated via various in vivo studies showing a bioavailability at least in the single digit percentage range. Owing to these properties advanced SEDDS turned out to be a game changing approach for the oral administration of hydrophilic macromolecular drugs.Graphical abstractUnlabelled Image
  • Unintended effects of drug carriers: Big issues of small particles
    • Abstract: Publication date: Available online 3 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Hamideh Parhiz, Makan Khoshnejad, Jacob W. Myerson, Elizabeth Hood, Priyal N. Patel, Jacob S. Brenner, Vladimir R. Muzykantov Humoral and cellular host defense mechanisms including diverse phagocytes, leukocytes, and immune cells have evolved over millions of years to protect the body from microbes and other external and internal threats. These policing forces recognize engineered sub-micron drug delivery systems (DDS) as such a threat, and react accordingly. This leads to impediment of the therapeutic action, extensively studied and discussed in the literature. Here, we focus on side effects of DDS interactions with host defenses. We argue that for nanomedicine to reach its clinical potential, the field must redouble its efforts in understanding the interaction between drug delivery systems and the host defenses, so that we can engineer safer interventions with the greatest potential for clinical success.Graphical abstractUnlabelled Image
  • Use of phage therapy to treat long-standing, persistent, or chronic
           bacterial infections
    • Abstract: Publication date: Available online 3 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Stephen T. Abedon Viruses of bacteria – known as bacteriophages or phages – have been used clinically as antibacterial agents for nearly 100 years. Often this phage therapy is of long-standing, persistent, or chronic bacterial infections, and this can be particularly so given prior but insufficiently effective infection treatment using standard antibiotics. Such infections, in turn, often have a biofilm component. Phages in modern medicine thus are envisaged to serve especially as anti-biofilm/anti-persistent infection agents. Here I review the English-language literature concerning in vivo experimental and clinical phage treatment of longer-lived bacterial infections. Overall, published data appears to be supportive of a relatively high potential for phages to cure infections which are long standing and which otherwise have resisted treatment with antibieiotics.Graphical abstractUnlabelled Image
  • Molecular imaging of β-cells: diabetes and beyond
    • Abstract: Publication date: Available online 3 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Weijun Wei, Emily B. Ehlerding, Xiaoli Lan, Quan-Yong Luo, Weibo Cai Since diabetes is becoming a global epidemic, there is a great need to develop early β-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic β-cells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of β-cell mass (BCM) and/or impairment of the function of individual β-cells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic β-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. β-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted β-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging β-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field.Graphical abstractUnlabelled Image
  • Zero-dimensional, one-dimensional, two-dimensional and three-dimensional
           biomaterials for cell fate regulation
    • Abstract: Publication date: Available online 30 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Can Zhang, Bei Xie, Yujian Zou, Dan Zhu, Lei Lei, Dapeng Zhao, Hemin Nie The interaction of biological cells with artificial biomaterials is one of the most important issues in tissue engineering and regenerative medicine. The interaction is strongly governed by physical and chemical properties of the materials and displayed with differentiated cellular behaviors, including cell self-renewal, differentiation, reprogramming, dedifferentiation, or transdifferentiation as a result. A number of engineered biomaterials with micro- or nano-structures have been developed to mimic structural components of cell niche and specific function of extra cellular matrix (ECM) over past two decades. In this review article, we briefly introduce the fabrication of biomaterials and their classification into zero-dimensional (0D), one-dimensional (1D), two-dimensional (2D) and three-dimensional (3D) ones. More importantly, the influence of different biomaterials on inducing cell self-renewal, differentiation, reprogramming, dedifferentiation, and transdifferentiation was discussed based on the progress at 0D, 1D, 2D and 3D levels, following which the current research limitations and research perspectives were provided.Graphical abstractUnlabelled Image
  • Regulatory challenges of nanomedicines and their follow-on versions: A
           generic or similar approach'
    • Abstract: Publication date: Available online 30 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Stefan Mühlebach Nanomedicines and follow-on versions (also called nanosimilars in the EU) have been on the market partially for decades although without recognition of their nano properties in the beginning; a substantial number is in clinical development. Nanomedicines are typically synthetic and belong to the non-biological complex drugs. They show a high variability in form, structure, and size. Additionally large molecule biologics show nano-characteristics meaning nano-dimension in size (1–100 nm) or specific properties related to these dimensions. The high complexity of nanomedicines with their heterogeneous structures do not allow a full physicochemical quality characterization, challenging the regulatory evaluation especially for follow-on versions upon comparison with the reference product. The generic paradigm with the sameness approach for quality and bioequivalence in blood plasma is not appropriate for nanomedicines where a similar approach is needed. After experiencing non-equivalence of authorized parenteral colloidal iron follow-on versions, EMA and FDA issued reflection papers and draft guidances for industry to present their current thinking on the evaluation of such complex products. A stepwise approach to evaluate the extent of similarity, from quality, including critical quality attributes (CQA) and assessment of nano properties, to a non-clinical biodistribution assay, required in the the EU but not in the US, and to clinical evaluation makes sense. The cumulated totality of evidence for the authorization of nanomedicine follow-on versions goes case-by-case. Interchangeability, or substitutability, is a challenge. However, a defined or even harmonized approval pathway for these follow-versions is still missing and causes potential differences in approval. To progress, a science-based discussion platform among stakeholders and experts in the field is necessary. An agenda has been agreed [5], namely CQA assessment, publication of scientific and clinical findings, consensus on nomenclature and labelling, and regulatory actions on substandard complex drug products. Consensus created in a public private approach will support progress towards a defined and harmonized regulatory pathway for nanomedicines and their follow-on versions. This will provide drug innovation but also larger access to follow-on versions of nanomedicines, both a benefit for the patient.
