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Pharmaceutical Research
Journal Prestige (SJR): 1.077
Citation Impact (citeScore): 3
Number of Followers: 147  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
Published by Springer-Verlag Homepage  [2350 journals]
  • Genetic Basis of Delayed Hypersensitivity Reactions to Drugs in Jewish and
           Arab Populations
    • Authors: Mohammed Aboukaoud; Shoshana Israel; Chaim Brautbar; Sara Eyal
      Abstract: Abstract Genetic variation can affect drug pharmacokinetics and pharmacodynamics and contribute to variability between individuals in response to medications. Specifically, differences in allele frequencies among individuals and ethnic groups have been associated with variation in their propensity to develop drug hypersensitivity reactions (HSRs). This article reviews the current knowledge on the genetic background of HSRs and its relevance to Jewish and Arab populations. The focus is on human leukocyte antigen (HLA) alleles and haplotypes as predictive markers of HSRs (“immunopharmacogenetics”), but other genes and alleles are described as well. Also discussed is the translation of the pharmacogenetic information to practice recommendations.
      PubDate: 2018-09-17
      DOI: 10.1007/s11095-018-2472-8
      Issue No: Vol. 35, No. 11 (2018)
  • Using Human Plasma as an Assay Medium in Caco-2 Studies Improves Mass
           Balance for Lipophilic Compounds
    • Authors: Kasiram Katneni; Thao Pham; Jessica Saunders; Gong Chen; Rahul Patil; Karen L. White; Nada Abla; Francis C. K. Chiu; David M. Shackleford; Susan A. Charman
      Abstract: Purpose To examine the utility of human plasma as an assay medium in Caco-2 permeability studies to overcome poor mass balance and inadequate sink conditions frequently encountered with lipophilic compounds. Methods Caco-2 permeability was assessed for reference compounds with known transport mechanisms using either pH 7.4 buffer or human plasma as the assay medium in both the apical and basolateral chambers. When using plasma, Papp values were corrected for the unbound fraction in the donor chamber. The utility of the approach was assessed by measuring the permeability of selected antimalarial compounds using the two assay media. Results Caco-2 cell monolayer integrity and P-gp transporter function were unaffected by the presence of human plasma in the donor and acceptor chambers. For many of the reference compounds having good mass balance with buffer as the medium, higher Papp values were observed with plasma, likely due to improved acceptor sink conditions. The lipophilic antimalarial compounds exhibited low mass balance with buffer, however the use of plasma markedly improved mass balance allowing the determination of more reliable Papp values. Conclusions The results support the utility of human plasma as an alternate Caco-2 assay medium to improve mass balance and permeability measurements for lipophilic compounds.
      PubDate: 2018-09-17
      DOI: 10.1007/s11095-018-2493-3
      Issue No: Vol. 35, No. 11 (2018)
  • Can Population Modelling Principles be Used to Identify Key PBPK
           Parameters for Paediatric Clearance Predictions' An Innovative
           Application of Optimal Design Theory
    • Authors: Elisa A. M. Calvier; Thu Thuy Nguyen; Trevor N. Johnson; Amin Rostami-Hodjegan; Dick Tibboel; Elke H. J. Krekels; Catherijne A. J. Knibbe
      Abstract: Purpose Physiologically-based pharmacokinetic (PBPK) models are essential in drug development, but require parameters that are not always obtainable. We developed a methodology to investigate the feasibility and requirements for precise and accurate estimation of PBPK parameters using population modelling of clinical data and illustrate this for two key PBPK parameters for hepatic metabolic clearance, namely whole liver unbound intrinsic clearance (CLint,u,WL) and hepatic blood flow (Qh) in children. Methods First, structural identifiability was enabled through re-parametrization and the definition of essential trial design components. Subsequently, requirements for the trial components to yield precise estimation of the PBPK parameters and their inter-individual variability were established using a novel application of population optimal design theory. Finally, the performance of the proposed trial design was assessed using stochastic simulation and estimation. Results Precise estimation of CLint,u,WL and Qh and their inter-individual variability was found to require a trial with two drugs, of which one has an extraction ratio (ER) ≤ 0.27 and the other has an ER ≥ 0.93. The proposed clinical trial design was found to lead to precise and accurate parameter estimates and was robust to parameter uncertainty. Conclusion The proposed framework can be applied to other PBPK parameters and facilitate the development of PBPK models.
