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Indexing & Abstracting Of
Pharmaceutical Research
YEAR 2017
Published by
LIBRARY & INFORMATION CENTRE
INDIAN PHARMACOPOEIA COMMISSION MINISTRY OF HEALTH & FAMILY WELFARE
GOVERNMENT OF INDIA
GHAZIABAD (UP)
i
INDEX
S.No. Contents Page No.
Volume 34, Issue 1, January 2017
1. Enabling Anyone to Translate Clinically Relevant Ideas to Therapies 01
2. Clinical Pharmacology Studies in Critically Ill Children 01
3. Aerosolization, Drug Permeation and Cellular Interaction of Dry Powder Pulmonary Formulat-
ions of Corticosteroids with Hydroxypropyl-β-Cyclodextrin as a Solubilizer 02
4. Novel Fish Oil-based Bigel System for Controlled Drug Delivery and its Influence on Immun-
omodulatory Activity of Imiquimod against Skin Cancer 03
5. Estimation of Intra-vitreal Half-Lifes in the Rabbit Eye with Semi-mechanistic Equations 03
6. Matrix Metalloproteinase Responsive Delivery of Myostatin Inhibitors 04
7. LC-MS/MS Method for Quantifying Adenosine, Guanosine and Inosine Nucleotides in Human
Cells 04
8. Degradation Mechanisms of Polysorbate 20 Differentiated by 18O-labeling and Mass Spectro-
metry 05
9. Bleomycin-Coated Microneedles for Treatment of Warts 06
10. Online Spectroscopic Monitoring of Drug Release Kinetics from Nanostructured Dual-Stimuli-
Responsive Conducting Polymer 07
11. Increased Active Tumor Targeting by An αvβ3-Targeting and Cell-Penetrating Bifunctional
Peptide-Mediated Dendrimer-Based Conjugate 07
12. Sugar-Modified Poly (propylene imine) Dendrimers Stimulate the NF-κB Pathway in a Myeloid
Cell Line 08
13. Tumor Targeting Synergistic Drug Delivery by Self-Assembled Hybrid Nanovesicles to
Overcome Drug Resistance 09
14. Intracellular Delivery of Nanobodies for Imaging of Target Proteins in Live Cells 10
15. Therapeutic Effects of AICAR and DOX Conjugated Multifunctional Nanoparticles in Sensiti-
zation and Elimination of Cancer Cells via Survivin Targeting 11
16. Population Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis of LY3015014, a Mo-
noclonal Antibody to Protein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Healthy Subjects
and Hypercholesterolemia Patients 12
17. Contrasting the Influence of Cationic Amino Acids on the Viscosity and Stability of a Highly
Concentrated Monoclonal Antibody 13
ii
18. Physicochemical Properties of Solid Phospholipid Particles as a Drug Delivery Platform for
Improving Oral Absorption of Poorly Soluble Drugs 14
19. The Tritiated Water Skin Barrier Integrity Test: Considerations for Acceptance Criteria with and
Without 14C-Octanol 15
20. Photo-oxidation of IgG1 and Model Peptides: Detection and Analysis of Triply Oxidized His and
Trp Side Chain Cleavage Products 16
Volume 34, Issue 2, February 2017
21. Role of Knowledge Management in Development and Lifecycle Management of Biopharmace-
uticals 16
22. Triple Drug Combination of Zidovudine, Efavirenz and Lamivudine Loaded Lactoferrin Nano-
particles: an Effective Nano First-Line Regimen for HIV Therapy 17
23. Improvement in Thermal Stability of Sucralose by γ-Cyclodextrin Metal-Organic Frame-
works 18
24. Comparative Study of Different Nano-Formulations of Curcumin for Reversal of Doxorubicin
Resistance in K562R Cells 19
25. SPECT-CT Comparison of Lung Deposition using a System combining a Vibrating-mesh Nebu-
lizer with a Valved Holding Chamber and a Conventional Jet Nebulizer: a Randomized Cross-
over Study 20
26. Preparation, Physicochemical Characterization and Anti-fungal Evaluation of Nystatin-Loaded
PLGA-Glucosamine Nanoparticles 21
27. Lipid Nanoparticles Loaded with an Antisense Oligonucleotide Gapmer against Bcl-2 for
Treatment of Lung Cancer 22
28. Multifractal Characterization of Pharmaceutical Hot-Melt Extrudates 23
29. A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Predic-
tion of Human Brain Target Site Concentrations 23
30. Design and In Vitro Evaluation of Bispecific Complexes and Drug Conjugates of Anticancer
Peptide, LyP-1 in Human Breast Cancer 24
31. Denatured Whey Protein Powder as a New Matrix Excipient: Design and Evaluation of
Mucoadhesive Tablets for Sustained Drug Release Applications 25
32. Why Have Clinical Trials of Antioxidants to Prevent Neurodegeneration Failed? - A Cellular In-
vestigation of Novel Phenothiazine-Type Antioxidants Reveals Competing Objectives for Phar-
maceutical Neuroprotection 26
iii
33. Comparison of Dialysis- and Solvatofluorochromism-Based Methods to Determine Drug Release
Rates from Polymer Nanoassemblies 27
34. Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined
with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft 28
35. Electrosprayed Myocet-like Liposomes: An Alternative to Traditional Liposome Production 28
36. Fabricating a Shell-Core Delayed Release Tablet Using Dual FDM 3D Printing for Patient-
Centred Therapy 29
37. Bromelain-Functionalized Multiple-Wall Lipid-Core Nanocapsules: Formulation, Chemical
Structure and Antiproliferative Effect against Human Breast Cancer Cells (MCF-7) 30
38. Bioflavonoid Fisetin Loaded α-Tocopherol-Poly(lactic acid)-Based Polymeric Micelles for Enh-
anced Anticancer Efficacy in Breast Cancers 30
39. Effects of Excipient Interactions on the State of the Freeze-Concentrate and Protein Stability 31
40. A Random Forest Approach for Counting Silicone Oil Droplets and Protein Particles in Anti-
body Formulations Using Flow Microscopy 31
Volume 34, Issue 3, March 2017
41. The Impact of Inspiratory Flow Rate on Drug Delivery to the Lungs with Dry Powder Inha-
lers 32
42. On the Nature of Physiologically-Based Pharmacokinetic Models –A Priori or a Posteriori
Mechanistic or Empirical 32
43. Drug Distribution Part 1. Models to Predict Membrane Partitioning 33
44. Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and
Membrane Partitioning 33
45. Supramolecular Cocrystals of Gliclazide: Synthesis, Characterization and Evaluation 34
46. Pharmacokinetics and Biodistribution of GDC-0449 Loaded Micelles in Normal and Liver
Fibrotic Mice 34
47. Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold
Nanoparticles Labeled with 177Lu 35
48. Intra and Extracellular Biosynthesis and Characterization of Iron Nanoparticles from Prokaryotic
Microorganisms with Anticoagulant Activity 36
49. Modeling the Effect of the Selective S1P1 Receptor Modulator Ponesimod on Subsets of Blood
Lymphocytes 36
iv
50. Biodegradable Polymersomes as Nanocarriers for Doxorubicin Hydrochloride: Enhanced Cytot-
oxicity in MCF-7/ADR Cells and Prolonged Blood Circulation 37
51. Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decre-
ases in Atazanavir Absorption 38
52. Effects of Histidine and Sucrose on the Biophysical Properties of a Monoclonal Antibody 39
53. Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible
Interaction with Skin Barrier Lipids 39
54. Preparation and evaluation of biopolymeric nanoparticles as drug delivery system in effective
treatment of rheumatoid arthritis 40
55. Sequential Exposure of Bortezomib and Vorinostat is Synergistic in Multiple Myeloma Cells 41
Volume 34, Issue 4, April 2017
56. Alternative Animal and Non-Animal Models for Drug Discovery and Development: Bonus or
Burden 41
57. Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on
Human Skin in the Context of the Use of a Nipple Shield Delivery System 42
58. Detection and Specific Elimination of EGFR+ Ovarian Cancer Cells Using a Near Infrared Phot-
oimmunotheranostic Approach 43
59. The Effect of Surface Charges on the Cellular Uptake of Liposomes Investigated by Live Cell
Imaging 43
60. Revealing pMDI Spray Initial Conditions: Flashing, Atomisation and the Effect of Ethanol 44
61. Bioequivalence Methodologies for Topical Drug Products: In Vitro and Ex Vivo Studies with a
Corticosteroid and an Anti-Fungal Drug 44
62. Electrospinnability of Poly Lactic-co-glycolic Acid (PLGA): the Role of Solvent Type and Solv-