  • Current state of in vivo panning technologies: Designing specificity and
           affinity into the future of drug targeting
    • Abstract: Publication date: Available online 28 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Heather H. Gustafson, Audrey Olshefsky, Meilyn Sylvestre, Drew L. Sellers, Suzie H. Pun Targeting ligands are used in drug delivery to improve drug distribution to desired cells or tissues and to facilitate cellular entry. In vivo biopanning, whereby billions of potential ligand sequences are screened in biologically-relevant and complex conditions, is a powerful method for identification of novel target ligands. This tool has impacted drug delivery technologies and expanded our arsenal of therapeutics and diagnostics. Within this review we will discuss current in vivo panning technologies and ways that these technologies can be improved to advance next-generation drug delivery strategies.Graphical abstractUnlabelled Image
  • Strategic design of extracellular vesicle drug delivery systems
    • Abstract: Publication date: Available online 28 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): James P.K. Armstrong, Molly M. Stevens Extracellular vesicles (EVs), nanoscale vectors used in intercellular communication, have demonstrated great promise as natural drug delivery systems. Recent reports have detailed impressive in vivo results from the administration of EVs pre-loaded with therapeutic cargo, including small molecules, nanoparticles, proteins and oligonucleotides. These results have sparked intensive research interest across a huge range of disease models. There are, however, enduring limitations that have restricted widespread clinical and pharmaceutical adoption. In this perspective, we discuss these practical and biological concerns, critically compare the relative merit of EVs and synthetic drug delivery systems, and highlight the need for a more comprehensive understanding of in vivo transport and delivery. Within this framework, we seek to establish key areas in which EVs can gain a competitive advantage in order to provide the tangible added value required for widespread translation.Graphical abstractUnlabelled Image
  • The emerging role of physiologically based pharmacokinetic modelling in
           solid drug nanoparticle translation
    • Abstract: Publication date: Available online 27 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Marco Siccardi, Steve Rannard, Andrew Owen The use of solid drug nanoparticles (SDN) has become an established approach to improve drug delivery, supporting enhancement of oral absorption and long-acting administration strategies. A broad range of SDNs have been successfully utilised for multiple products and several development programmes are currently underway across different therapeutic areas. With some approaches, a large range of material space is available with diversity in physical characteristics, excipient choice and pharmacological behaviour. The selection of SDN lead candidates is a complex process including a broad range of in vitro and in vivo data, and a better understanding of how physical characteristics relate to performance is required. Physiologically-based pharmacokinetic (PBPK) modelling is based upon a comprehensive integration of experimental data into a mathematical description of drug distribution, allowing simulation of SDN pharmacokinetics that can be qualified in vivo prior to human prediction. This review aims to provide a description of how PBPK can find application into the development of SDN. Integration of predictive PBPK modelling into SDN development allows a better understanding of the SDN dose-response relationship, supporting a framework for rational optimisation while reducing the risk of failure in developing safe and effective nanomedicines.Graphical abstractUnlabelled Image
  • Use of nano engineered approaches to overcome the stromal barrier in
           pancreatic cancer
    • Abstract: Publication date: Available online 26 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Huan Meng, Andre E. Nel While chemotherapy is the only approved non-surgical option for the majority of pancreatic cancer patients, it rarely results in a cure. The failure to respond to chemotherapy is due to the presence of an abundant dysplastic stroma that interferes in drug delivery and as a result of drug resistance. It is appropriate, therefore, to consider the stromal contribution to the resistance to chemotherapy and sidestepping this barrier with nanocarriers that improve survival outcome. In this paper, we provide a short overview of the role of the stroma in chemotherapy resistance, including the use of nanocarriers to negate this barrier. We provide a perspective and guidance towards the implementation of nanotherapeutic approaches to improve therapeutic delivery and efficacy of PDAC management.Graphical abstractUnlabelled Image
  • Advanced in vitro models of vascular biology: Human induced pluripotent
           stem cells and organ-on-chip technology
    • Abstract: Publication date: Available online 23 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Amy Cochrane, Hugo J. Albers, Robert Passier, Christine L. Mummery, Albert van den Berg, Valeria V. Orlova, Andries D. van der Meer The vascular system is one of the first to develop during embryogenesis and is essential for all organs and tissues in our body to develop and function. It has many essential roles including controlling the absorption, distribution and excretion of compounds and therefore determines the pharmacokinetics of drugs and therapeutics. Vascular homeostasis is under tight physiological control which is essential for maintaining tissues in a healthy state. Consequently, disruption of vascular homeostasis plays an integral role in many disease processes, making cells of the vessel wall attractive targets for therapeutic intervention. Experimental models of blood vessels can therefore contribute significantly to drug development and aid in predicting the biological effects of new drug entities. The increasing availability of human induced pluripotent stem cells (hiPSC) derived from healthy individuals and patients have accelerated advances in developing experimental in vitro models of the vasculature: human endothelial cells (ECs), pericytes and vascular smooth muscle cells (VSMCs), can now be generated with high efficiency from hiPSC and used in ‘microfluidic chips’ (also known as ‘organ-on-chip’ technology) as a basis for in vitro models of blood vessels. These near physiological scaffolds allow the controlled integration of fluid flow and three-dimensional (3D) co-cultures with perivascular cells to mimic tissue- or organ-level physiology and dysfunction in vitro. Here, we review recent multidisciplinary developments in these advanced experimental models of blood vessels that combine hiPSC with microfluidic organ-on-chip technology. We provide examples of their utility in various research areas and discuss steps necessary for further integration in biomedical applications so that they can be contribute effectively to the evaluation and development of new drugs and other therapeutics as well as personalized (patient-specific) treatments.Graphical abstractUnlabelled Image