      PubDate: 2018-09-14
      DOI: 10.1007/s11095-018-2487-1
      Issue No: Vol. 35, No. 11 (2018)
  • Drug-Polymer Interaction, Pharmacokinetics and Antitumor Effect of
           PEG-PLA/Taxane Derivative TM-2 Micelles for Intravenous Drug Delivery
    • Authors: Qiao Wang; Yi Liu; Chenguang Pu; Hongjuan Zhang; Xinyi Tan; Jingxin Gou; Haibing He; Tian Yin; Yu Zhang; Yanjiao Wang; Xing Tang
      Abstract: Purpose A novel polymer micelle was prepared with a high drug loading, good stability, high tolerance and better anti-tumor effect. Methods TM-2 was encapsulated in poly-block-poly (D, L-lactic acid) self-assembled micelles by the thin-film hydration method. From the critical micelle concentrations of the copolymers, particle size, drug loading and encapsulation efficiency of drug-loading micelles, the appropriate polymer material could be assessed. Comparisons between TM-2 solution and TM-2 micelles were done to evaluate the pharmacokinetics and toxicity in rats, compared with Taxol to evaluate the anti-tumor effect in mice. Results The optimized TM-2 micelles achieved a high drug loading (~20%) with the polymer material of PEG2k-PLA2.5k, with a particle size of 30 nm and no significant change in particle size after lyophilization. The result of pharmacokinetic experiment displayed that the half-life in vivo was obviously prolonged. The maximum tolerated dose of TM-2 micelles was approximately 25 mg/kg in rats, and the relative tumor growth rate of Taxol (15 mg/kg), TM-2 (10 mg/kg), TM-2 (15 mg/kg) and TM-2 (40 mg/kg) in mice were 49.35%, 49.14%, 36.44 and 9.98% respectively. Conclusions TM-2 micelles with high drug loading increased drug solubility, improved tolerance, antitumor effects and reduced toxicity.
      PubDate: 2018-09-13
      DOI: 10.1007/s11095-018-2477-3
      Issue No: Vol. 35, No. 11 (2018)
  • pH-Promoted Release of a Novel Anti-Tumour Peptide by “Stealth”
           Liposomes: Effect of Nanocarriers on the Drug Activity in Cis-Platinum
           Resistant Cancer Cells
    • Authors: Francesca Sacchetti; Gaetano Marverti; Domenico D’Arca; Leda Severi; Eleonora Maretti; Valentina Iannuccelli; Salvatore Pacifico; Glauco Ponterini; Maria Paola Costi; Eliana Leo
      Abstract: Purpose To evaluate the potential effects of PEGylated pH-sensitive liposomes on the intracellular activity of a new peptide recently characterized as a novel inhibitor of the human thymidylate synthase (hTS) over-expressed in many drug-resistant human cancer cell lines. Methods Peptide-loaded pH-sensitive PEGylated (PpHL) and non-PEGylated liposomes (nPpHL) were carefully characterized and delivered to cis-platinum resistant ovarian cancer C13* cells; the influence of the PpHL on the drug intracellular activity was investigated by the Western Blot analysis of proteins involved in the pathway affected by hTS inhibition. Results Although PpHL and nPpHL showed different sizes, surface hydrophilicities and serum stabilities, both carriers entrapped the drug efficiently and stably demonstrating a pH dependent release; moreover, the different behavior against J774 macrophage cells confirmed the ability of PEGylation in protecting liposomes from the reticuloendothelial system. Comparable effects were instead observed against C13* cells and biochemical data by immunoblot analysis indicated that PEGylated pH-sensitive liposomes do not modify the proteomic profile of the cells, fully preserving the activity of the biomolecule. Conclusion PpHL can be considered as efficient delivery systems for the new promising anti-cancer peptide.