ent Composition 45
63. In vitro Phase I- and Phase II-Drug Metabolism in the Liver of Juvenile and Adult Göttingen
Minipigs 45
64. Complex Nature of Protein Carbonylation Specificity after Metal-Catalyzed Oxidation 46
65. Biodegradable Poly (ester-urethane) Carriers Exhibiting Controlled Release of Epirubicin 47
66. Stability and Pharmacological Effects of Gene-Recombinant Wild Type and Mutant Human
Adrenocorticotropic Hormone 47
67. Interference from Proteins and Surfactants on Particle Size Distributions Measured by Nanop-
article Tracking Analysis (NTA) 48
v
68. Nimodipine Ophthalmic Formulations for Management of Glaucoma 48
69. Development of Novel Warfarin-Silica Composite for Controlled Drug Release 49
70. Challenges in Determining Intrinsic Viscosity under Low Ionic Strength Solution Conditions 49
71. In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet
Erosion under Fasting and Postprandial Status 50
72. Mathematical Modelling of Convection Enhanced Delivery of Carmustine and Paclitaxel for
Brain Tumour Therapy 50
73. Evaluation of the Utility of Chimeric Mice with Humanized Livers for the Characterization and
Profiling of the Metabolites of a Selective Inhibitor (YM543) of the Sodium-Glucose Cotran-
sporter 2 51
Volume 34, Issue 5, May 2017
74. A Review of Disintegration Mechanisms and Measurement Techniques 51
75. Microstructure of Tablet—Pharmaceutical Significance, Assessment, and Engineering 52
76. Application of UV Imaging in Formulation Development 52
77. The Properties of HPMC: PEO Extended Release Hydrophilic Matrices and their Response to
Ionic Environments 53
78. Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum
Frequency Generation (SFG) Microscopy 53
79. Characterization of Heterogeneity and Spatial Distribution of Phases in Complex Solid Disper-
sions by Thermal Analysis by Structural Characterization and X-ray Micro Computed Tomogr-
aphy 54
80. The Combined Use of Imaging Approaches to Assess Drug Release from Multicomponent Solid
Dispersions 55
81. The Impact of Granule Density on Tabletting and Pharmaceutical Product Performance 55
82. Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release
Tablets by Terahertz Transmission Measurements 56
83. Visualization and Non-Destructive Quantification of Inkjet-Printed Pharmaceuticals on Different
Substrates Using Raman Spectroscopy and Raman Chemical Imaging 57
84. Analysis of 3D Prints by X-ray Computed Microtomography and Terahertz Pulsed Imaging 57
85. Achieving the Promise of Therapeutic Extracellular Vesicles: the Devil is in Details of Therape-
utic Loading 58
vi
86. Supramolecular Chitosan Micro-Platelets Synergistically Enhance Anti-Candida albicans Acti-
vity of Amphotericin B Using an Immunocompetent Murine Model 58
87. Ocular safety of Intravitreal Clindamycin Hydrochloride Released by PLGA Implants 59
88. Versatile Methodology to Encapsulate Gold Nanoparticles in PLGA Nanoparticles Obtained by
Nano-Emulsion Templating 60
89. Determination of the Porosity of PLGA Microparticles by Tracking Their Sedimentation Velo-
city Using a Flow Imaging Microscope (FlowCAM) 60
90. Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-
Fluorocytosine, and Saline for Sodium Supplementation 61
91. Maturation of Oxycodone Pharmacokinetics in Neonates and Infants: a Population Pharmaco-
kinetic Model of Three Clinical Trials 61
92. Evaluation of the ROS Inhibiting Activity and Mitochondrial Targeting of Phenolic Compounds
in Fibroblast Cells Model System and Enhancement of Efficiency by Natural Deep Eutectic
Solvent (NADES) Formulation 62
Volume 34, Issue 6, June 2017
93. Insights and Lessons from a Scientific Conference on Non-Invasive Delivery of Macromol-
ecules 62
94. Formulation, Delivery and Stability of Bone Morphogenetic Proteins for Effective Bone Regen-
eration 63
95. Combination of SEDDS and Preactivated Thiomer Technology: Incorporation of a Preactivated
Thiolated Amphiphilic Polymer into Self-Emulsifying Delivery Systems 63
96. High Penetration of Paclitaxel in Abdominal Wall of Rabbits after Hyperthermic Intraperitoneal
Administration of Nab-Paclitaxel Compared to Standard Paclitaxel Formulation 64
97. Development of a Level A in Vitro-in Vivo Correlation for Veliparib (ABT-888) Extended
Release Tablet Formulation 64
98. Formulation of a Sustained Release Docetaxel Loaded Cockle Shell-Derived Calcium Carbonate
Nanoparticles against Breast Cancer 65
99. Multiple Lipid Nanoparticles (MLN), a New Generation of Lipid Nanoparticles for Drug Deli-
very Systems: Lamivudine-MLN Experimental Design 66
100. Innovative Microcapsules for Pancreatic β-Cells Harvested from Mature Double-Transgenic
Mice: Cell Imaging, Viability, Induced Glucose-Stimulated Insulin Measurements and Proinfl-
ammatory Cytokines Analysis 67
vii
101. Preclinical Evaluation of the Short-Term Toxicity of 4-(N)-Docosahexaenoyl 2´, 2´- Difluorode-
oxycytidine (DHA-dFdC) 68
102. Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase
Substrate Drugs in Humans 69
103. Vitamin E-rich Nanoemulsion Enhances the Antitumor Efficacy of Low-Dose Paclitaxel by
Driving Th1 Immune Response 69
104. Preparation and Evaluation of PLGA-Coated Capsaicin Magnetic Nanoparticles 70
105. The Cytotoxic Action of Cytochrome C/Cardiolipin Nanocomplex (Cyt-CL) on Cancer Cells in
Culture 71
106. Impact of Micellar Surfactant on Supersaturation and Insight into Solubilization Mechanisms in
Supersaturated Solutions of Atazanavir 72
107. Preparation of Drug-Loaded PLGA-PEG Nanoparticles by Membrane-Assisted Nanoprecipi-
tation 73
108. Inter-Subject Variability in OCT1 Activity in 27 Batches of Cryopreserved Human Hepatocytes
and Association with OCT1 mRNA Expression and Genotype 73
109. Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enha-
ncers 74
110. Velocity Field Visualization in USP Dissolution Apparatus 3 Using Particle Image Veloci-
metry 75
Volume 34, Issue 7, July 2017
111. The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market 75
112. Insights into Nano and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using
Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance
Spectroscopy 76
113. Bilateral Effects of Excipients on Protein Stability: Preferential Interaction Type of Excipient
and Surface Aromatic Hydrophobicity of Protein 77
114. Cyclosporine A Loaded Electrospun Poly (D,L-Lactic Acid)/Poly(Ethylene Glycol) Nanofibers:
Drug Carriers Utilizable in Local Immunosuppression 77
115. Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Regulate the Disposition of
Acacetin Glucuronides 78
116. Mathematical Modeling and Experimental Validation of Nanoemulsion-Based Drug Transport
across Cellular Barriers 79
viii
117. An Efficient and Rapid Method to Monitor the Oxidative Degradation of Protein Pharmaceu-
ticals: Probing Tyrosine Oxidation with Fluorogenic Derivatization 80
118. Exploring the Carbamazepine Interaction with Human Pregnane X Receptor and Effect on ABC-
C2 Using in Vitro and in Silico Approach 80
119. Continuous Transdermal Delivery of L-DOPA Based on a Self-Assembling Nanomicellar
System 81
120. Photochemically Controlled Drug Dosing from a Polymeric Scaffold 81
121. A Trivalent Enzymatic System for Uricolytic Therapy of HPRT Deficiency and Lesch-Nyhan
Disease 82
122. Characterization of Temperature Profiles in Skin and Transdermal Delivery System When
Exposed to Temperature Gradients In Vivo and In Vitro 82
123. Improved Stability and Enhanced Oral Bioavailability of Atorvastatin Loaded Stearic Acid
Modified Gelatin Nanoparticles 83
124. Anti-Inflammatory Therapeutic Effect of Adiponectin Gene Delivery Using a Polymeric Carrier
in an Acute Lung Injury Model 83
125. Development of In Vitro-In Vivo Correlation for Potassium Chloride Extended Release Tablet
Formulation Using Urinary Pharmacokinetic Data 84
Volume 34, Issue 8, August 2017
