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Pharmaceutical Research
Journal Prestige (SJR): 1.077
Citation Impact (citeScore): 3
Number of Followers: 157  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
Published by Springer-Verlag Homepage  [2352 journals]
  • Recovery of OATP1B Activity after Living Kidney Transplantation in
           Patients with End-Stage Renal Disease
    • Authors: Yosuke Suzuki; Hiroyuki Ono; Ryota Tanaka; Fuminori Sato; Yuhki Sato; Keiko Ohno; Hiromitsu Mimata; Hiroki Itoh
      Abstract: Purpose Recently, several studies have shown that renal failure decreases the metabolic clearance of drugs and the transportation capability of some drug transporters. However, whether organic anion transporting polypeptide (OATP)1B activities decrease in renal failure remains unknown. In this study, we measured plasma concentrations of coproporphyrin-I (CP-I), a specific endogenous OATP1B probe, in patients with end stage renal disease before and after living kidney transplantation and evaluated the effect of renal function on OATP1B activity. Methods This prospective study recruited 13 patients with end-stage renal disease. Plasma CP-I concentrations were measured before and 7, 14, 30 and 90 days after living kidney transplantation. Results Plasma CP-I concentrations decreased over time after living kidney transplantation and showed significant difference on day 90 compared with before living kidney transplantation [1.12 ± 0.59 vs 0.65 ± 0.27 ng/mL, p < 0.05 (95% CI of difference − 0.927, −0.013)]. A significant negative correlation was observed between estimated glomerular filtration rate and plasma CP-I concentration (r = −0.30, p < 0.05), suggesting recovery of OATP1B activity with improvement in renal function. Conclusions OATP1B activity may decrease in renal failure and dose adjustment of OATP1B substrates may be needed in patients with renal failure.
      PubDate: 2019-02-26
      DOI: 10.1007/s11095-019-2593-8
      Issue No: Vol. 36, No. 4 (2019)
  • Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug
    • Authors: Mihir Shah; Sara Cabrera-Ghayouri; Lori-Ann Christie; Katherine S. Held; Veena Viswanath
      Abstract: ABSTRACT Preclinical models of human diseases are critical to our understanding of disease etiology, pathology, and progression and enable the development of effective treatments. An ideal model of human disease should capture anatomical features and pathophysiological mechanisms, mimic the progression pattern, and should be amenable to evaluating translational endpoints and treatment approaches. Preclinical animal models have been developed for a variety of human ophthalmological diseases to mirror disease mechanisms, location of the affected region in the eye and severity. These models offer clues to aid in our fundamental understanding of disease pathogenesis and enable progression of new therapies to clinical development by providing an opportunity to gain proof of concept (POC). Here, we review preclinical animal models associated with development of new therapies for diseases of the ocular surface, glaucoma, presbyopia, and retinal diseases, including diabetic retinopathy and age-related macular degeneration (AMD). We have focused on summarizing the models critical to new drug development and described the translational features of the models that contributed to our understanding of disease pathogenesis and establishment of preclinical POC.
      PubDate: 2019-02-25
      DOI: 10.1007/s11095-019-2588-5
      Issue No: Vol. 36, No. 4 (2019)
  • A Theoretical Model for the Cell Cycle and Drug Induced Cell Cycle Arrest
           of FUCCI Systems with Cell-to-Cell Variation during Mitosis
    • Authors: Hyeonjeong Bae; Young-Hyun Go; Taejin Kwon; Bong June Sung; Hyuk-Jin Cha
      Abstract: Purpose Since the molecular mechanism of the cell cycle was established, various theoretical models of this process have been developed. A recent study revealed significant variability in cell cycle duration between mother and daughter cells, but this observation has not been incorporated into the theoretical models. Methods We used fluorescent ubiquitination-based cell cycle indicator (FUCCI) systems and live-monitored the heterogeneity of cell cycle progression within daughter cells, which accounts for dephasing synchrony. To incorporate the variable cell cycle durations into a model, we modified a two-ordinary differential equation (ODE) model based on reciprocal activation between CDK1 and APC. Results Our model reproduced the experimental population profile, in which cell cycle synchrony dephased due to variability. Based on this model, we determined parameters for CDK1 and APC in the cell cycle profile after treatment with antimitotic drugs and associated the parameters with the drugs’ mode of action as cell cycle inhibitors. Conclusion This suggests that this model is useful for determining the mode of action of unknown small molecules on the cell cycle.