      PubDate: 2018-09-12
      DOI: 10.1007/s11095-018-2489-z
      Issue No: Vol. 35, No. 11 (2018)
  • Cationic Liposomes: A Flexible Vaccine Delivery System for
           Physicochemically Diverse Antigenic Peptides
    • Authors: Jeroen Heuts; Eleni Maria Varypataki; Koen van der Maaden; Stefan Romeijn; Jan Wouter Drijfhout; Anton Terwisscha van Scheltinga; Ferry Ossendorp; Wim Jiskoot
      Abstract: Purpose Personalized peptide-based cancer vaccines will be composed of multiple patient specific synthetic long peptides (SLPs) which may have various physicochemical properties. To formulate such SLPs, a flexible vaccine delivery system is required. We studied whether cationic liposomes are suitable for this purpose. Methods Fifteen SIINFEKL T cell epitope-containing SLPs, widely differing in hydrophobicity and isoelectric point, were separately loaded in cationic liposomes via the dehydration-rehydration method. Particle size and polydispersity index (PDI) were measured via dynamic light scattering (DLS), and zeta potential with laser Doppler electrophoresis. Peptide loading was fluorescently determined and the immunogenicity of the formulated peptides was assessed in co-cultures of dendritic cells (DCs) and CD8+ T-cells in vitro. Results All SLPs were loaded in cationic liposomes by using three different loading method variants, depending on the SLP characteristics. The fifteen liposomal formulations had a comparable size (< 200 nm), PDI (< 0.3) and zeta potential (22–30 mV). Cationic liposomes efficiently delivered the SLPs to DCs that subsequently activated SIINFEKL-specific CD8+ T-cells, indicating improved immunological activity of the SLPs. Conclusion Cationic liposomes can accommodate a wide range of different SLPs and are therefore a potential delivery platform for personalized cancer vaccines.
      PubDate: 2018-09-12
      DOI: 10.1007/s11095-018-2490-6
      Issue No: Vol. 35, No. 11 (2018)
  • Modeling Sex Differences in Anti-inflammatory Effects of Dexamethasone in
           Arthritic Rats
    • Authors: Dawei Song; Debra C. DuBois; Richard R. Almon; William J. Jusko
      Abstract: Purpose Collagen-induced arthritic (CIA) rats are used commonly for preclinical pharmacologic research into rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid (CS), remains an important component in combination therapy for RA. Although sex differences in RA and CS pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, there has been no such comprehensive evaluation of sex differences in CIA rats. Methods Paw size measurements were obtained for males and females from four groups of animals: healthy controls, non-drug treated arthritic animals, and both 0.225 and 2.25 mg/kg DEX-treated arthritic animals. A turnover model for disease progression, minimal PBPK model for drug concentrations, and inhibitory indirect response model were applied using population PK/PD modeling. Results The clearances of DEX were 43% greater in males, but other PK parameters were similar. The temporal profiles of paw swelling exhibited earlier progression, peak edema times, and disease remission in females. DEX suppressed paw edema well in both males and females with similar capacity (Imax) values (=1.0), but DEX potency was less in females with higher IC50 values (0.101 versus 0.015 ng/mL). Conclusions The pharmacology of DEX was well characterized in CIA rats. This study addresses knowledge gaps about sex differences and can be a guide for more mechanistic assessment of sex, drug, and disease differences in RA.
      PubDate: 2018-09-06
      DOI: 10.1007/s11095-018-2483-5
      Issue No: Vol. 35, No. 11 (2018)
  • Molecular Targets of the Hydrophobic Block of Pluronics in Cells: a Photo
           Affinity Labelling Approach
    • Authors: A. Zhirnov; E. Nam; G. Badun; A. Romanyuk; A. Ezhov; N. Melik-Nubarov; I. Grozdova
      Abstract: Purpose Pluronics are known as inhibitors of multidrug resistance thus making tumor cells sensitive to therapeutic doses of drugs. The purpose of our study consists in revealing molecular targets of the hydrophobic poly(propylene oxide) block of pluronics in living cells and the dependence of the polymers chemosensitizing efficiency upon targeting. Methods A photo sensitive tracer was attached to the hydrophobic poly(propylene oxide) block of 3H-labeled tert-Bu-EO-PO copolymer. The conjugate was used for treatment cells in culture. We searched for its complexes with cellular lipids or proteins using RP TLC and SDS-electrophoresis, respectively. The chemosensitizing efficiency of pluronics was evaluated by their least concentrations sufficient for MDR reversion (CMDR). Results The poly(propylene oxide) block inserts in the lipid core of plasma membrane. No preferential binding of the conjugate with any cellular protein, particularly P-gp, has been detected. FITC-labeled pluronic L61 bound to alcohol insoluble cellular targets did not participate in MDR reversion. CMDR values of 13 block copolymers have been determined. These values inversely correlated with the polymers affinity toward lipids and the ability to accelerate flip-flop. Conclusion Insertion of the hydrophobic poly(propylene oxide) block of amphiphiles in the lipid core of plasma membrane and acceleration of flip-flop of lipids underlie the mechanism of MDR reversion.