  • Bioengineered cellular and cell membrane-derived vehicles for actively
           targeted drug delivery: So near and yet so far
    • Abstract: Publication date: Available online 21 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Thanuja M.Y., Anupama C., Sudhir H. Ranganath Cellular carriers for drug delivery are attractive alternatives to synthetic nanoparticles owing to their innate homing/targeting abilities. Here, we review molecular interactions involved in the homing of Mesenchymal stem cells (MSCs) and other cell types to understand the process of designing and engineering highly efficient, actively targeting cellular vehicles. In addition, we comprehensively discuss various genetic and non-genetic strategies and propose futuristic approaches of engineering MSC homing using micro/nanotechnology and high throughput small molecule screening. Most of the targeting abilities of a cell come from its plasma membrane, thus, efforts to harness cell membranes as drug delivery vehicles are gaining importance and are highlighted here. We also recognize and report the lack of detailed characterization of cell membranes in terms of safety, structural integrity, targeting functionality, and drug transport. Finally, we provide insights on future development of bioengineered cellular and cell membrane-derived vesicles for successful clinical translation.Graphical abstractUnlabelled Image
  • 3D bioprinting of functional tissue models for personalized drug screening
           and in vitro disease modeling
    • Abstract: Publication date: Available online 21 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Xuanyi Ma, Justin Liu, Wei Zhu, Min Tang, Natalie Lawrence, Claire Yu, Maling Gou, Shaochen Chen 3D bioprinting is emerging as a promising technology for fabricating complex tissue constructs with tailored biological components and mechanical properties. Recent advances have enabled scientists to precisely position materials and cells to build functional tissue models for in vitro drug screening and disease modeling. This review presents state-of-the-art 3D bioprinting techniques and discusses the choice of cell source and biomaterials for building functional tissue models that can be used for personalized drug screening and disease modeling. In particular, we focus on 3D-bioprinted liver models, cardiac tissues, vascularized constructs, and cancer models for their promising applications in medical research, drug discovery, toxicology, and other pre-clinical studies.Graphical abstractSchematic diagram showing the use of 3D bioprinting to build in vitro constructs that can be used for drug testing and disease modeling.Unlabelled Image
  • Intracellular delivery of colloids: Past and future contributions from
    • Abstract: Publication date: Available online 20 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Peter Tiefenboeck, Jong Ah Kim, Jean-Christophe Leroux The manipulation of single cells and whole tissues has been possible since the early 70’s, when semi-automatic injectors were developed. Since then, microinjection has been used to introduce an ever-expanding range of colloids of up to 1000 nm in size into living cells. Besides injecting nucleic acids to study transfection mechanisms, numerous cellular pathways have been unraveled through the introduction of recombinant proteins and blocking antibodies. The injection of nanoparticles has also become popular in recent years to investigate toxicity mechanisms and intracellular transport, and to conceive semi-synthetic cells containing artificial organelles. This article reviews colloidal systems such as proteins, nucleic acids and nanoparticles that have been injected into cells for different research aims, and discusses the scientific advances achieved through them. The colloids' intracellular processing and ultimate fate are also examined from a drug delivery perspective with an emphasis on the differences observed for endocytosed versus microinjected material.Graphical abstractUnlabelled Image
  • Practical guidelines for the characterization and quality control of pure
           drug nanoparticles and nano-cocrystals in the pharmaceutical industry
    • Abstract: Publication date: Available online 18 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Leena Peltonen The number of poorly soluble drug candidates is increasing, and this is also seen in the research interest towards drug nanoparticles and (nano-)cocrystals; improved solubility is the most important application of these nanosystems. In order to confirm the functionality of these nanoparticles throughout their lifecycle, repeatability of the formulation processes, functional performance of the formed systems in pre-determined way and system stability, a thorough physicochemical understanding with the aid of necessary analytical techniques is needed. Even very minor deviations in for example particle size or size deviation in nanoscale can alter the product bioavailability, and the effect is even more dramatic with the smallest particle size fractions. Also, small particle size sets special requirements for the analytical techniques. In this review most important physicochemical properties of drug nanocrystals and nano-cocrystals are presented, suitable analytical techniques, their pros and cons, are described with the extra input on practical point of view.Graphical abstractUnlabelled Image
  • Local delivery of adenosine receptor agonists to promote bone regeneration
           and defect healing
    • Abstract: Publication date: Available online 18 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Christopher D. Lopez, Jonathan M. Bekisz, Carmen Corciulo, Aranzazu Mediero, Paulo G. Coelho, Lukasz Witek, Roberto L. Flores, Bruce N. Cronstein Adenosine receptor activation has been investigated as a potential therapeutic approach to heal bone. Bone has enhanced regenerative potential when influenced by either direct or indirect adenosine receptor agonism. As investigators continue to elucidate how adenosine influences bone cell homeostasis at the cellular and molecular levels, a small but growing body of literature has reported successful in vivo applications of adenosine delivery. This review summarizes the role adenosine receptor ligation plays in osteoblast and osteoclast biology and remodeling/regeneration. It also reports on all the modalities described in the literature at this point for delivery of adenosine through in vivo models for bone healing and regeneration.Graphical abstractUnlabelled Image
  • Microphysiological systems meet hiPSC technology – New tools for disease
           modeling of liver infections in basic research and drug development