      PubDate: 2019-02-22
      DOI: 10.1007/s11095-019-2570-2
      Issue No: Vol. 36, No. 4 (2019)
  • New Insights into Using Lipid Based Suspensions for ‘Brick Dust’
           Molecules: Case Study of Nilotinib
    • Authors: Niklas J. Koehl; René Holm; Martin Kuentz; Brendan T. Griffin
      Abstract: Purpose Lipid suspensions have been shown to be a suitable bio-enabling formulation approach for highly lipophilic or ‘grease ball’ drug molecules, but studies on ‘brick dust’ drugs are lacking. This study explored the utility of lipid suspensions for enhancing oral bioavailability of the rather hydrophobic drug nilotinib in vivo in rats. Methods Four lipid suspensions were developed containing long chain triglycerides, medium chain triglyceride, long chain monoglycerides and medium chain monoglycerides and in vivo bioavailability was compared to an aqueous suspension. Additionally, in vitro lipolysis and wettability tests were conducted. Results Nilotinib lipid suspensions did not show a bioavailability increase compared to an aqueous suspension. The bioavailability was lower for triglyceride suspensions, relative to both monoglyceride and an aqueous suspension. The long chain monoglyceride displayed a significantly higher bioavailability relative to triglycerides. In vitro lipolysis results suggested entrapment of nilotinib crystals within poorly dispersible triglycerides, leading to slower nilotinib release and absorption. This was further supported by higher wettability of nilotinib by lipids. Conclusion Monoglycerides improved oral bioavailability of nilotinib in rats, relative to triglycerides. For ‘brick dust’ drugs formulated as lipid suspensions, poorly dispersible formulations may delay the release of drug crystals from the formulation leading to reduced absorption. Graphical An aqueous and four lipid suspensions have been evaluated in in vitro and in vivo to gain insights into the potential benefits and limitations of lipid suspensions.
      PubDate: 2019-02-22
      DOI: 10.1007/s11095-019-2590-y
      Issue No: Vol. 36, No. 4 (2019)
  • Correction to: Comparative Study of the Dose-Dependence of OATP1B
           Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in
           Healthy Volunteers
    • Authors: Issey Takehara; Takashi Yoshikado; Keiko Ishigame; Daiki Mori; Ken-ichi Furihata; Nobuaki Watanabe; Osamu Ando; Kazuya Maeda; Hiroyuki Kusuhara; Yuichi Sugiyama
      Abstract: There was a miscalculation of coproporphyrin I AUC0-24h in the published article (Volume 35, Number 7). After the correction of AUC0-24h, AUC ratio and R-square were re-calculated. Then, following corrections were made in the abstract, the body, Fig. 3, Fig. 4 and Table 2 in this article.
      PubDate: 2019-02-21
      DOI: 10.1007/s11095-019-2585-8
      Issue No: Vol. 36, No. 4 (2019)
  • Metal Organic Framework (MOF) Particles as Potential Bacteria-Mimicking
           Delivery Systems for Infectious Diseases: Characterization and Cellular
           Internalization in Alveolar Macrophages
    • Authors: Ailin Guo; Mikhail Durymanov; Anastasia Permyakova; Saad Sene; Christian Serre; Joshua Reineke
      Abstract: Purpose Intramacrophagic bacteria pose a great challenge for the treatment of infectious diseases despite many macrophage targeted drug delivery approaches explored. The use of biomimetic approaches for treating infectious diseases is promising, but not studied extensively. The study purpose is to evaluate iron-based metal-organic frameworks (MOF) as a potential bacteria-mimicking delivery system for infectious diseases. Methods Two types of carboxylated MOFs, MIL-88A(Fe) and MIL-100(Fe) were developed as “pathogen-like” particles by surface coating with mannose. MOF morphology, cellular uptake kinetics, and endocytic mechanisms in 3D4/21 alveolar macrophages were characterized. Results MIL-88A(Fe) is rod-shape (aspect ratio 1:5) with a long-axis size of 3628 ± 573 nm and MIL-100(Fe) is spherical with diameter of 103.9 ± 7.2 nm. Cellular uptake kinetics of MOFs showed that MIL-100(Fe) nanoparticles were internalized at a faster rate and higher extent compared to MIL-88A(Fe) microparticles. Mannosylation did not improve the uptake of MIL-100(Fe) particles, whereas it highly increased MIL-88A(Fe) cellular uptake and number of cells involved in internalization. Cell uptake inhibition studies indicated that macropinocytosis/phagocytosis was the main endocytic pathway for internalization of MOFs. Accumulation of MOF particles in acidic compartments was clearly observed. Conclusions The successfully synthesized “pathogen-like” particles provide a novel application of MOF-based particles as biomimetic delivery system for intramacrophagic-based infections.