      PubDate: 2018-09-06
      DOI: 10.1007/s11095-018-2484-4
      Issue No: Vol. 35, No. 11 (2018)
  • Selective Inhibition on Organic Cation Transporters by Carvedilol Protects
           Mice from Cisplatin-Induced Nephrotoxicity
    • Authors: Dong Guo; Hong Yang; Qing Li; Hyo Jung Bae; Obinna Obianom; Sujuan Zeng; Tong Su; James E. Polli; Yan Shu
      Abstract: Purpose The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs), located in the basolateral and apical membrane of proximal tubular cells respectively, are crucial determinants of renal elimination and/or toxicity of cationic drugs such as cisplatin. The purpose of this study was to discover selective OCT inhibitors over MATEs, and explore their potential to protect against cisplatin-induced nephrotoxicity that is clinically common. Methods The inhibition by select compounds on the uptake of the probe substrate metformin was assessed in HEK293 cells overexpressing human OCT2, OCT1, MATE1, MATE2-K, and mouse Oct2, Oct1, and Mate1. Furthermore, the effects of carvedilol on organic cation transporter-mediated cellular and renal accumulation of metformin and cisplatin, and particularly the toxicity associated with cisplatin, were investigated in HEK293 cells and mice. Results Five selective OCT inhibitors were identified through the screening of forty-one drugs previously reported as the inhibitors of OCTs and/or MATEs. Among them, carvedilol showed the most selectivity on OCTs over MATEs (IC50: 3.6 μM for human OCT2, 103 μM for human MATE1 and 202 μM for human MATE2-K) in the cellular assays in vitro, with the selectivity in mice as well. Moreover, carvedilol treatment could significantly decrease cisplatin accumulation and ameliorate its toxicity both in vitro in cells and in vivo in mouse kidney. Conclusions Our data indicate that selective inhibition of OCTs by carvedilol may protect from cisplatin-induced nephrotoxicity by restraining the cellular entry of cisplatin via OCTs, while having no impact on its elimination through MATEs.
      PubDate: 2018-09-06
      DOI: 10.1007/s11095-018-2486-2
      Issue No: Vol. 35, No. 11 (2018)
  • Correction to: Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery
           for Lung Cancer
    • Authors: Nishant S. Gandhi; Sudhakar Godeshala; Dana-Lynn T. Koomoa-Lange; Bhavani Miryala; Kaushal Rege; Mahavir B. Chougule
      Abstract: Under the heading “Methods-Synthesis of the Bioreducible Modified-PAE (mPAE)”, on page 3, line 14–17, there is an error. The quantity unit of PAE and 2-iminothiolane hydrochloride needs to be corrected to mg instead of g.