126. Personalized Drug Dosage – Closing the Loop 84
127. The Routine Clinical use of Pharmacogenetic Tests: What it Will Require 84
128. Preemptive Panel-Based Pharmacogenetic Testing: The Time is Now 85
129. Therapeutic Drug Monitoring of Golimumab in the Treatment of Ulcerative Colitis 85
130. Are Polymorphisms in Genes Relevant to Drug Disposition Predictors of Susceptibility to Drug-
Induced Liver Injury 86
131. A Clinical Cassette Dosing Study for Evaluating the Contribution of Hepatic OATPs and
CYP3A to Drug-Drug Interactions 86
132. Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues
Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect
of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects 87
133. Transmembrane Domain Single-Nucleotide Polymorphisms Impair Expression and Transport
Activity of ABC Transporter ABCG2 87
ix
134. Investigation of Glycochenodeoxycholate Sulfate and Chenodeoxycholate Glucuronide as
Surrogate Endogenous Probes for Drug Interaction Studies of OATP1B1 and OATP1B3 in
Healthy Japanese Volunteers 88
135. CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Fail-
ure 88
136. In Vitro Transport Activity and Trafficking of MRP2/ABCC2 Polymorphic Variants 89
137. Regulatory Variants Modulate Protein Kinase C α (PRKCA) Gene Expression in Human
Heart 89
138. Network Reconstruction Reveals that Valproic Acid Activates Neurogenic Transcriptional
Programs in Adult Brain Following Traumatic Injury 90
139. RLIP76 Inhibition: A Promising Developmental Therapy for Neuroblastoma 90
140. A Functional Iron Oxide Nanoparticles Modified with PLA-PEG-DG as Tumor-Targeted MRI
Contrast Agent 91
141. Mesoporous Silica Nanoparticle-Coated Microneedle Arrays for Intradermal Antigen Deli-
very 91
142. Effect of Relative Humidity on Bipolar Electrostatic Charge Profiles of dry Powder Aerosols 92
143. Systematic Investigation of the Role of Surfactant Composition and Choice of oil: Design of a
Nanoemulsion-Based Adjuvant Inducing Concomitant Humoral and CD4+ T-Cell Responses 92
144. Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensi-
tive Block Copolymer Hydrogels 93
145. Selection of P-Glycoprotein Inhibitor and Formulation of Combinational Nanoformulation Cont-
aining Selected Agent Curcumin and DOX for Reversal of Resistance in K562 Cells 93
Volume 34, Issue 9, September 2017
146. High-Tech Drugs in Creaky Formulations 94
147. The Need for Restructuring the Disordered Science of Amorphous Drug Formulations 94
148. Polycaprolactone Based Nanoparticles Loaded with Indomethacin for Anti-Inflammatory
Therapy: From Preparation to Ex Vivo Study 95
149. Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-
Induced Dermal Blood Flow in Healthy and Migraine Subjects 96
150. Impact of the Charge Ratio on the In Vivo Immunogenicity of Lipoplexes 96
151. Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent
Solubility of Poorly Water-Soluble Compounds 97
x
152. On the Road to Development of an in Vitro Permeation Test (IVPT) Model to Compare Heat
Effects on Transdermal Delivery Systems: Exploratory Studies with Nicotine and Fentanyl 97
153. High Throughput Prediction Approach for Monoclonal Antibody Aggregation at High
Concentration 98
154. Doxorubicin Hydrochloride Loaded Zymosan-Polyethylenimine Biopolymeric Nanoparticles for
Dual ‗Chemoimmunotherapeutic‘ Intervention in Breast Cancer 98
155. A Two-way Randomized Cross-over Pharmacokinetic and Pharmacodynamic Study of an Inno-
vative Oral Solution of Midazolam (ADV6209) 99
156. The Cardiotoxic Mechanism of Doxorubicin (DOX) and Pegylated Liposomal DOX in Mice
Bearing C-26 Colon Carcinoma: a Study focused on microRNA Role for Toxicity Assessment of
New Formulations 100
157. Design of Isoniazid Smart Nanogel by Gamma Radiation-Induced Template Polymerization for
Biomedical Application 101
158. Design and Evaluation of RGD-Modified Gemini Surfactant-Based Lipoplexes for Targeted
Gene Therapy in Melanoma Model 101
159. Chemoprevention of Breast Cancer by Transdermal Delivery of α-Santalol through Breast Skin
and Mammary Papilla (Nipple) 102
160. Diclofenac Loaded Lipid Nanovesicles Prepared by Double Solvent Displacement for Skin Drug
Delivery 102
161. Influence of Ethanol on Darunavir Hepatic Clearance and Intracellular PK/PD in HIV-Infected
Monocytes, and CYP3A4-Darunavir Interactions Using Inhibition and in Silico Binding
Studies 103
162. Increasing the Bile Acid Sequestration Performance of Cationic Hydrogels by Using an
Advanced/Controlled Polymerization Technique 103
163. Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First
Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycoba-
cterium Tuberculosis 104
164. Multi-Reservoir Phospholipid Shell Encapsulating Protamine Nanocapsules for Co-Delivery of
Letrozole and Celecoxib in Breast Cancer Therapy 105
165. Expression, Purification and Characterization of GMZ2‘.10C, a Complex Disulphide-Bonded
Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-
Causing Plasmodium falciparum Parasite 106
https://link.springer.com/article/10.1007/s11095-017-2201-8https://link.springer.com/article/10.1007/s11095-017-2201-8
xi
Volume 34, Issue 10, October 2017
166. Reflections on the Future of Pharmaceutical Public-Private Partnerships: From Input to Imp-
act 106
167. Optimizing the Bioavailability of Subcutaneously Administered Biotherapeutics Through Mech-
anochemical Drivers 107
168. Scanning Electron Microscope Observations of Powder Sticking on Punches during a Limited
Number (N < 5) of Compactions of Acetylsalicylic Acid 107
169. Drug Delivery Nanoparticles with Locally Tunable Toxicity Made Entirely from a Light-Activa-
table Prodrug of Doxorubicin 108
170. Development of a Two-Dimensional Model for Predicting Transdermal Permeation with the
Follicular Pathway: Demonstration with a Caffeine Study 108
171. Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after
Deposition 109
172. Computational Analysis on Down-Regulated Images of Macrophage Scavenger Receptor 110
173. Gentamicin-Loaded Polysaccharide Membranes for Prevention and Treatment of Post-operative
Wound Infections in the Skeletal System 111
174. Anti-Tuberculosis Bacteriophage D29 Delivery with a Vibrating Mesh Nebulizer, Jet Nebulizer,
and Soft Mist Inhaler 112
175. Galactosyl Pentadecene Reversibly Enhances Transdermal and Topical Drug Delivery 112
176. Item Response Theory as an Efficient Tool to Describe a Heterogeneous Clinical Rating Scale in
De Novo Idiopathic Parkinson‘s Disease Patients 113
177. Individual Bayesian Information Matrix for Predicting Estimation Error and Shrinkage of
Individual Parameters Accounting for Data below the Limit of Quantification 113
178. Influence of Molecular size on the clearance of antibody fragments 114
179. Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus
Formulations Exposed to Different Stress Conditions 114
180. Hemodynamic Effects of Lipid-Based Oxygen Microbubbles via Rapid Intravenous Injection in
Rodents 115
181. A Dose Ranging Pharmacokinetic Evaluation of IQP-0528 Released from Intravaginal Rings in
Non-Human Primates 116
182. Chitooligosaccharides Modified Reduction-Sensitive Liposomes: Enhanced Cytoplasmic Drug
Delivery and Osteosarcomas-Tumor Inhibition in Animal Models 117
xii
183. Design, Preparation and Evaluation of HPMC-Based PAA or SA Freeze-Dried Scaffolds for
Vaginal Delivery of Fluconazole 118
184. Rhamnolipids Enhance in Vivo Oral Bioavailability of Poorly Absorbed Molecules 118
185. Injectable Sustained-Release Depots of PLGA Microspheres for Insoluble Drugs Prepared by
hot-Melt Extrusion 119
Volume 34, Issue 11, November 2017
186. Dissolving Microneedle Patches for Dermal Vaccination 119
187. BITC and S-Carvone Restrain High-Fat Diet-Induced Obesity and Ameliorate Hepatic Steatosis
and Insulin Resistance 120
188. Effect of Aggregation on the Hydrodynamic Properties of Bovine Serum Albumin 120
189. Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmaco-
kinetic Study 121
190. Rapid-Acting and Human Insulins: Hexamer Dissociation Kinetics upon Dilution of the
Pharmaceutical Formulation 122
191. Precision Ocular Drug Delivery via Aerosol Ring Vortices 122
192. Novel Gemcitabine Conjugated Albumin Nanoparticles: a Potential Strategy to Enhance Drug
Efficacy in Pancreatic Cancer Treatment 123
193. Rheological Characterization of Molten Polymer-Drug Dispersions as a Predictive Tool for
Pharmaceutical Hot-Melt Extrusion Processability 124
194. Long Acting Ionically Paired Embonate Based Nanocrystals of Donepezil for the Treatment of
Alzheimer‘s Disease: a Proof of Concept Study 125
195. Role of the OATP Transporter Family and a Benzbromarone-SensitiveEfflux Transporter in the
Hepatocellular Disposition of Vincristine 126
196. In Silico Absorption Analysis of Valacyclovir in Wildtype and Pept1 Knockout Mice Following
Oral Dose Escalation 127
197. Elucidation of the Mechanism of Increased Activity of Immunostimulatory DNA by the
Formation of Polypod-like Structure 127
198. Liposomes co-Loaded with 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3 (PFKFB3)
shRNA Plasmid and Docetaxel for the Treatment of non-small Cell Lung Cancer 128
199. Development of Halofluorochromic Polymer Nanoassemblies for the Potential Detection of
Liver Metastatic Colorectal Cancer Tumors Using Experimental and Computational Appro-
aches 129
xiii
200. Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case
Example of a Late-Stage Discovery Compound 130
201. Utility of Göttingen minipigs for Prediction of Human Pharmacokinetic Profiles after Dermal
Drug Application 131
202. Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin 132
203. Post-Synthetic Modification Nanoscale Metal-Organic Frameworks for Targeted Drug Delivery
in Cancer Cells 132
Volume 34, Issue 12, December 2017
204. Biocompatible Synthetic Lung Fluid Based on Human Respiratory Tract Lining Fluid
Composition 133
205. Morphometric Characterization of Rat and Human Alveolar Macrophage Cell Models and their
Response to Amiodarone using High Content Image Analysis 134
206. Expression and Activity of Breast Cancer Resistance Protein (BCRP/ABCG2) in Human Distal
Lung Epithelial Cells in Vitro 135
207. Oligopeptide Transport in Rat Lung Alveolar Epithelial Cells is Mediated by Pept2 136
208. The Differential Absorption of a Series of P-Glycoprotein Substrates in Isolated Perfused Lungs
from Mdr1a/1b Genetic Knockout Mice can be Attributed to Distinct Physico-Chemical
Properties: an Insight into Predicting Transporter-Mediated, Pulmonary Specific Disposition 137
209. Endocytic Uptake, Transport and Macromolecular Interactions of Anionic PAMAM Dendrimers
within Lung Tissue 138
210. A Comparison of Drug Transport in Pulmonary Absorption Models: Isolated Perfused rat Lungs,
Respiratory Epithelial Cell Lines and Primary Cell Culture 139
211. Predicting Pulmonary Pharmacokinetics from In Vitro Properties of Dry Powder Inhalers 140
212. Benchmarking of Human Dose Prediction for Inhaled Medicines from Preclinical In Vivo
Data 141
213. Good Things in Small Packages: an Innovative Delivery Approach for Inhaled Insulin 142
214. Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer 143
215. Model-Based Methods in the Biopharmaceutical Process Lifecycle 143
216. Metformin – a Future Therapy for Neurodegenerative Diseases 144
217. Biophysical Aspects of Alzheimer‘s Disease: Implications for Pharmaceutical Sciences 144
218. Endothelial LRP1 – A Potential Target for the Treatment of Alzheimer‘s Disease 145
xiv
219. Disease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer‘s
Disease 145
220. Multiparticulate Delivery System for Potential Colonic Targeting Using Bovine Serum Albumin
as a Model Protein 146
221. Study of Moisture Sorption and Dielectric Processes of Starch and Sodium Starch Glycolate 147
222. Melt Extrusion of High-Dose Co-Amorphous Drug-Drug Combinations 148
223. Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of
Radiation-Induced Lung Injury 149
224. miR-542-3p Appended Sorafenib/All-trans Retinoic Acid (ATRA)-Loaded Lipid Nanoparticles
to Enhance the Anticancer Efficacy in Gastric Cancers 149
225. Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model
Development, Dose Selection for First Time in Children and PK Study Design 150
226. Delivery of HSP90 Inhibitor Using Water Soluble Polymeric Conjugates with High Drug
Payload 151
227. Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and
Elvitegravir Loaded Nanoparticles in Humanized Mice Model 152
228. Photodegradation Pathways of Protein Disulfides: Human Growth Hormone 153
229. Purification of Drug Loaded PLGA Nanoparticles Prepared by Emulsification Solvent
Evaporation Using Stirred Cell Ultrafiltration Technique 154
230. In Vitro-In Vivo Relationship of Amorphous Insoluble API (Progesterone) in PLGA
Microspheres 155
231. Folate Conjugated Hybrid Nanocarrier for Targeted Letrozole Delivery in Breast Cancer
Treatment 155
232. Administration of a Sol-Gel Formulation of Phenylephrine Using Low-Temperature Hollow
Microneedle for Treatment of Intermittent Fecal Incontinence 156
233. Chemical and Biophysical Characteristics of Monoclonal Antibody Solutions Containing
Aggregates Formed during Metal Catalyzed Oxidation 157
234. Co-Delivery of Doxorubicin and survivin shRNA-Expressing Plasmid via Microenvironment-
Responsive Dendritic Mesoporous Silica Nanoparticles for Synergistic Cancer Therapy 158
235. Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissol-
ution 159
236. Multidose Preservative Free Eyedrops by Selective Removal of Benzalkonium Chloride from
Ocular Formulations 160
xv
237. A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in L6 Myotubes and
Augments Insulin Secretion from Pancreatic Beta-Cells by Activating AMPK 161
238. EphA2 Targeted Doxorubicin-Nanoliposomes for Osteosarcoma Treatment 162
239. Dependence of Friability on Tablet Mechanical Properties and a Predictive Approach for Binary
Mixtures 163
240. Nanoparticulate Impurities Isolated from Pharmaceutical-Grade Sucrose Are a Potential Threat
to Protein Stability 164
241. Microradiopharmaceutical for Metastatic Melanoma 165
***
1
Volume 34, Issue 1, January 2017
Enabling Anyone to Translate Clinically Relevant Ideas to Therapies
Sean Ekins Natalie DiazJulia ChungPaul MathewsAaron McMurtray
ABSTRACT
How do we inspire new ideas that could lead to potential treatments for rare or neglected diseases, and
allow for serendipity that could help to catalyze them? How many potentially good ideas are lost
because they are never tested? What if those ideas could have lead to new therapeutic approaches and
major healthcare advances? If a clinician or anyone for that matter, has a new idea they want to test to
develop a molecule or therapeutic that they could translate to the clinic, how would they do it without
a laboratory or funding? These are not idle theoretical questions but addressing them could have
potentially huge economic implications for nations. If we fail to capture the diversity of ideas and test
them we may also lose out on the next blockbuster treatments. Many of those involved in the process
of ideation may be discouraged and simply not know where to go. We try to address these questions
and describe how there are options to raising funding, how even small scale investments can foster
preclinical or clinical translation, and how there are several approaches to outsourcing the experiments,
whether to collaborators or commercial enterprises. While these are not new or far from complete
solutions, they are first steps that can be taken by virtually anyone while we work on other solutions to
build a more concrete structure for the ―idea—hypothesis testing—proof of concept—translation—
breakthrough pathway‖.