    • Abstract: Publication date: Available online 15 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Martin Raasch, Enrico Fritsche, Andreas Kurtz, Michael Bauer, Alexander S. Mosig Complex cell culture models such as microphysiological models (MPS) mimicking human liver functionality in vitro are in the spotlight as alternative to conventional cell culture and animal models. Promising techniques like microfluidic cell culture or micropatterning by 3D bioprinting are gaining increasing importance for the development of MPS to address the needs for more predictivity and cost efficiency. In this context, human induced pluripotent stem cells (hiPSCs) offer new perspectives for the development of advanced liver-on-chip systems by recreating an in vivo like microenvironment that supports the reliable differentiation of hiPSCs to hepatocyte-like cells (HLC). In this review we will summarize current protocols of HLC generation and highlight recently established MPS suitable to resemble physiological hepatocyte function in vitro. In addition, we are discussing potential applications of liver MPS for disease modeling related to systemic or direct liver infections and the use of MPS in testing of new drug candidates.Graphical abstractUnlabelled Image
  • Repurposing drugs as inhaled therapies in asthma
    • Abstract: Publication date: Available online 12 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sandra D. Anderson For the first 40 years of the 20th century treatment for asthma occurred in response to an asthma attack. The treatments were given by injection or orally and included the adrenergic agonists adrenalin/epinephrine and ephedrine and a phosphodiesterase inhibitor theophylline. Epinephrine became available as an aerosol in 1930. After 1945, isoprenaline, a non-selective beta agonist, became available for oral use but it was most widely used by inhalation. Isoprenaline was short-acting with unwanted cardiac effects. More selective beta agonists, with a longer duration of action and fewer side-effects became available, including orciprenaline in 1967, salbutamol in 1969 and terbutaline in 1970. The inhaled steroid beclomethasone was available by 1972 and budesonide by 1982. Spirometry alone and in response to exercise was used to assess efficacy and duration of action of these drugs for the acute benefits of beta2 agonists and the chronic benefits of corticosteroids. Early studies comparing oral and aerosol beta2 agonists found equivalence in bronchodilator effect but the aerosol treatment was superior in preventing exercise-induced bronchoconstriction. Inhaled drugs are now widely used including the long-acting beta2 agonists, salmeterol and formoterol, and the corticosteroids, fluticasone, ciclesonide, mometasone and triamcinolone, that act locally and have low systemic bio-availability. Repurposing drugs as inhaled therapies permitted direct delivery of low doses of drug to the site of action reducing the incidence of unwanted side-effects and permitting the prophylactic treatment of asthma.Graphical abstractUnwanted side-effects are greatest when beta2 agonists and steroids are given by tablet or injection and least when they are given by inhalation.Unlabelled Image
  • Inhalation of repurposed drugs to treat pulmonary hypertension
    • Abstract: Publication date: Available online 8 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Tobias Gessler Pulmonary arterial hypertension (PAH) is a rare, but severe and life-threatening disease characterized by vasoconstriction and remodeling of the pulmonary arterioles, leading to progressive increase in pulmonary vascular resistance and ultimately to right-heart failure. In the last two decades, significant progress in treatment of PAH has been made, with currently 12 drugs approved for targeted therapy. Among these, the stable prostacyclin analogues iloprost and treprostinil have been repurposed for inhalation. The paper highlights the development of the two drugs emphasizing the rationale and advantages of the inhalative approach.Despite substantial advances in the specific, mainly vasodilatory PAH therapy, disease progression is mostly inevitable and mortality remains unacceptably high. Thus, introduction of new drugs targeting the cancer-like remodeling of the diseased pulmonary arteries is urgently needed. Inhalation offers pulmonary selectivity and will hopefully pioneer the repurposing of novel highly potent drugs for effective aerosol therapy of PAH.Graphical abstractUnlabelled Image
  • Repurposing of statins via inhalation to treat lung inflammatory
    • Abstract: Publication date: Available online 8 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Peta Bradbury, Daniela Traini, Alaina J. Ammit, Paul M. Young, Hui Xin Ong Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism. Recent research has identified statins to have other protective pleiotropic properties including anti-inflammatory, anti-oxidant, muco-inhibitory effects that may be beneficial for the treatment of chronic inflammatory lung diseases. However, clinical studies have yielded conflicting results. This review will summarise some of the current evidences for statins pleiotropic effects that could be applied for the treatment of chronic inflammatory lung diseases, their mechanisms of actions, and the potential to repurpose statins as an inhaled therapy, including a detailed discussion on their different physical-chemical properties and how these characteristics could ultimately affect treatment efficacies. The repurposing of statins from conventional anti-cholesterol oral therapy to inhaled anti-inflammatory formulation is promising, as it provides direct delivery to the airways, reduced risk of side effects, increased bioavailability and tailored physical-chemical properties for enhanced efficacy.Graphical abstractUnlabelled Image
  • Repurposing of gamma interferon via inhalation delivery
    • Abstract: Publication date: Available online 7 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Gerald C. Smaldone Pulmonary diseases frequently involve imbalances in immunity. The inability to control bacteria in tuberculosis is a failed response to a pathogen. Idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disease, can lead to respiratory failure and death within 3 years of diagnosis. Chronic obstructive pulmonary disease (COPD) progresses until death and in recent years has been labeled an autoimmune disease. Proposed mechanistic pathways of pathophysiology involve uncontrolled healing governed by pro-fibrotic cytokines that are unresponsive to the standard anti-inflammatory agents (e.g., corticosteroids). Interferon-γ (IFN-γ), currently delivered as a subcutaneous injection for chronic granulomatous disease and osteopetrosis, is a cytokine that can stimulate macrophage function and inhibit fibrotic pathways. In recent studies, our group has repurposed IFN-γ as an inhaled aerosol, targeted directly to the lung to treat a host of diseases affected by dysregulated immunity. At present, we have studied its potential in treating tuberculosis and IPF. In a controlled clinical trial in tuberculosis, inhaled IFN-γ was effective while parenteral IFN-γ was not, indicating that macrophages can be effectively immune-stimulated by aerosol therapy. A similar approach has been taken in IPF. In a two-year safety study treating patients with IPF, the drug was safe and the pretreatment decline in pulmonary function was reversed. Furthermore, the same fibrotic pathways active in the lung parenchyma in IPF may be at fault in the airways of COPD patients. These experiences warrant the continued evaluation of inhaled IFN-γ in human clinical trials.Graphical abstractUnlabelled Image
  • Progress, obstacles, and limitations in the use of stem cells in
           organ-on-a-chip models