      PubDate: 2018-09-05
      DOI: 10.1007/s11095-018-2488-0
      Issue No: Vol. 35, No. 11 (2018)
  • Co-Delivery of Teriflunomide and Methotrexate from Hydroxyapatite
           Nanoparticles for the Treatment of Rheumatoid Arthritis: In Vitro
           Characterization, Pharmacodynamic and Biochemical Investigations
    • Authors: Shweta Pandey; Vijay Kumar; Ankita Leekha; Nishant Rai; Farhan Jalees Ahmad; Anita Kamra Verma; Sushama Talegaonkar
      Abstract: Purpose The present investigation was aimed at developing Teriflunomide (TEF) and Methotrexate (MTX) loaded hydroxyapatite nanoparticles and increasing tolerability towards combination therapy against rheumatoid arthritis by reducing hepatotoxicity. Methods Drug-loaded HAp-NPs were synthesized by wet-chemical precipitation method and optimized by Box-Behnken experimental design. The developed NPs were subjected to in vitro and in vivo characterization. In-vivo pharmacodynamics and biochemical studies were performed on adjuvant- induced arthritis model treated with different formulations; MTX-TEF-SOL, TEF-HAp-NP, MTX-HAp-NP, TEF-MTX-HAp-NP, FOLITRAX-10 and AUBAGIO. Results The size of the optimized formulations, TEF-HAp-NP and MTX-HAp-NP, was found to be 224.3 ± 83.80 nm and 268.3 ± 73.86 nm with drug loading 53.11 ± 0.84% and 67.04 ± 1.12% respectively. In vitro release of TEF from TEF-HAp-NP (70.41 ± 1.22%) and MTX from MTX-HAp-NP (82.43 ± 1.31%) up to 24 h revealed sustained release pattern. Results of the arthritic assessment study showed a significant (P < 0.05) reduction in ankle diameter (61.30 ± 7.42) and arthritis score (2.35 ± 0.24) with a marked restoration of ankle joint micro-architecture in TEF-MTX-HAp-NP treated group. During Hepatotoxicity studies, liver histopathology revealed that the formulation MTX-TEF-HAp-NP was least hepatotoxic with less hepatocyte swelling and fibrous connective tissue proliferation while Folitrax-10 was found to be most hepatotoxic. Biochemical studies revealed that Folitrax-10 significantly (P < 0.05) increased the GOT (313.64 ± 16) and GPT level (334.46 ± 13) while insignificant (P > 0.05) change in GOT (263.68 ± 17) and GPT (229.38 ± 10) level was recorded with TEF-MTX-HAp-NP. Conclusions We report that the subcutaneous delivery of TEF-MTX-HAp-NP was most effective as it successfully reduced the dosage by half for maximizing therapeutic efficacy and minimizing side effects. Graphical ᅟ
      PubDate: 2018-09-05
      DOI: 10.1007/s11095-018-2478-2
      Issue No: Vol. 35, No. 11 (2018)
  • Radiolabeled PLGA Nanoparticles for Effective Targeting of Bendamustine in
           Tumor Bearing Mice
    • Authors: Iliyas Khan; Avinash Gothwal; Ankur Kaul; Rashi Mathur; Anil Kumar Mishra; Umesh Gupta
      Abstract: Purpose Bendamustine is an important drug for the treatment of chronic lymphatic leukaemia (CLL), non-Hodgkin lymphoma (NHL). However, its delivery is challenging due to its instability. Current approach reports the development and characterization of bendamustine encapsulated PLGA nanoparticles for the effective targeting to leukemic cells. Methods The prepared, bendamustine loaded PLGA nanoparticles (BLPNP) were developed and characterized for particle size, zeta potential and polydispersity index. The formed nanoparticles were further characterized with the help of electron microscopy for surface morphology. The formed nanoparticles were evaluated for cytotoxicity, cell uptake, ROS and cell apoptosis against THP-1 leukemic cells as a part of in vitro evaluation. In vivo organ bio-distribution and tumor regression studies were performed to track in vivo behaviour of BLPNP. Results The average particle size was 138.52 ± 3.25 nm, with 0.192 ± 0.036 PDI and − 25.4 ± 1.38 mV zeta potential. TEM images revealed the homogeneous particle size distribution with uniform shape. In vitro release exhibited a sustained drug-release behaviour up to 24 h. Cytotoxicity against THP-1 cells through MTT assay observed IC50 value of 27.8 ± 2.1 μM for BLPNP compared to pure drug, which was 50.42 ± 3.4 μM. Moreover, in vitro studies like cell-uptake and cell apoptosis studies further confirmed the higher accumulation of BLPNP in comparison to the pure drug. Organ distribution and tumor regression studies were performed to track in vivo behaviour of bendamustine loaded nanoparticles. Conclusion The overall study described a promising approach in terms of safety, least erythrocytic toxicity, better IC50 value with enhance tumor targeting and regression.