      PubDate: 2019-02-21
      DOI: 10.1007/s11095-019-2589-4
      Issue No: Vol. 36, No. 4 (2019)
  • Ophthalmic Drug Discovery and Development: Regulatory Aspects of Patient
           Focused Drug Development in Ophthalmology
    • Authors: Cheryl L. Rowe-Rendleman
      Abstract: In 2009, members of the ophthalmic research community held a joint meeting with members of the Food and Drug Administration (FDA) and the National Eye Institute (NEI) to define and describe the types of patient-focused drug development (PFDD) tools used in ophthalmology. Since then numerous reports have been published which indicate that many of the questionnaires used for patient-reported outcomes (PROs) in ophthalmic clinical development lack rigor and reliability according to modern methods. In 2017, the FDA began development of a series of four methodological guidances for sponsors of clinical trials on the significance of PFDD. The new guidances delineate the FDA’s thinking and commitments under the Prescription Drug User Fee Act to implement a more structured approach to the assessment of risks and benefits in clinical trials. In these guidances, the FDA provides steps that drug and device manufacturers should follow, not only to obtain, but also to develop reliable and validated tools that measure patients’ experience in clinical trials. Subsequent efforts have resulted in the development and validation of PROs specifically for ophthalmology. The purpose of this paper is to assesses the PROs currently used in ophthalmology and to provide practical strategies for incorporating them into clinical trials.
      PubDate: 2019-02-21
      DOI: 10.1007/s11095-019-2577-8
      Issue No: Vol. 36, No. 4 (2019)
  • The Controlled Release and Anti-Inflammatory Activity of a
           Tetramethylpyrazine-Loaded Thermosensitive Poloxamer Hydrogel
    • Authors: Hongmei Xia; Hongliu Jin; Yongfeng Cheng; Zhiqing Cheng; Yinxiang Xu
      Abstract: Purpose Tetramethylpyrazine-loaded poloxamer hydrogel materials were studied to achieve the controlled release of tetramethylpyrazine. Methods First, hydrogels having different concentrations of poloxamer 407 and poloxamer 188 were prepared. The gelling temperature and viscosity were measured. Second, we investigated the tetramethylpyrazine release rate from the thermosensitive poloxamer hydrogel materials in vitro and ex vivo. Finally, further study of the pharmacological efficacy of the tetramethylpyrazine-loaded thermosensitive poloxamer hydrogel materials was also investigated in vivo. Results The in vitro, ex vivo and in vivo experimental results showed that the tetramethylpyrazine-loaded poloxamer hydrogel with the appropriate gelling temperature, good adhesion and easy preparation controlled the release of tetramethylpyrazine. Conclusions The hydrogel with the suitable nasal temperature and a satisfactory adhesion was selected. The relevant tests were carried out, including the determination of the concentration of drugs in the brain homogenate and the anti-inflammatory test after different modes of administration. So the poloxamer hydrogel was a novel carrier to deliver TMP to pass across the blood brain barrier via nasal administration.