    • Abstract: Publication date: Available online 6 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Alexa Wnorowski, Huaxiao Yang, Joseph C. Wu In recent years, drug development costs have soared, primarily due to the failure of preclinical animal and cell culture models, which do not directly translate to human physiology. Organ-on-a-chip (OOC) is a burgeoning technology with the potential to revolutionize disease modeling, drug discovery, and toxicology research by strengthening the relevance of culture-based models while reducing costly animal studies. Although OOC models can incorporate a variety of tissue sources, the most robust and relevant OOC models going forward will include stem cells. In this review, we will highlight the benefits of stem cells as a tissue source while considering current limitations to their complete and effective implementation into OOC models.Graphical abstractUnlabelled Image
  • Engineered delivery strategies for enhanced control of growth factor
           activities in wound healing
    • Abstract: Publication date: Available online 5 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Yiming Niu, Qiu Li, Ya Ding, Lei Dong, Chunming Wang Growth factors (GFs) are versatile signalling molecules that orchestrate the dynamic, multi-stage process of wound healing. Delivery of exogenous GFs to the wound milieu to mediate healing in an active, physiologically-relevant manner has shown great promise in laboratories; however, the inherent instability of GFs, accompanied with numerous safety, efficacy and cost concerns, has hindered the clinical success of GF delivery. In this article, we highlight that the key to overcoming these challenges is to enhance the control of the activities of GFs throughout the delivering process. We summarise the recent strategies based on biomaterials matrices and molecular engineering, which aim to improve the conditions of GFs for delivery (at the ‘supply’ end of the delivery), increase the stability and functions of GFs in extracellular matrix (in transportation to target cells), as well as enhance the GFs/receptor interaction on the cell membrane (at the ‘destination’ end of the delivery). Many of these investigations have led to encouraging outcomes in various in vitro and in vivo regenerative models with considerable translational potential.Graphical abstractUnlabelled Image
  • Reduction-sensitive polymeric nanomedicines: An emerging multifunctional
           platform for targeted cancer therapy
    • Abstract: Publication date: Available online 24 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Huanli Sun, Yifan Zhang, Zhiyuan Zhong The development of smart delivery systems that are robust in circulation and quickly release drugs following selective internalization into target cancer cells is a key to precision cancer therapy. Interestingly, reduction-sensitive polymeric nanomedicines showing high plasma stability and triggered cytoplasmic drug release behavior have recently emerged as one of the most exciting platforms for targeted delivery of various anticancer drugs including small chemical drugs, proteins, and nucleic acids. In vivo studies in varying tumor models reveal that these reduction-sensitive multifunctional nanomedicines outperform the currently used clinical formulations and reduction-insensitive counterparts, bringing about not only significantly enhanced tumor selectivity, accumulation and inhibition efficacy but also markedly reduced systemic toxicity and improved therapeutic index. In this review, we will highlight the cutting-edge advancement with a focus on in vivo performances as well as future perspectives on reduction-sensitive polymeric nanomedicines for targeted cancer therapy.Graphical abstractUnlabelled Image
  • Perspectives on the past, present, and future of cancer nanomedicine
    • Abstract: Publication date: Available online 18 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Yu Seok Youn, You Han Bae The justification of cancer nanomedicine relies on enhanced permeation (EP) and retention (R) effect and the capability of intracellular targeting due primarily to size after internalization (endocytosis) into the individual target cells. The EPR effect implies improved efficacy. Affinity targeting for solid tumors only occur after delivery to individual cells, which help internalization and/or retention. The design principles have been supported by animal results in numerous publications, but hardly translated. The natures of EP and R, such as frequency of large openings in tumor vasculature and their dynamics, are not understood, in particular, in clinical settings. Although various attempts to address the issues related to EP and delivery, by modifying design factors and manipulating tumor microenvironment, are being reported, they are still verified in artificial rodent tumors which do not mimic the nature of human tumor physiology/pathology in terms of transport and delivery. The clinical trials of experimental nanomedicine have experienced unexpected adverse effects with modest improvement in efficacy when compared to current frontline therapy. Future nanomedicine may require new design principles without consideration of EP and affinity targeting. A possible direction is to set new approaches to intentionally minimize adverse effects, rather than aiming at better efficacy, which can widen the therapeutic window of an anticancer drug of interest. Broadening indications and administration routes of developed therapeutic nanotechnology would benefit patients.Graphical abstractUnlabelled Image
  • Stem cell-based retina models
    • Abstract: Publication date: Available online 17 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Kevin Achberger, Jasmin C. Haderspeck, Alexander Kleger, Stefan Liebau From the early days of cell biological research, the eye—especially the retina—has evoked broad interest among scientists. The retina has since been thoroughly investigated and numerous models have been exploited to shed light on its development, morphology, and function. Apart from various animal models and human clinical and anatomical research, stem cell-based models of animal and human cells of origin have entered the field, especially during the last decade. Despite the observation that the retina of different species comprises endogenous stem cells, most stem cell-related research in the human retina is now based on pluripotent stem cell models. Herein, systems of two-dimensional (2D) cultures and co-cultures of distinctly differentiated retinal subtypes revealed a variety of cellular aspects but have in many aspects been replaced by three-dimensional (3D) structures—the so-called retinal organoids. These organoids not only contain all major retinal cell subtypes compared to the physiological situation, but also show a distinct layering in close proximity to the in vivo morphology. Nevertheless, all these models have inherent advantages and disadvantages, which are expounded and summarized in this review. Finally, we discuss current application aspects of stem cell-based retina models and the specific promises they hold for the future.Graphical abstractUnlabelled Image
  • Production of pure drug nanocrystals and Nano Co-crystals by
           confinement methods