      PubDate: 2018-08-31
      DOI: 10.1007/s11095-018-2482-6
      Issue No: Vol. 35, No. 11 (2018)
  • Fabrication of TPGS-Stabilized Liposome-PLGA Hybrid Nanoparticle Via a New
           Modified Nanoprecipitation Approach: In Vitro and In Vivo Evaluation
    • Authors: Mengyuan Zhang; Jianhua He; Wenli Zhang; Jianping Liu
      Abstract: Purpose In this study, a new modified nanoprecipitation approach that more efficient and simpler than conventional approach was developed to synthesize D-alpha-Tocopheryl polyethylene glycol 1000 succinate stabilized liposome-PLGA hybrid nanoparticle, loaded with simvastatin (ST-TLPN). Methods The optimum formulation was screened via investigation of the impact of TPGS mass within polymeric core and lipid shell on the physicochemical properties of nanoparticles respectively. FTIR, and drug release of ST-TLPN were also systematically determined. Finally, the cellular internalization was evaluated using the murine macrophage cell line, in vivo pharmacokinetic behavior and antiatherogenic efficacies were elaborately examined in atherosclerotic rabbit models. Results With the weight ratio of TPGS-to-PLGA in organic phase of 30% and TPGS-to-lipid in aqueous phase of 35%, ST-TLPN exhibited core-shell structure, sub-100 nm size, EE% of over 90% and a slow release profile. The excellent cellular uptake was displayed in RAW264.7 cell line. Improved pharmacokinetic behavior, and enhanced antiatherogenic efficacy of ST-TLPN in the model animals were also revealed compared with ST-loaded PLGA nanoparticles. Conclusion These findings suggest the modified nanoprecipitation method holds great potential for fabricating LPN, aided by the multiple functions of TPGS. And the prepared TLPN is a promising delivery system for use in the pharmaceutical field.
      PubDate: 2018-08-30
      DOI: 10.1007/s11095-018-2485-3
      Issue No: Vol. 35, No. 11 (2018)
  • Orcinol Glucoside Loaded Polymer - Lipid Hybrid Nanostructured Lipid
           Carriers: Potential Cytotoxic Agents against Gastric, Colon and Hepatoma
           Carcinoma Cell Lines
    • Authors: Prasant Nahak; Rahul L. Gajbhiye; Gourab Karmakar; Pritam Guha; Biplab Roy; Shila Elizabeth Besra; Alexey G. Bikov; Alexander V. Akentiev; Boris A. Noskov; Kaushik Nag; Parasuraman Jaisankar; Amiya Kumar Panda
      Abstract: Purpose Orcinol glucoside (OG) - loaded nanostructured lipid carrier (NLC), coated with polyethylene glycol-25/55-stearate (PEG-25/55-SA), were explored for delivering OG to improve in vitro cytotoxicity against gastrointestinal tract (GIT), colon and hepatoma carcinoma cell lines. It is being expected that the PEGylated formulations would possess the sustainability in withstanding the adverse physiological extremities like the most significant metabolic activities and phase I / II enzymatic activities in the intestines. Methods NLCs were prepared using tristearin, oleic acid and PEG-25/55-stearate by hot homogenization-ultrasonic dispersion; characterized by DLS, TEM, SEM, AFM, entrapment efficiency and drug loading capacity studies. Results NLC diameter ranged from 160 to 230 nm with negative zeta potential of −8 to −20 mV. TEM/SEM and AFM studies suggest spherical and smooth surface morphologies. Differential scanning calorimetry studies reveal the loss of crystallinity when OG was incorporated into the NLC. NLCs showed initial burst release, followed by sustained release of OG. PEG-NLC exhibited superior anticancer activity against GIT and also in hepatoma cancer cell lines. Conclusions This is the first report demonstrating a practical approach for possible oral delivery of OG in GIT and targeting hepatoma cancer, warranting further in vivo studies for superior management of GIT cancer.