      PubDate: 2019-02-19
      DOI: 10.1007/s11095-019-2580-0
      Issue No: Vol. 36, No. 4 (2019)
  • Impact of a Heat Shock Protein Impurity on the Immunogenicity of
           Biotherapeutic Monoclonal Antibodies
    • Authors: Shraddha S. Rane; Rebecca J. Dearman; Ian Kimber; Shahid Uddin; Stephen Bishop; Maryam Shah; Adrian Podmore; Alain Pluen; Jeremy P. Derrick
      Abstract: Purpose Anti-drug antibodies can impair the efficacy of therapeutic proteins and, in some circumstances, induce adverse health effects. Immunogenicity can be promoted by aggregation; here we examined the ability of recombinant mouse heat shock protein 70 (rmHSP70) - a common host cell impurity - to modulate the immune responses to aggregates of two therapeutic mAbs in mice. Methods Heat and shaking stress methods were used to generate aggregates in the sub-micron size range from two human mAbs, and immunogenicity assessed by intraperitoneal exposure in BALB/c mice. Results rmHSP70 was shown to bind preferentially to aggregates of both mAbs, but not to the native, monomeric proteins. Aggregates supplemented with 0.1% rmHSP70 induced significantly enhanced IgG2a antibody responses compared with aggregates alone but the effect was not observed for monomeric mAbs. Dendritic cells pulsed with mAb aggregate showed enhanced IFNγ production on co-culture with T cells in the presence of rmHSP70. Conclusion The results indicate a Th1-skewing of the immune response by aggregates and show that murine rmHSP70 selectively modulates the immune response to mAb aggregates, but not monomer. These data suggest that heat shock protein impurities can selectively accumulate by binding to mAb aggregates and thus influence immunogenic responses to therapeutic proteins.
      PubDate: 2019-02-15
      DOI: 10.1007/s11095-019-2586-7
      Issue No: Vol. 36, No. 4 (2019)
  • Evaluation of the Immunomodulatory Effects of All-Trans Retinoic Acid
           Solid Lipid Nanoparticles and Human Mesenchymal Stem Cells in an A549
           Epithelial Cell Line Model
    • Authors: Christina M. Payne; Liam P. Burke; Brenton Cavanagh; Daniel O’Toole; Sally-Ann Cryan; Helena M. Kelly
      Abstract: Purpose To investigate two potential strategies aimed at targeting the inflammatory pathogenesis of COPD: a small molecule, all trans retinoic acid (atRA) and human mesenchymal stem cells (hMSCs). Methods atRA was formulated into solid lipid nanoparticles (SLNs) via the emulsification-ultrasonication method, and these SLNs were characterised physicochemically. Assessment of the immunomodulatory effects of atRA-SLNs on A549 cells in vitro was determined using ELISA. hMSCs were suspended in a previously developed methylcellulose, collagen and beta-glycerophosphate hydrogel prior to investigating their immunomodulatory effects in vitro. Results SLNs provided significant encapsulation of atRA and also sustained its release over 72 h. A549 cells were viable following the addition of atRA SLNs and showed a reduction in IL-6 and IL-8 levels. A549 cells also remained viable following addition of the hMSC/hydrogel formulation – however, this formulation resulted in increased levels of IL-6 and IL-8, indicating a potentially pro-inflammatory effect. Conclusion Both atRA SLNs and hMSCs show potential for modulating the environment in inflammatory disease, though through different mechanisms and leading to different outcomes – despite both being explored as strategies for use in inflammatory disease. atRA shows promise by acting in a directly anti-inflammatory manner, whereas further research into the exact mechanisms and behaviours of hMSCs in inflammatory diseases is required.
      PubDate: 2019-02-13
      DOI: 10.1007/s11095-019-2583-x
      Issue No: Vol. 36, No. 4 (2019)
  • Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The
           Role of Niacinamide
    • Authors: Jonas Kildegaard; Stephen T. Buckley; Rasmus H. Nielsen; Gro K. Povlsen; Torben Seested; Ulla Ribel; Helle B. Olsen; Svend Ludvigsen; Claus B. Jeppesen; Hanne H. F. Refsgaard; Kristian M. Bendtsen; Niels R. Kristensen; Susanne Hostrup; Jeppe Sturis
      Abstract: Purpose Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart containing two additional excipients: niacinamide, to increase early absorption, and L-arginine, to optimize stability. The aim of this study was to evaluate the impact of niacinamide on insulin aspart absorption and to investigate the mechanism of action underlying the accelerated absorption. Methods The impact of niacinamide was assessed in pharmacokinetic analyses in pigs and humans, small angle X-ray scattering experiments, trans-endothelial transport assays, vascular tension measurements, and subcutaneous blood flow imaging. Results Niacinamide increased the rate of early insulin aspart absorption in pigs, and pharmacokinetic modelling revealed this effect to be most pronounced up to ~30–40 min after injection in humans. Niacinamide increased the relative monomer fraction of insulin aspart by ~35%, and the apparent permeability of insulin aspart across an endothelial cell barrier by ~27%. Niacinamide also induced a concentration-dependent vasorelaxation of porcine arteries, and increased skin perfusion in pigs. Conclusion Niacinamide mediates the acceleration of initial insulin aspart absorption, and the mechanism of action appears to be multifaceted. Niacinamide increases the initial abundance of insulin aspart monomers and transport of insulin aspart after subcutaneous administration, and also mediates a transient, local vasodilatory effect.