    • Abstract: Publication date: Available online 5 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Flavia Fontana, Patricia Figueiredo, Pei Zhang, Jouni T. Hirvonen, Dongfei Liu, Helder A. Santos The use of drug nanocrystals in the drug formulation is increasing due to the large number of poorly water-soluble drug compounds synthetized and due to the advantages brought by the nanonization process. The downsizing processes are done using a top-down approach (milling and homogenization currently employed at the industrial level), while the crystallization process is performed by bottom-up techniques (e.g., antisolvent precipitation to the use of supercritical fluids or spray and freeze drying). In addition, the production of nanocrystals in confined environment can be achieved within microfluidics channels. This review analyzes the processes for the preparation of nanocrystals and co-crystals, divided by top-down and bottom-up approaches, together with their combinations. The combination of both strategies merges the favorable features of each process and avoids the disadvantages of single processes. Overall, the applicability of drug nanocrystals is highlighted by the widespread research on the production processes at the engineering, pharmaceutical, and nanotechnology level.Graphical abstractUnlabelled Image
  • Electrospinning: An enabling nanotechnology platform for drug delivery and
           regenerative medicine
    • Abstract: Publication date: Available online 2 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Shixuan Chen, Ruiquan Li, Xiaoran Li, Jingwei Xie Electrospinning provides an enabling nanotechnology platform for generating a rich variety of novel structured materials in many biomedical applications including drug delivery, biosensing, tissue engineering, and regenerative medicine. In this review article, we begin with a thorough discussion on the method of producing 1D, 2D, and 3D electrospun nanofiber materials. In particular, we emphasize on how the 3D printing technology can contribute to the improvement of traditional electrospinning technology for the fabrication of 3D electrospun nanofiber materials as drug delivery devices/implants, scaffolds or living tissue constructs. We then highlight several notable examples of electrospun nanofiber materials in specific biomedical applications including cancer therapy, guiding cellular responses, engineering in vitro 3D tissue models, and tissue regeneration. Finally, we finish with conclusions and future perspectives of electrospun nanofiber materials for drug delivery and regenerative medicine.Graphical abstractThis review summarizes the methods for producing 1D electrospun fragment, 1D nanofiber bundles, 2D nanofiber membranes, and 3D nanofiber scaffolds. Next, the combination of electrospinning with 3D printing, flexible electrode, and microfluidcs are discussed. And the review highlights the biomedical applications of nanofiber scaffolds, including drug delivery, controlling cellular behaviors, engineering in vitro 3D tissue/tumor models, and regenerative medicine.Unlabelled Image
  • Cell encapsulation: Overcoming barriers in cell transplantation in
           diabetes and beyond
    • Abstract: Publication date: Available online 30 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Marco Farina, Jenolyn F. Alexander, Usha Thekkedath, Mauro Ferrari, Alessandro Grattoni Cell-based therapy is emerging as a promising strategy for treating a wide range of human diseases, such as diabetes, blood disorders, acute liver failure, spinal cord injury, and several types of cancer. Pancreatic islets, blood cells, hepatocytes, and stem cells are among the many cell types currently used for this strategy. The encapsulation of these “therapeutic” cells is under intense investigation to not only prevent immune rejection but also provide a controlled and supportive environment so they can function effectively. Some of the advanced encapsulation systems provide active agents to the cells and enable a complete retrieval of the graft in the case of an adverse body reaction. Here, we review various encapsulation strategies developed in academic and industrial settings, including the state-of-the-art technologies in advanced preclinical phases as well as those undergoing clinical trials, and assess their advantages and challenges. We also emphasize the importance of stimulus-responsive encapsulated cell systems that provide a “smart and live” therapeutic delivery to overcome barriers in cell transplantation as well as their use in patients.Graphical abstractUnlabelled Image
  • Fibrillin microfibrils and proteases, key integrators of fibrotic pathways
    • Abstract: Publication date: Available online 27 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Paola Zigrino, Gerhard Sengle Supramolecular networks composed of multi-domain ECM proteins represent intricate cellular microenvironments which are required to balance tissue homeostasis and direct remodeling. Structural deficiency in ECM proteins results in imbalances in ECM-cell communication resulting often times in fibrotic reactions. To understand how individual components of the ECM integrate communication with the cell surface by presenting growth factors or providing fine-tuned biomechanical properties is mandatory for gaining a better understanding of disease mechanisms in the quest for new therapeutic approaches. Here we provide an overview about what we can learn from inherited connective tissue disorders caused primarily by mutations in fibrillin-1 and binding partners as well as by altered ECM processing leading to defined structural changes and similar functional knock-in mouse models. We will utilize this knowledge to propose new molecular hypotheses which should be tested in future studies.Graphical abstractUnlabelled Image
  • Intervertebral disc regeneration: From cell therapy to the development of
           novel bioinspired endogenous repair strategies
    • Abstract: Publication date: Available online 26 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Johann Clouet, Marion Fusellier, Anne Camus, Catherine Le Visage, Jérôme Guicheux Low back pain (LBP), frequently associated with intervertebral disc (IVD) degeneration, is a major public health concern. LBP is currently managed by pharmacological treatments and, if unsuccessful, by invasive surgical procedures, which do not counteract the degenerative process.Considering that IVD cell depletion is critical in the degenerative process, the supplementation of IVD with reparative cells, associated or not with biomaterials, has been contemplated. Recently, the discovery of reparative stem/progenitor cells in the IVD has led to increased interest in the potential of endogenous repair strategies. Recruitment of these cells by specific signals might constitute an alternative strategy to cell transplantation. Here, we review the status of cell-based therapies for treating IVD degeneration and emphasize the current concept of endogenous repair as well as future perspectives. This review also highlights the challenges of the mobilization/differentiation of reparative progenitor cells through the delivery of biologics factors to stimulate IVD regeneration.Graphical abstractUnlabelled Image