      PubDate: 2018-08-27
      DOI: 10.1007/s11095-018-2469-3
      Issue No: Vol. 35, No. 10 (2018)
  • Hyaluronic Acid Layer-By-Layer (LbL) Nanoparticles for Synergistic
    • Authors: Juan Zhao; Zhuoya Wan; Chuchu Zhou; Qin Yang; Jianxia Dong; Xu Song; Tao Gong
      Abstract: Purpose The aim of this study was to design hyaluronic acid (HA) layer-by-layer (LbL) nanoparticles, which carried paclitaxel (PTX) and Indocyanine green (ICG) to both tumor cells and tumor associated cells to achieve synergistic chemo-photothermal therapeutic effect. Methods The LbL-engineered nanoparticles (PDIH) were prepared by dopamine self-polymerization on PTX nanocrystal to form thin, surface-adherent polydopamine (PDA) films, which subsequently absorbed ICG and HA. The tumor cell and tumor associated cell targeting and antitumor efficacy of PDIH were investigated both in vitro an in vivo using 4 T1 murine mammary cancer cell lines and mice bearing orthotopic 4 T1 breast tumor. Results PDIH presented a long-rod shape in TEM and showed enhanced photothermal effect and cytotoxicity upon NIR laser irradiation both in vitro and in vivo. PDIH also displayed high target ability to CD44 overexpressed tumor cells and tumor associated cells mediated by HA. In vivo antitumor study indicated that PDIH therapeutic strategy could achieve remarkable antitumor efficacy. Conclusion PDIH showed excellent tumor-targeting property and chemo-photothermal therapeutic efficacy.
      PubDate: 2018-08-24
      DOI: 10.1007/s11095-018-2480-8
      Issue No: Vol. 35, No. 10 (2018)
  • In Silico Prediction of Major Clearance Pathways of Drugs among 9 Routes
           with Two-Step Support Vector Machines
    • Authors: Naomi Wakayama; Kota Toshimoto; Kazuya Maeda; Shun Hotta; Takashi Ishida; Yutaka Akiyama; Yuichi Sugiyama
      Abstract: Purpose The clearance pathways of drugs are critical elements for understanding the pharmacokinetics of drugs. We previously developed in silico systems to predict the five clearance pathway using a rectangular method and a support vector machine (SVM). In this study, we improved our classification system by increasing the number of clearance pathways available for our prediction (CYP1A2, CYP2C8, CYP2C19, and UDP-glucuronosyl transferases (UGTs)) and by accepting multiple major pathways. Methods Using the four default descriptors (charge, molecular weight, logD at pH 7.0, and unbound fraction in plasma), three kinds of SVM-based predictors based on traditional single-step approach or two-step focusing approaches with subset or partition clustering were developed. The two-step approach with subset clustering resulted in the highest prediction performance. The feature-selection of additional descriptors based on a greedy algorithm was employed to further improve the predictability. Results The prediction accuracy for each pathway was increased to more than 0.83 with the exception of CYP2C19 and UGTs pathways, whose accuracies were below 0.7. Prediction performance of CYP1A2, CYP3A4 and renal excretion pathways were found to be acceptable using external dataset. Conclusions We successfully constructed a novel SVM-based predictor for the multiple major clearance pathways based on chemical structures.
      PubDate: 2018-08-24
      DOI: 10.1007/s11095-018-2479-1
      Issue No: Vol. 35, No. 10 (2018)
  • Formulation of High-Performance Dry Powder Aerosols for Pulmonary Protein
    • Authors: Erin M. Wilson; J. Christopher Luft; Joseph M. DeSimone
      Abstract: Purpose Pulmonary delivery of biologics is of great interest, as it can be used for the local treatment of respiratory diseases or as a route to systemic drug delivery. To reach the full potential of inhaled biologics, a formulation platform capable of producing high performance aerosols without altering protein native structure is required. Methods A formulation strategy using Particle Replication in Non-wetting Templates (PRINT) was developed to produce protein dry powders with precisely engineered particle morphology. Stability of the incorporated proteins was characterized and the aerosol properties of the protein dry powders was evaluated in vitro with an Andersen Cascade Impactor (ACI). Results Model proteins bovine serum albumin (BSA) and lysozyme were micromolded into 1 μm cylinders composed of more than 80% protein, by mass. Extensive characterization of the incorporated proteins found no evidence of alteration of native structures. The BSA formulation produced a mass median aerodynamic diameter (MMAD) of 1.77 μm ± 0.06 and a geometric standard deviation (GSD) of 1.51 ± 0.06 while the lysozyme formulation had an MMAD of 1.83 μm ± 0.12 and a GSD of 1.44 ± 0.03. Conclusion Protein dry powders manufactured with PRINT could enable high-performance delivery of protein therapeutics to the lungs.