Clinical Pharmacology Studies in Critically Ill Children
Nilay ThakkarSara SalernoChristoph P. HornikDaniel Gonzalez
ABSTRACT
Developmental and physiological changes in children contribute to variation in drug disposition with
age. Additionally, critically ill children suffer from various life-threatening conditions that can lead to
pathophysiological alterations that further affect pharmacokinetics (PK). Some factors that can alter
PK in this patient population include variability in tissue distribution caused by protein binding
changes and fluid shifts, altered drug elimination due to organ dysfunction, and use of medical
interventions that can affect drug disposition (e.g., extracorporeal membrane oxygenation and
continuous renal replacement therapy). Performing clinical studies in critically ill children is
challenging because there is large inter-subject variability in the severity and time course of organ
dysfunction; some critical illnesses are rare, which can affect subject enrollment; and critically ill
children usually have multiple organ failure, necessitating careful selection of a study design. As a
result, drug dosing in critically ill children is often based on extrapolations from adults or non-
critically ill children. Dedicated clinical studies in critically ill children are urgently needed to identify
optimal dosing of drugs in this vulnerable population. This review will summarize the effect of critical
illness on pediatric PK, the challenges associated with performing studies in this vulnerable
subpopulation, and the clinical PK studies performed to date for commonly used drugs.
2
Aerosolization, Drug Permeation and Cellular Interaction of Dry Powder Pulmonary
Formulations of Corticosteroids with Hydroxypropyl-β-Cyclodextrin as a Solubilizer
Ville VartiainenLuis M. Bimbo Jouni HirvonenEsko I. KauppinenJanne Raula
ABSTRACT
Purpose: The purpose of this study was to assess the feasibility of hydroxypropyl-β-cyclodextrin as a
solubilizer for the corticosteroids prednisolone and fludrocortisone acetate in dry powder inhalation
formulations.
Methods: The dry particles were simultaneously produced and coated with nanosized L-leucine
crystals using an aerosol flow reactor method. The aerosolization performances of carrier-free powders
were studied using Easyhaler® and Twister™ at 2 and 4 kPa pressure drops over the inhalers. Drug
permeation properties of the formulations were tested across a Calu-3 cell monolayer. Toxicity and
reactive oxygen species induction were tested against Calu-3 and A549 cell lines.
Results: The hydroxypropyl-β-cyclodextrin in the powders promoted the dissolution of
fludrocortisone the most followed by that of prednisolone. Fine particle fractions were 52–70% from
emitted doses which showed good repeatability with a coefficient variation of 0.9–0.17. In addition,
hydroxypropyl-β-cyclodextrin enhanced the permeation of the corticosteroids. The powders showed
neither statistically significant toxicity nor reactive oxygen species induction in the tested cell lines.
Conclusions: This study demonstrated the preparation and function of fine powder formulations which
combine improved dissolution of poorly soluble drugs with good aerosolization performance. These
results are expected to promote particle engineering as a way to develop new types of therapeutic
pulmonary powders.
3
Novel Fish Oil-based Bigel System for Controlled Drug Delivery and its Influence on
Immunomodulatory Activity of Imiquimod against Skin Cancer
Khurram Rehman, Mohd Hanif Zulfakar
ABSTRACT
Purpose: To characterize bigel system as a topical drug delivery vehicle and to establish the
immunomodulatory role of imiquimod-fish oil combination against skin cancer and inflammation
resulting from chemical carcinogenesis.
Methods: Imiquimod-loaded fish oil bigel colloidal system was prepared using a blend of carbopol
hydrogel and fish oil oleogel. Bigels were first characterized for their mechanical properties and
compared to conventional gel systems. Ex vivo permeation studies were performed on murine skin to
analyze the ability of the bigels to transport drug across skin and to predict the release mechanism via
mathematical modelling. Furthermore, to analyze pharmacological effectiveness in skin cancer and
controlling imiquimod-induced inflammatory side effects, imiquimod-fish oil combination was tested
in vitro on epidermoid carcinoma cells and in vivo in Swiss albino mice cancer model.
Results: Imiquimod-loaded fish oil bigels exhibited higher drug availability inside the skin as
compared to individual imiquimod hydrogel and oleogel controls through quasi-Fickian diffusion
mechanism. Imiquimod-fish oil combination in bigel enhanced the antitumor effects and significantly
reduced serum pro-inflammatory cytokine levels such as tumor necrosis factor-alpha and interleukin-6,
and reducing tumor progression via inhibition of vascular endothelial growth factor. Imiquimod-fish
oil combination also resulted in increased expression of interleukin-10, an anti-inflammatory cytokine,
which could also aid anti-tumor activity against skin cancer.
Conclusion: Imiquimod administration through a bigel vehicle along with fish oil could be beneficial
for controlling imiquimod-induced inflammatory side effects and in the treatment of skin cancer.
Estimation of Intra-vitreal Half-Lifes in the Rabbit Eye with Semi-mechanistic Equations
Walter Schmitt
ABSTRACT
Purpose: To develop an alternative method for estimating vitreal half-lifes in the rabbit eye based on
simple equations for the physical processes of dissipation and the physiochemical properties of
therapeutic substances applied by intravitreal drug administration.
Methods: Equations were derived to describe diffusion in the vitreous humor and permeation through
the back-of-the-eye tissue, and the volume of distribution. The model was validated using reported
half-life values from 83 compounds collected from literature.
Results: The rate limiting step for dissipation from the vitreous depends mainly on the molecular
weight. Dissipation of very low molecular weight (MW) substances (350 Da uptake into the back of
the eye tissue becomes limiting, and large molecules >500 Da predominantly take an alternative path
being cleared through the front of the eye for which diffusion towards the posterior chamber turns out
to be limiting.
Conclusions: The equations derived in this analysis provide a simple method to predict vitreal half-
lifes for a diverse group of molecules and can be easily implemented in early drug development.
4
Matrix Metalloproteinase Responsive Delivery of Myostatin Inhibitors
Alexandra C. BraunMarcus GutmannRegina EbertFranz JakobHenning GieselerTessa LühmannLorenz
Meinel
ABSTRACT
Purpose: The inhibition of myostatin - a member of the transforming growth factor (TGF–β) family -
drives regeneration of functional skeletal muscle tissue. We developed a bioresponsive drug delivery
system (DDS) linking release of a myostatin inhibitor (MI) to inflammatory flares of myositis to
provide self-regulated MI concentration gradients within tissues of need.
Methods: A protease cleavable linker (PCL) – responding to MMP upregulation – is attached to the
MI and site-specifically immobilized on microparticle surfaces.