      PubDate: 2019-02-11
      DOI: 10.1007/s11095-019-2578-7
      Issue No: Vol. 36, No. 3 (2019)
  • Analyzing the Mechanisms Behind Macrolide Antibiotic-Induced Liver Injury
           Using Quantitative Systems Toxicology Modeling
    • Authors: Jeffrey L. Woodhead; Kyunghee Yang; David Oldach; Chris MacLauchlin; Prabhavathi Fernandes; Paul B. Watkins; Scott Q. Siler; Brett A. Howell
      Abstract: Purpose Macrolide antibiotics are commonly prescribed treatments for drug-resistant bacterial infections; however, many macrolides have been shown to cause liver enzyme elevations and one macrolide, telithromycin, has been pulled from the market by its provider due to liver toxicity. This work seeks to assess the mechanisms responsible for the toxicity of macrolide antibiotics. Methods Five macrolides were assessed in in vitro systems designed to test for bile acid transporter inhibition, mitochondrial dysfunction, and oxidative stress. The macrolides were then represented in DILIsym, a quantitative systems pharmacology (QST) model of drug-induced liver injury, placing the in vitro results in context with each compound’s predicted liver exposure and known biochemistry. Results DILIsym results suggest that solithromycin and clarithromycin toxicity is primarily due to inhibition of the mitochondrial electron transport chain (ETC) while erythromycin toxicity is primarily due to bile acid transporter inhibition. Telithromycin and azithromycin toxicity was not predicted by DILIsym and may be caused by mechanisms not currently incorporated into DILIsym or by unknown metabolite effects. Conclusions The mechanisms responsible for toxicity can be significantly different within a class of drugs, despite the structural similarity among the drugs. QST modeling can provide valuable insight into the nature of these mechanistic differences.
      PubDate: 2019-02-07
      DOI: 10.1007/s11095-019-2582-y
      Issue No: Vol. 36, No. 3 (2019)
  • Improving Stability and Dissolution of Amorphous Clofazimine by Polymer
    • Abstract: Purpose To inhibit the surface crystallization and enhance the dissolution of the basic amorphous drug clofazimine by polymer nano-coating. Methods The free surface of amorphous clofazimine was coated by dip coating in an alginate solution at pH 7. The stability of the coated amorphous drug against crystallization was evaluated by X-ray diffraction and light microscopy. The effect of coating on dissolution rate was measured in simulated gastric fluid in an USP-II apparatus at 37°C. Results At pH 7, the weak base clofazimine (pKa = 8.5) is positively charged, while the weak alginic acid (pKa = 3.5) is negatively charged, allowing coating by electrostatic deposition. Coated amorphous particles remain nearly amorphous after one year under the accelerated testing condition 40°C/75% R.H. and show faster dissolution than uncoated particles. In the first hour of dissolution, coated amorphous particles dissolve 50% faster than uncoated amorphous particles, and a factor of 3 faster than crystalline particles of the same size. Conclusions A pharmaceutically acceptable polymer, alginate, is coated on amorphous clofazimine by electrostatic deposition and effectively inhibits its surface crystallization and enhances its dissolution rate. This is the first time the nano-coating technique is applied to a basic drug using the principle of electrostatic deposition, demonstrating the generality of the approach.