  • Sphingolipids as targets for inhalation treatment of cystic fibrosis
    • Abstract: Publication date: Available online 24 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Katrin Anne Becker, Joachim Riethmüller, Aaron P. Seitz, Aaron Gardner, Ryan Boudreau, Markus Kamler, Burkhard Kleuser, Edward Schuchman, Charles C. Caldwell, Michael J. Edwards, Heike Grassmé, Malcolm Brodlie, Erich Gulbins Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of β1-integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of β1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non-mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation.Graphical abstractMechanisms of ceramide and sphingosine alterations in cystic fibrosis (CF) epithelial cells and potential treatmentsCFTR deficiency results in increased ceramide levels that mediate surface clustering of β1-integrins. The luminal clustering of β1-integrins mediates a down-regulation of the expression of acid ceramidase (AC) in CF airway epithelial cells. This results in a vicious cycle with a further increase of ceramide concentrations and a decrease of sphingosine levels. Ceramide also induces cell death and a release of DNA into the airways. The low sphingosine concentrations in CF upper airways allow pathogens to reach the lung in which the viscous mucus containing dead cells and DNA promotes their adherence, growth and chronic infection. Treatments that directly reduce ceramide, for instance by blocking the acid sphingomyelinase (ASM), and/or normalize expression of β1-integrins and thereby correct expression levels of acid ceramidase and ceramide will reduce infection and inflammation, in CF lungs. Inhalation of sphingosine may predominantly mediate direct killing of pathogens. Sm: Sphingomyelin; C: ceramide; Sg: Sphingosine; ®: ®1-integrin, L: Ligands of ®1-integrin; FIASMA: Functional inhibitors of the acid sphingomyelinase.Unlabelled Image
  • Regulatory pitfalls and opportunities when repurposing for inhalation
    • Abstract: Publication date: Available online 19 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Svetlana Lyapustina This article reviews regulatory considerations for companies wishing to develop drugs for delivery via the respiratory tract (e.g., by oral inhalation or intranasally) using molecules previously approved for a different therapeutic indication and/or a different delivery route. Conceptually, such repurposing has many medical and business advantages, but turning promising ideas into real products requires overcoming a number of practical challenges. Obtaining regulatory approval to market a candidate product comes at the end of a product development, but being aware of the regulatory requirements is necessary before the development even starts. Understanding the scope and type of data that regulatory agencies would like to see may have a decisive influence on the design of the development program itself. For example, even for repurposed drugs, safety, efficacy, quality, and usability must be demonstrated, either from prior knowledge or through newly generated data. Furthermore, products for respiratory delivery have unique regulatory challenges due to the nature of these drug-device combinations.Graphical abstractUnlabelled Image
  • Impact of aging, Alzheimer's disease and Parkinson's disease on the
           blood-brain barrier transport of therapeutics
    • Abstract: Publication date: Available online 14 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Yijun Pan, Joseph A. Nicolazzo Older people are at a greater risk of medicine-induced toxicity resulting from either increased drug sensitivity or age-related pharmacokinetic changes. The scenario is further complicated with the two most prevalent age-related neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD). With aging, AD and PD, there is growing evidence of altered structure and function of the blood-brain barrier (BBB), including modifications to tight junctions and efflux transporters, such as P-glycoprotein. The subsequent impact on CNS drug exposure and risk of neurotoxicity from systemically-acting medicines is less well characterized. The purpose of this review, therefore, is to provide an overview of the multiple changes that occur to the BBB as a result of aging, AD and PD, and the impact that such changes have on CNS exposure of drugs, based on studies conducted in aged rodents or rodent models of disease, and in elderly people with and without AD or PD.Graphical abstractUnlabelled Image
  • Dosage form modification and oral drug delivery in older people
    • Abstract: Publication date: Available online 13 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Esther T.L. Lau, Kathryn J. Steadman, Julie A.Y. Cichero, Lisa M. Nissen Many people cannot swallow whole tablets and capsules. The cause ranges from difficulties overriding the natural instinct to chew solids/foodstuff before swallowing, to a complex disorder of swallowing function affecting the ability to manage all food and fluid intake. Older people can experience swallowing difficulties because of co-morbidities, age-related physiological changes, and polypharmacy. To make medicines easier to swallow, many people will modify the medication dosage form e.g. split or crush tablets, and open capsules. Some of the challenges associated with administering medicines to older people, and issues with dosage form modification will be reviewed. Novel dosage forms in development are promising and may help overcome some of the issues. However, until these are more readily available, effective interdisciplinary teams, and improving patient health literacy will help reduce the risk of medication misadventures in older people.Graphical abstractUnlabelled Image
  • Scarless wound healing: From development to senescence
    • Abstract: Publication date: Available online 12 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Harris Pratsinis, Eleni Mavrogonatou, Dimitris Kletsas An essential element of tissue homeostasis is the response to injuries, cutaneous wound healing being the most studied example. In the adults, wound healing aims at quickly restoring the barrier function of the skin, leading however to scar, a dysfunctional fibrotic tissue. On the other hand, in fetuses a scarless tissue regeneration takes place. During ageing, the wound healing capacity declines; however, in the absence of comorbidities a higher quality in tissue repair is observed. Senescent cells have been found to accumulate in chronic unhealed wounds, but more recent reports indicate that their transient presence may be beneficial for tissue repair. In this review data on skin wound healing and scarring are presented, covering the whole spectrum from early embryonic development to adulthood, and furthermore until ageing of the organism.Graphical abstractUnlabelled Image
  • Delivering drugs to the lungs: The history of repurposing in the treatment
           of respiratory diseases