Results: The PCL disintegrated in a matrix metalloproteinase (MMP) 1, 8, and particularly MMP-9
concentration dependent manner, with MMP-9 being an effective surrogate biomarker correlating with
the activity of myositis. The bioactivity of particle-surface bound as well as released MI was
confirmed by luciferase suppression in stably transfected HEK293 cells responding to myostatin
induced SMAD phosphorylation.
Conclusions: We developed a MMP-responsive DDS for MI delivery responding to inflammatory
flare of a diseased muscle matching the kinetics of MMP-9 upregulation, with MMP-9 kinetics
matching (patho-) physiological myostatin levels.
Graphical Abstract: Schematic illustration of the matrix metalloproteinase responsive delivery
system responding to inflammatory flares of muscle disease. The protease cleavable linker readily
disintegrates upon entry into the diseased tissue, therby releasing the mystatin inhibitor.
LC-MS/MS Method for Quantifying Adenosine, Guanosine and Inosine Nucleotides in Human
Cells
Leah C. JimmersonLane R. BushmanMichelle L. RayPeter L. AndersonJennifer J. Kiser
ABSTRACT
Purpose: To develop and validate a method for the simultaneous measurement of adenosine,
guanosine, and inosine derived from mono (MP) and triphosphate (TP) forms in peripheral blood
mononuclear cells (PBMCs), red blood cells (RBCs) and dried blood spots (DBS).
Methods: Solid phase extraction of cell lysates followed by dephosphorylation to molar equivalent
nucleoside and LC-MS/MS quantification.
Results: The assay was linear for each of the three quantification ranges: 10–2000, 1.0–200 and 0.25–
50 pmol/sample for adenosine, guanosine, and inosine, respectively. Intraassay (n = 6) and interassay
(n = 18) precision (%CV) were within 1.7 to 16% while accuracy (%deviation) was within −11.5 to
14.7% for all three analytes. Nucleotide monophosphates were less concentrated than triphosphates
(except for inosine) and levels in PBMCs were higher than RBCs for all three nucleotides (10, 55, and
5.6 fold for ATP, GTP and ITP, respectively). DBS samples had an average (SD) of −26% (22.6%)
lower TP and 184% (173%) higher MP levels compared to paired RBC lysates, suggesting hydrolysis
of the TP in DBS.
Conclusion: This method was accurate and precise for physiologically relevant concentrations of
adenosine, guanosine and inosine nucleotides in mono- and triphosphate forms, providing a
bioanalytical tool for quantitation of nucleotides for clinical studies.
5
Degradation Mechanisms of Polysorbate 20 Differentiated by 18O-labeling and Mass
Spectrometry
Lin ZhangSandeep YadavBarthélemy DemeuleY. John WangOlivier MozziconacciChristian
Schӧneich
ABSTRACT
Purpose: To investigate the mechanisms of polysorbate (PS) degradation with the added objective of
differentiating the hydrolysis and oxidation pathways.
Methods: Ultra-performance liquid chromatography mass spectrometry (UPLC-MS) was utilized to
characterize all-laurate polysorbate 20 (PS20) and its degradants. 18O stable isotope labeling was
implemented to produce 18O-labeled degradation products of all-laurate PS20 in H218O, with
subsequent UPLC-MS analysis for location of the cleavage site on the fatty acid-containing side chain
of PS20.
Results: The analysis reveals that hydrolysis of all-laurate PS20 leads to a breakdown of the ester
linkage to liberate free lauric acid, showing a distinct dependence on pH. Using a hydrophilic free
radical initiator, 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH) to study the oxidative
degradation of all-laurate PS20, we demonstrate that free lauric acid and polyoxyethylene (POE)
laurate are two major decomposition products. Measurement of 18O incorporation into free lauric acid
indicated that hydrolysis primarily led to 18O incorporation into free lauric acid via ―acyl-cleavage‖ of
the fatty acid ester bond. In contrast, AAPH-exposure of all-laurate PS20 produced free lauric acid
without 18O-incorporation.
Conclusions: The 18O-labeling technique and unique degradant patterns of all-laurate PS20 described
here provide a direct approach to differentiate the types of PS degradation.
6
Bleomycin-Coated Microneedles for Treatment of Warts
Han Sol LeeHa Ryeong RyuJoo Young Roh Jung-Hwan Park
ABSTRACT
Purpose: Bleomycin-coated microneedles were devised for delivery of bleomycin into the sub-
epidermal skin layer for the treatment of warts in order to provide patient convenience and reduce
patient pain and fear.
Method: Poly-lactic-acid (L-PLA) microneedles were fabricated by a molding process and then the
tips were partially coated using a dip-coating method based on a microstructure well. The mechanical
strength of the pre-coated polymer microneedles was observed by inserting them in porcine foot and
back skin. The holes were stained with trypan blue and the mechanical failure of the microneedles was
investigated using a scanning electron microscope (SEM). The initial distribution of a model drug
using microneedles was compared with distribution by intralesional injection. The amount of drug
leaked below the skin using microneedles was measured and compared with that leaked by
intralesional injection. The pharmacokinetic properties of bleomycin-coated microneedles were
studied. The bleomycin remaining on the coated microneedles after the in vivo pharmacokinetic study
was measured.
Results: Bleomycin was successfully coated on the tips of L-PLA microneedles. More than 80% of the
bleomycin dissolved into the skin in vitro within 15 min. L-PLA microneedles possessed sufficient
mechanical strength to penetrate skin with a thick stratum corneum. Compared to intralesional
injection, tip-coated microneedles were more effective in distributing a drug into the sub-epidermal
skin layer. A pharmacokinetic study of bleomycin-coated microneedles showed 50 min of Tmax.
Conclusions: Bleomycin-coated microneedles appeared to be a convenient and painless alternative to
conventional intralesional injection of bleomycin. The microneedles delivered bleomycin into the
targeted dermal layer regardless of body site. Bleomycin-coated microneedles therefore provide a
suitable method for the treatment of warts.
7
Online Spectroscopic Monitoring of Drug Release Kinetics from Nanostructured Dual-Stimuli-
Responsive Conducting Polymer
Naader Alizadeh Ehsan ShamaeliMasooma Fazili
ABSTRACT
Purpose: The potential of electrochemical/temperature dual stimuli-responsive conducting polymer to
be used as general drug delivery systems. It allows on-demand release of incorporated drug is
kinetically investigated in real time.
Methods: Online spectroscopic monitoring was used to investigate the electrochemically/thermally
controlled release behavior of a model drug (naproxen) from drug-doped polypyrrole (DDPPy) film.
Avrami‘s equation has been used to study the kinetics and further analyzing has been carried out using
the Arrhenius and the Eyring equations. Furthermore, drug release behavior, with two other
electrochemical techniques was investigated.
Results: It was observed both temperature and electrical stimuli increase the rate of release while
electrical potential has a greater effect as revealed in the values of release rate constant (from 0.0068 to
0.018 min−1 at 37°C). It was also shown that a linear relationship exists between the applied electrical
potentials and release activation parameters.
Conclusion: The electronic properties of the conducting polymer has an important role in release
kinetics, there might be a single mechanism with the same limiting step. In addition, it was
demonstrated the rate of drug release from DDPPy dramatically depends on the amounts as well as
modes of applying potential which provides enhanced control of drug-release kinetics which can be
accelerated or even sustained.
Increased Active Tumor Targeting by An αvβ3-Targeting and Cell-Penetrating Bifunctional
Peptide-Mediated Dendrimer-Based Conjugate
Pengkai MaHuajun YuXuemei ZhangHongjie MuYongchao ChuLing NiPingping XingYiyun
WangKaoxiang Sun
ABSTRACT
Purpose: A bifunctional RGDTAT peptide-modified PEG-PAMAM dendrimer conjugate RGDTAT-
PEG-PAMAM (RTPP) was established for the targeted treatment of αvβ3-overexpressing tumor cells.