      PubDate: 2019-03-15
  • Efficacy of Surface-Modified PLGA Nanoparticles as a Function of Cervical
           Cancer Type
    • Abstract: Purpose Hypovascularization of cervical tumors, coupled with intrinsic and acquired drug resistance, has contributed to marginal therapeutic outcomes by hindering chemotherapeutic transport and efficacy. Recently, the heterogeneous penetration and distribution of cell penetrating peptide (CPP, here MPG) and polyethylene glycol (PEG) modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were evaluated as a function of tumor type and morphology in cervical cancer spheroids modeling hypovascularized tumor nodules. Building upon this work, this study investigates the efficacy imparted by surface-modified Doxorubicin-loaded NPs transported into hypovascularized tissue. Methods NP efficacy was measured in HeLa, CaSki, and SiHa cells. NP internalization and association, and associated cell viability, were determined in monolayer and spheroid models. Results MPG and PEG-NP co-treatment was most efficacious in HeLa cells, while PEG NPs were most efficacious in CaSki cells. NP surface-modifications were unable to improve efficacy, relative to unmodified NPs, in SiHa cells. Conclusions The results highlight the dependence of efficacy on tumor type and the associated microenvironment. The results further relate previous NP transport studies to efficacy, as a function of surface-modification and cell type. Longer-term, this information may help guide the design of NP-mediated strategies to maximize efficacy based on patient-specific cervical tumor origin and characteristics.
      PubDate: 2019-03-13
  • Nanomedicines for Infectious Diseases
    • PubDate: 2019-03-11
  • A Macromolecular Janus Kinase (JAK) Inhibitor Prodrug Effectively
           Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice
    • Abstract: Background Tofacitinib (Tofa) has been approved for moderately to severely active ulcerative colitis (UC). To improve its therapeutic efficacy and limit dose-dependent toxicity, we developed a macromolecular prodrug of Tofa (P-Tofa). If the prodrug design improves the potency and duration of Tofa therapy, it would widen its therapeutic window, potentially leading to improved safety and better clinical management of UC. Methods P-Tofa was synthesized by conjugating Tofa to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer via a cleavable carbamate linker. DSS-induced UC mouse model were treated with Tofa (daily oral gavage, from day 8), P-Tofa (single intravenous administration on day 8, dose equivalent to Tofa treatment) and saline. Healthy mice were used as a positive control. The therapeutic efficacy was evaluated using disease activity index (DAI), endoscopic score and end-point histology. The optical imaging, immunohistochemistry and flow cytometry were used to understand P-Tofa’s working mechanism. Results DAI results suggested that a single dose P-Tofa treatment was more efficacious than dose equivalent daily Tofa treatment. Endoscopic evaluation and histology analyses confirmed that while both P-Tofa and Tofa protected the colon, P-Tofa treated group was observed with better colon integrity with less tissue damage. Optical imaging, flow cytometry and immunohistochemistry results showed that P-Tofa passively targeted the inflamed colon and being retained via cellular sequestration. Conclusions Single intravenous administration of P-Tofa was more effective than dose equivalent daily oral Tofa gavage in ameliorating DSS-induced colitis. This observed superior therapeutic efficacy may be attributed to P-Tofa’s passive targeting to and retention by the inflamed colon.
      PubDate: 2019-03-11
  • Surface Modification of Polymeric Nanoparticles with M2pep Peptide for
           Drug Delivery to Tumor-Associated Macrophages
    • Abstract: Purpose Tumor-associated macrophages (TAMs) with immune-suppressive M2-like phenotype constitute a significant part of tumor and support its growth, thus making an attractive therapeutic target for cancer therapy. To improve the delivery of drugs that control the survival and/or functions of TAMs, we developed nanoparticulate drug carriers with high affinity for TAMs. Methods Poly(lactic-co-glycolic acid) nanoparticles were coated with M2pep, a peptide ligand selectively binding to M2-polarized macrophages, via a simple surface modification method based on tannic acid-iron complex. The interactions of M2pep-coated nanoparticles with macrophages of different phenotypes were tested in vitro and in vivo. PLX3397, an inhibitor of the colony stimulating factor-1 (CSF-1)/CSF-1 receptor (CSF-1R) pathway and macrophage survival, was delivered to B16F10 tumors via M2pep-modified PLGA nanoparticles. Results In bone marrow-derived macrophages polarized to M2 phenotype, M2pep-coated nanoparticles showed greater cellular uptake than those without M2pep. Consistently, M2pep-coated nanoparticles showed relatively high localization of CD206+ macrophages in B16F10 tumors. PLX3397 encapsulated in M2pep-coated nanoparticles attenuated tumor growth better than the free drug counterpart. Conclusion These results support that M2pep-coating can help nanoparticles to interact with M2-like TAMs and facilitate the delivery of drugs that control the tumor-supportive functions of TAMs.