    • Abstract: Publication date: Available online 11 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Stephen P. Newman The repurposing of drug delivery by the pulmonary route has been applied to treatment and prophylaxis of an increasingly wide range of respiratory diseases. Repurposing has been most successful for the delivery of inhaled bronchodilators and corticosteroids in patients with asthma and chronic obstructive pulmonary disease (COPD). Repurposing utilizes the advantages that the pulmonary route offers in terms of more targeted delivery to the site of action, the use of smaller doses, and a lower incidence of side-effects. Success has been more variable for other drugs and treatment indications. Pulmonary delivery is now well established for delivery of inhaled antibiotics in cystic fibrosis (CF), and in the treatment of pulmonary arterial hypertension (PAH). Other inhaled treatments such as those for idiopathic pulmonary fibrosis (IPF), lung transplant rejection or tuberculosis may also become routine. Repurposing has progressed in parallel with the development of new drugs, inhaler devices and formulations.Graphical abstractUnlabelled Image
  • Nucleic acids delivering nucleic acids
    • Abstract: Publication date: Available online 6 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Silvia Catuogno, Carla Lucia Esposito, Gerolama Condorelli, Vittorio de Franciscis Nucleic acid therapeutics, including siRNAs, miRNAs/antimiRs, gRNAs and ASO, represent innovative and highly promising molecules for the safe treatment of a wide range of pathologies. The efficiency of systemic treatments is impeded by 1) the need to overcome physical and functional barriers in the organism, and 2) to accumulate in the intracellular active site at therapeutic concentrations. Although oligonucleotides either as modified naked molecules or complexed with delivery carriers have revealed to be effectively delivered to the affected target cells, this is restricted to topic treatments or to a few highly vascularized tissues. Therefore, the development of effective strategies for therapeutic nucleic acid selective delivery to target tissues is of primary importance in order to reduce the occurrence of undesired effects on non-target healthy tissues and to permit their translation to clinic. Due to their high affinity for specific ligands, high tissue penetration and chemical flexibility, short single-stranded nucleic acid aptamers are emerging as very attractive carriers for various therapeutic oligonucleotides. Yet, different aptamer-based bioconjugates, able to provide accumulation into target tissues, as well as efficient processing of therapeutic oligonucleotides, have been developed. In this respect, nucleic acid aptamer-mediated delivery strategies represent a powerful approach able to increase the therapeutic efficacy also highly reducing the overall toxicity. In this review, we will summarize recent progress in the field and discuss achieved objectives and optimization of aptamers as delivery carriers of short oligonucleotides.Graphical abstractUnlabelled Image
  • Aptamers as targeting ligands and therapeutic molecules for overcoming
           drug resistance in cancers
    • Abstract: Publication date: Available online 6 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Gang Zhou, Olivier Latchoumanin, Lionel Hebbard, Wei Duan, Christopher Liddle, Jacob George, Liang Qiao Traditional anticancer therapies are often unable to completely eradicate the tumor bulk due to multi-drug resistance (MDR) of cancers. A number of mechanisms such as micro-environmental stress and overexpression of drug efflux pumps are involved in the MDR process. Hence, therapeutic strategies for overcoming MDR are urgently needed to improve cancer treatment efficacy. Aptamers are short single-stranded oligonucleotides or peptides exhibiting unique three-dimensional structures and possess several unique advantages over conventional antibodies such as low immunogenicity and stronger tissue-penetration capacity. Aptamers targeting cancer-associated receptors have been explored to selectively deliver a therapeutic cargo (anticancer drugs, siRNAs, miRNAs and drug-carriers) to the intratumoral compartment where they can exert better tumor-killing effects. In this review, we summarize current knowledge of the multiple regulatory mechanisms of MDR, with a particular emphasis on aptamer-mediated novel therapeutic agents and strategies that seek to reversing MDR. The challenges associated with aptamer-based agents and approaches are also discussed.Graphical abstractUnlabelled Image
  • Repurposing excipients as active inhalation agents: The mannitol story
    • Abstract: Publication date: Available online 5 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sandra D. Anderson, Evangelia Daviskas, John D. Brannan, Hak Kim Chan The story of how we came to use inhaled mannitol to diagnose asthma and to treat cystic fibrosis began when we were looking for a surrogate for exercise as a stimulus to identify asthma. We had proposed that exercise-induced asthma was caused by an increase in osmolarity of the periciliary fluid. We found hypertonic saline to be a surrogate for exercise but an ultrasonic nebuliser was required. We produced a dry powder of sodium chloride but it proved unstable. We developed a spray dried preparation of mannitol and found that bronchial responsiveness to inhaling mannitol identified people with currently active asthma. We reasoned that mannitol had potential to replace the ‘osmotic’ benefits of exercise and could be used as a treatment to enhance mucociliary clearance in patients with cystic fibrosis. These discoveries were the start of a journey to develop several registered products that are in clinical use globally today.Graphical abstractUnlabelled Image
  • Aptamer chemistry
    • Abstract: Publication date: Available online 4 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Pascal Röthlisberger, Marcel Hollenstein Aptamers are single-stranded DNA or RNA molecules capable of tightly binding to specific targets. These functional nucleic acids are obtained by an in vitro Darwinian evolution method coined SELEX (Systematic Evolution of Ligands by EXponential enrichment). Compared to their proteinaceous counterparts, aptamers offer a number of advantages including a low immunogenicity, a relative ease of large-scale synthesis at affordable costs with little or no batch-to-batch variation, physical stability, and facile chemical modification. These alluring properties have propelled aptamers into the forefront of numerous practical applications such as the development of therapeutic and diagnostic agents as well as the construction of biosensing platforms. However, commercial success of aptamers still proceeds at a weak pace. The main factors responsible for this delay are the susceptibility of aptamers to degradation by nucleases, their rapid renal filtration, suboptimal thermal stability, and the lack of functional group diversity. Here, we describe the different chemical methods available to mitigate these shortcomings. Particularly, we describe the chemical post-SELEX processing of aptamers to include functional groups as well as the inclusion of modified nucleoside triphosphates into the SELEX protocol. These methods will be illustrated with successful examples of chemically modified aptamers used as drug delivery systems, in therapeutic applications, and as biosensing devices.Graphical abstractUnlabelled Image
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