Methods: The RGDTAT peptide was synthesized and attached to PAMAM using PEG to construct
the RTPP conjugate. The methotrexate (MTX) encapsulated RTPPM complex was prepared and
characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and in vitro
release. The targeting ability was then studied in cells and tumor-bearing nude mice using fluorescence
microscopy, confocal fluorescence microscopy, flow cytometry, and in vivo imaging. The cytotoxicity
and pharmacokinetics of the RTPPM complex was also evaluated in cells and rats.
Results: The successful synthesis of the RTPP conjugate was confirmed by 1H-NMR. DLS and TEM
measurements revealed that the size was 37 nm and the complex had a spherical shape. RTPP and
RTPPM were taken up by αvβ3-overexpressing cells more efficiently than by αvβ3-lowexpressing
cells.
Conclusions: The bifunctional peptide-mediated dendrimer-based RTPP conjugate can serve as a
promising nanocarrier for targeted drug delivery to improve anti-tumor activity.
8
Sugar-Modified Poly (propylene imine) Dendrimers Stimulate the NF-κB Pathway in a Myeloid
Cell Line
Izabela Jatczak-Pawlik Michal GorzkiewiczMaciej StudzianDietmar AppelhansBrigitte VoitLukasz
PulaskiBarbara Klajnert-Maculewicz
ABSTRACT
Purpose: Fourth-generation poly (propylene imine) dendrimers fully surface-modified by maltose
(dense shell, PPI-m DS) were shown to be biocompatible in cellular models, which is important for
their application in drug delivery. We decided to verify also their inherent bioactivity, including
immunomodulatory activity, for potential clinical applications. We tested their effects on the THP-1
monocytic cell line model of innate immunity effectors.
Methods: To estimate the cytotoxicity of dendrimers the reasazurin assay was performed. The
expression level of NF-κB targets: IGFBP3, TNFAIP3 and TNF was determined by quantitative real-
time RT-PCR. Measurement of NF-κB p65 translocation from cytoplasm to nucleus was conducted
with a high-content screening platform and binding of NF-κB to a consensus DNA probe was
determined by electrophoretic mobility shift assay. The cytokine assay was performed to measure
protein concentration of TNFalpha and IL-4.
Results: We found that PPI-m DS did not impact THP-1 viability and growth even at high
concentrations (up to 100 μM). They also did not induce expression of genes for important signaling
pathways: Jak/STAT, Keap1/Nrf2 and ER stress. However, high concentrations of 4th generation PPI-
m DS (25–100 μM), but not their 3rd generation counterparts, induced nuclear translocation of p65
NF-κB protein and its DNA-binding activity, leading to NF-κB-dependent increased expression of
mRNA for NF-κB targets: IGFBP3, TNFAIP3 and TNF. However, no increase in pro-inflammatory
cytokine secretion was detected.
Conclusion: We conclude that maltose-modified PPI dendrimers of specific size could exert a modest
immunomodulatory effect, which may be advantageous in clinical applications (e.g. adjuvant effect in
anti-cancer vaccines).
9
Tumor Targeting Synergistic Drug Delivery by Self-Assembled Hybrid Nanovesicles to
Overcome Drug Resistance
Meng-Qing GongCong WuXiao-Yan HeJing-Yi ZongJin-Long WuRen-Xi ZhuoSi-Xue Cheng
ABSTRACT
Purpose: To overcome multi-drug resistance (MDR) in tumor chemotherapy, a polymer/inorganic
hybrid drug delivery platform with tumor targeting property and enhanced cell uptake efficiency was
developed.
Method: To evaluate the applicability of our delivery platform for the delivery of different drug
resistance inhibitors, two kinds of dual-drug pairs (doxorubicin/buthionine sulfoximine and
doxorubicin/tariquidar, respectively) were loaded in heparin-biotin/heparin/protamine sulfate/calcium
carbonate nanovesicles to realize simultaneous delivery of an anticancer drug and a drug resistance
inhibitor into drug-resistant tumor cells.
Results: Prepared by self-assembly, the drug loaded hybrid nanovesicles with a mean size less than
210 nm and a negative zeta potential exhibit good stability in serum contained aqueous media. The in
vitro cytotoxicity evaluation indicates that hybrid nanovesicles with tumor targeting biotin moieties
have an enhanced tumor cell inhibitory effect. In addition, dual-drug loaded hybrid nanovesicles
exhibit significantly stronger cell growth inhibition as compared with doxorubicin (DOX) mono-drug
loaded nanovesicles due to the reduced intracellular glutathione (GSH) content by buthionine
sulfoximine (BSO) or the P-glycoprotein (P-gp) inhibition by tariquidar (TQR).
Conclusions: The tumor targeting nanovesicles prepared in this study, which can simultaneously
deliver multiple drugs and effectively reverse drug resistance, have promising applications in drug
delivery for tumor treatments. The polymer/inorganic hybrid drug delivery platform developed in this
study has good applicability for the co-delivery of different anti-tumor drug/drug resistance inhibitor
pairs to overcome MDR.
Graphical Abstract: A polymer/inorganic hybrid drug delivery platform with enhanced cell uptake
was developed for tumor targeting synergistic drug delivery. The heparin-biotin/heparin/protamine
sulfate/calcium carbonate nanovesicles prepared in this study can deliver an anticancer drug and a drug
resistance inhibitor into drug-resistant tumor cells simultaneously to overcome drug resistance
efficiently.
10
Intracellular Delivery of Nanobodies for Imaging of Target Proteins in Live Cells
Ruth RöderJonas HelmaTobias PreißJoachim O. RädlerHeinrich LeonhardtErnst Wagner
ABSTRACT
Purpose: Cytosolic delivery of nanobodies for molecular target binding and fluorescent labeling in
living cells.
Methods: Fluorescently labeled nanobodies were formulated with sixteen different sequence-defined
oligoaminoamides. The delivery of formulated anti-GFP nanobodies into different target protein-
containing HeLa cell lines was investigated by flow cytometry and fluorescence microscopy.
Nanoparticle formation was analyzed by fluorescence correlation spectroscopy.
Results: The initial oligomer screen identified two cationizable four-arm structured oligomers (734,
735) which mediate intracellular nanobody delivery in a receptor-independent (734) or folate receptor
facilitated (735) process. The presence of disulfide-forming cysteines in the oligomers was found
critical for the formation of stable protein nanoparticles of around 20 nm diameter. Delivery of labeled
GFP nanobodies or lamin nanobodies to their cellular targets was demonstrated by fluorescence
microscopy including time lapse studies.
Conclusion: Two sequence-defined oligoaminoamides with or without folate for receptor targeting
were identified as effective carriers for intracellular nanobody delivery, as exemplified by GFP or
lamin binding in living cells. Due to the conserved nanobody core structure, the methods should be
applicable for a broad range of nanobodies directed to different intracellular targets.
11
Therapeutic Effects of AICAR and DOX Conjugated Multifunctional Nanoparticles in
Sensitization and Elimination of Cancer Cells via Survivin Targeting
Cenk Daglioglu Burcu Okutucu
ABSTRACT
Purpose: Resistance to chemotherapy is one of the major problems facing current cancer research.
Enhancing tumor cell response to anticancer agents increases chemotherapeutic effectiveness. We have
recently addressed this issue and reported on producing multifunctional nanoparticles (Fe3O4@ SiO2
(FITC)-FA/AICAR/DOX) aiming to overcome chemoresistance with synergetic effect of AICAR and
DOX. In the present study, we demonstrated that these nanoparticles not only show enhanced cellular
uptake and cytotoxic effect but can also show enhanced pro-apoptotic and anti-proliferative effects in
five different tumor-derived cell lines (A549, HCT-116, HeLa, Jurkat and MIA PaCa-2).
Methods: The nanoparticles were examined by using flow cytometric analyses of apoptosis and cell
cycle. In addition, we performed caspase-3 activity assay, which supported our flow cytometric data.
Furthermore, we demonstrated the applicability of this approach in a variety of cancer types
confirming the potential widespread utility of this approach.