      PubDate: 2018-08-23
      DOI: 10.1007/s11095-018-2452-z
      Issue No: Vol. 35, No. 10 (2018)
  • Efficient Nose-to-Lung Aerosol Delivery with an Inline DPI Requiring Low
           Actuation Air Volume
    • Authors: Dale Farkas; Michael Hindle; P. Worth Longest
      Abstract: Purpose To demonstrate efficient aerosol delivery through an in vitro nasal model using a dry powder inhaler (DPI) requiring low actuation air volumes (LV) applied during low-flow nasal cannula (LFNC) therapy. Methods A previously developed LV-DPI was connected to a LFNC system with 4 mm diameter tubing. System connections and the nasal cannula interface were replaced with streamlined components. To simulate nasal respiration, an in vitro nasal model was connected to a downstream lung simulator that produced either passive or deep nasal respiration. Performance of a commercial mesh nebulizer system was also considered. Results For the optimized system, steady state cannula emitted dose was 75% of the capsule loaded dose. With cyclic nasal breathing, delivery efficiency to the tracheal filter was 53–55% of the loaded dose, which was just under the design target of 60%. Compared with a commercially available mesh nebulizer, the optimal LV-DPI was 40-fold more efficient and 150 times faster in terms of delivering aerosol to the lungs. Conclusions The optimized LV-DPI system is capable of high efficiency lung delivery of powder aerosols through a challenging nasal cannula interface.
      PubDate: 2018-08-21
      DOI: 10.1007/s11095-018-2473-7
      Issue No: Vol. 35, No. 10 (2018)
  • In Silico Prediction of Diffusion Interaction Parameter (k D ), a Key
           Indicator of Antibody Solution Behaviors
    • Authors: Dheeraj S. Tomar; Satish K. Singh; Li Li; Matthew P. Broulidakis; Sandeep Kumar
      Abstract: Purpose To develop resource-sparing in silico approaches that aim to reduce experimental effort and material required by developability assessments (DA) of monoclonal antibody (mAb) drug candidates. Methods A battery of standardized biophysical experiments was performed on high concentration formulations of 16 drug product development stage mAbs using a platform buffer. Full-length molecular models of these mAbs were also generated via molecular modeling. These models were used to computationally estimate molecular descriptors of these 16 mAbs. Pairwise and multi-parameter correlations among experimentally measured biophysical attributes and calculated molecular descriptors were obtained via statistical analyses. Results Diffusion interaction parameter (kD) showed statistically significant pairwise correlations (p-values <0.005) with thermal stability, viscosity, isoelectric point, and apparent solubility of the antibodies in our dataset. kD also showed statistically significant pairwise correlations (p-values <0.005) with several computationally calculated molecular descriptors (pI, net charge, charge on the Fv region, and zeta potential.) These pairwise correlations were further refined by multivariate analyses. These analyses yielded several useful equations for prediction of kD from antibody sequences, structural models, and experimentally measured biophysical attributes. Conclusions Diffusion interaction parameter (kD) was found to be a key biophysical property for the mAbs in our dataset. It connects conformational heterogeneity of an antibody with its colloidal and rheological behaviors. The equations derived in this work shall enable rapid, resource-sparing, and cost-effective DAs of biologic drug candidates.
      PubDate: 2018-08-20
      DOI: 10.1007/s11095-018-2466-6
      Issue No: Vol. 35, No. 10 (2018)
  • Doing it All - How Families are Reshaping Rare Disease Research
    • Authors: Sean Ekins; Ethan O. Perlstein
      Abstract: Abstract The face of rare disease drug discovery and development is changing right before our eyes. The outliers of the past were the plucky parents who summoned up the courage to try to treat their children against all odds. Think of the rare disease focused movies ‘Lorenzo’s Oil’ and ‘Extraordinary Measures’ but now accelerated to develop treatments even quicker. Parents, patient advocates and their collaborators are now capable of doing it all themselves. We think this will have profound implications for everyone from the incumbent rare disease foundations that have held sway for decades to the multibillion dollar rare disease market, BioPharma companies, VCs and angel investors that inhabit this space. The repercussions of this disruption will no doubt impact healthcare in general and ultimately influence how we develop treatments for major diseases as well. We present several lines of evidence for our viewpoint from our personal experiences interacting with many rare disease families and patient advocates in recent years.
      PubDate: 2018-08-16
      DOI: 10.1007/s11095-018-2481-7
      Issue No: Vol. 35, No. 10 (2018)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
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