      PubDate: 2019-03-11
  • A Multifunctional Hydrogel Delivers Gold Compound and Inhibits Human Lung
           Cancer Xenograft
    • Abstract: Purpose Interpenetrating network system (IPN), consisting of polyethylene glycol (PEG) –diacrylate (PEGdA) and modified gelatin, is a biocompatible and biodegradable hydrogel and has been studied for the local delivery of bioactive molecules and drugs. Gold(III) porphyrin(AuP) is a stable metal compound in the development for anticancer application when administered systemically. The aim of this work is to develop a novel formulation for AuP based on IPN for local delivery. Methods IPN loaded with AuP hydrogel was optimized and synthesized. Drug release kinetics, cytotoxicity against tumor cells, and antitumor activity in lung cancer bearing nude mice were studied. Results AuP released from the IPN followed a first order kinetics in vitro. The AuP loaded IPN showed higher cytotoxicity against human lung cancer cell lines compared to IPN only. In mice bearing human lung cancer xenograft, AuP loaded IPN inhibited tumor growth and reduced angiogenesis. No sign of systemic toxicity was observed for all treatment groups. Conclusion AuP loaded IPN provides an improved formulation over systemic delivery for tumor inhibition to complement surgical intervention. Graphical Injectable multifunctional matrix of polyethylene glycol and gelatin derivatives for the delivery of gold porphyrinto inhibit tumor growth.
      PubDate: 2019-03-08
  • A Comprehensive Physicochemical, In Vitro and Molecular Characterization
           of Letrozole Incorporated Chitosan-Lipid Nanocomplex
    • Abstract: Purpose The aim of this study is to show a new mesomicroscopic insight into Letrozole (LTZ) loaded nanocomplexes and their ex vivo characteristics as a drug delivery system. Methods The LTZ loaded hybrid chitosan-based carrier was fabricated using a modified ionic crosslinking technique and characterized in more detail. To understand the mechanism of LTZ action encapsulated in the hybrid polymer-lipid carrier, all-atom molecular dynamics simulations were also used. Results The physicochemical properties of the carrier demonstrated the uniform morphology, but different drug loading ratios. In vitro cytotoxic activity of the optimized carrier demonstrated IC50 of 67.85 ± 0.55 nM against breast cancer cell line. The ex vivo study showed the positive effect of nanocomplex on LTZ permeability 7–10 fold greater than the free drug. The molecular dynamic study also confirmed the prsence of hydrophobic peak of lipids at a distance of 5 Å from the center of mass of LTZ which proved drug entrapment in the core of nanocomplex. Conclusions The hybrid nanoparticle increased the cytotoxicity and tissue permeability of LTZ for oral delivery. This study also confirmed the atomic mesostructures and interaction of LTZ in the core of hybrid polymer-lipid nanoparticles.
      PubDate: 2019-03-08
  • Biomimetic Hydroxyapatite a Potential Universal Nanocarrier for Cellular
           Internalization & Drug Delivery
    • Abstract: Purpose Functional biomaterials can be used as drug loading devices, components for tissue engineering or as biological probes. As such, the design, synthesis and evaluation of a variety of local-drug delivery structures has been undertaken over the past few decades with the ultimate aim of providing materials that can encapsulate a diverse array of drugs (in terms of their sizes, chemical compositions and chemical natures (i.e. hydrophilic/hydrophobic). Methods Presented here is the evaluation of specifically hollow 1D structures consisting of nanotubes (NTs) of HAp and their efficacy for cellular internalization using two distinguished anti-cancer model drugs: Paclitaxel (hydrophobic) and Doxorubicin hydrochloride (hydrophilic). Results Importantly, it has been observed through this work that HAp NTs consistently showed not only higher drug loading capacity as compared to HAp nanospheres (NSs) but also had better efficacy with respect to cell internalization/encapsulation. The highly porous structure, with large surface area of nanotube morphology, gave the advantage of targeted delivery due to its high drug loading and retention capacity. This was done using the very simple techniques of physical adsorption to load the drug/dye molecules and therefore this can be universally applied to a diverse array of molecules. Conclusions Our synthesized nanocarrier can be widely employed in biomedical applications due to its bio-compatible, bio-active and biodegradable properties and as such can be considered to be a universal carrier. Graphical Schematic representation for a comparative study of hydroxyapatite (hollow nanotubes vs solid nanospheres) with variety of drug/ dye molecules
      PubDate: 2019-03-07
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