Results: With the concept of co-delivery of AICAR and DOX in the nanoparticle formulation, the use
of AICAR against survivin (BIRC5) sensitized cancer cells to DOX chemotherapy which resulted in
effective cancer cell elimination. These result showed that combination therapy involving both a
molecularly targeted therapy and chemotherapeutic agent has the ability to retain and enhance
therapeutic efficacy.
Conclusion: Fe3O4@SiO2 (FITC)-FA/AICAR/DOX nanoparticles is superior to monotherapy via the
synergetic effect of AICAR and DOX and also the nanoparticle formulation could overcome issues of
toxicity with targeted therapy while maintaining the potent anticancer effects of AICAR and DOX.
Graphical Abstract: Apoptosis analysis of A549 cells by flow cytometry-based PE-annexin-V / 7-
ADD double staining treated with low-dose (10 μg/ml) concentration of (1) Fe3O4@SiO2(FITC)-FA
(2) Fe3O4@SiO2(FITC)-FA/AICAR, (3) Fe3O4@SiO2(FITC)-FA/DOX or (4) Fe3O4@SiO2(FITC)-
FA/AICAR/DOX nanoparticles. Viable cells labelled with PE-annexin-V(-)/7-ADD(-), early apoptotic
cells labelled with PE-annexin-V(+)/7-ADD(-) and apoptotic cells labelled with PE-annexin-V(+)/ 7-
ADD(+) in flow cytometric graphics.
12
Population Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis of LY3015014, a
Monoclonal Antibody to Protein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Healthy
Subjects and Hypercholesterolemia Patients
Tong Shen Douglas E. JamesKathryn A. Krueger
ABSTRACT
Purpose: LY3015014 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to
the catalytic domain of PCSK9 and reduce low-density lipoprotein cholesterol (LDL-C) in patients
with hypercholesterolemia that is poorly controlled by maximally tolerated statin therapy. The
objective of this pharmacokinetic/pharmacodynamics (PK/PD) analysis was to characterize the PK and
PD properties of LY3015014 and assess the effect of covariates on the LY3015014 PK-PD profiles.
Methods: Single and multiple dose data from three phase1 studies in healthy subjects (n = 133), as
well as a phase 2 study in hypercholesterolemia patients (n = 527) were combined into a single dataset
for analysis. In this dataset, healthy subjects received single intravenous (IV) doses of 0.03 to 10
mg/kg, or multiple subcutaneous (SC) doses of 1.0 to 3.0 mg/kg, administered every 2 to 4 weeks,
while patients received 20 to 300 mg every 4 weeks or 100 to 300 every 8 weeks. PK/PD analysis was
performed using NONMEM (ICON, software version 7.0 level 3). PK and PD modeling were
conducted sequentially, with PK parameters fixed during the development of the PK/PD model. PD
parameters and estimated intersubject and intrasubject variability were obtained based on
pharmacological drug exposure-response relationships. Age, baseline total PCSK9, body weight,
diabetes diagnosis, hypercholesterolemia disease status, dose, ezetimibe administration, gender, ethnic
origin, metabolic syndrome, and satin administration were evaluated as potential covariates in the PK
model. Baseline total PCSK9, baseline LDL-C, diabetes diagnosis, disease status, ezetimibe
administration, gender, ethnic origin, metabolic syndrome, and Statin administration were evaluated as
potential covariates in the PD model.
Results: LY3015014 PK profile was consistent across all the studies and between healthy subjects and
hypercholesterolemia patients. The PK time course data were well described by a two compartment
PK model with first order absorption, and covariates identified for PK parameters included weight on
both clearance (CL) and central volume (V2), dose on CL, race on bioavailability (F), and age on V2.
The PD (LDL-C) was described using an indirect response model with LY3015014 acting to stimulate
the elimination of LDL-C. Covariates identified to have a statistically significant impact on PD were
coadministration of statins, baseline LDL-C, metabolic syndrome status and gender.
Conclusions: The population PK/PD model adequately describes the PK and PD profiles of LY3
015014. Identification of clinically significant covariates will support the design and dose selection for
the pivotal registration studies, ensuring that patients are dosed appropriately.
13
Contrasting the Influence of Cationic Amino Acids on the Viscosity and Stability of a Highly
Concentrated Monoclonal Antibody
Barton J. DearJessica J. HungThomas M. TruskettKeith P. Johnston
ABSTRACT
Purpose: To explain the effects of cationic amino acids and other co-solutes on the viscosity, stability
and protein-protein interactions (PPI) of highly concentrated (≥200 mg/ml) monoclonal antibody
(mAb) solutions to advance subcutaneous injection.
Methods: The viscosities of ≥200 mg/ml mAb1 solutions with various co-solutes and pH were
measured by capillary rheometry in some cases up to 70,000 s−1. The viscosities are analyzed in terms
of dilute PPI characterized by diffusion interaction parameters (kD) from dynamic light scattering
(DLS). MAb stability was measured by turbidity and size exclusion chromatography (SEC) after 4
weeks of 40°C storage.
Results: Viscosity reductions were achieved by reducing the pH, or adding histidine, arginine,
imidazole or camphorsulfonic acid, each of which contains a hydrophobic moiety. The addition of
inorganic electrolytes or neutral osmolytes only weakly affected viscosity. Systems with reduced
viscosities also tended to be Newtonian, while more viscous systems were shear thinning.
Conclusions: Viscosity reduction down to 20 cP at 220 mg/ml mAb1 was achieved with co-solutes
that are both charged and contain a hydrophobic interaction domain for sufficient binding to the
protein surface. These reductions are related to the DLS diffusion interaction parameter, kD, only after
normalization to remove the effect of charge screening. Shear rate profiles demonstrate that select co-
solutes reduce protein network formation.
14
Physicochemical Properties of Solid Phospholipid Particles as a Drug Delivery Platform for
Improving Oral Absorption of Poorly Soluble Drugs
Kohsaku Kawakami Aoi Miyazaki Mayuko Fukushima Keiko SatoYuko Yamamura Kohta Mohri
Shinji Sakuma
ABSTRACT
Purpose: A novel drug delivery platform, mesoporous phospholipid particle (MPP), is introduced. Its
physicochemical properties and ability as a carrier for enhancing oral absorption of poorly soluble
drugs are discussed.
Methods: MPP was prepared through freeze-drying a cyclohexane/t-butyl alcohol solution of
phosphatidylcholine. Its basic properties were revealed using scanning electron microscopy, x-ray
diffraction, thermal analysis, hygroscopicity measurement, and so on. Fenofibrate was loaded to MPP
as a poorly soluble model drug, and effect of MPP on the oral absorption behavior was observed.
Results: MPP is spherical in shape with a diameter typically in the range of 10–15 μm and a wide
surface area that exceeds 10 m2/g. It has a bilayer structure that may accommodate hydrophobic drugs
in the acyl chain region. When fenofibrate was loaded in MPP as a model drug, it existed partially in a
crystalline state and improvement in the dissolution behavior was achieved in the presence of a
surfactant, because of the formation of mixed micelles composed of phospholipids and surfactants in
the dissolution media. MPP greatly improved the oral absorption of fenofibrate compared to that of the
crystalline drug and its efficacy was almost equivalent to that of an amorphous drug dispersion.
Conclusion: MPP is a promising option for improving the oral absorption of poorly soluble drugs
based on the novel mechanism of dissolution improvement.
15
The Tritiated Water Skin Barrier Integrity Test: Considerations for Acceptance Criteria with
and Without 14C-Octanol
Paul A. LehmanKacie BeatchSam G. RaneyThomas J. Franz
ABSTRACT
Purpose: A study was designed to assess barrier integrity simultaneously using separate compounds
(probes) for polar and non-polar pathways through the skin, 3H2O and 14C-octanol, respectively; and
to determine whether the two probe approach could better define barrier integrity.
Methods: A 5-min dose of water containing 3H2O and 14C -octanol was applied to ex vivo human
skin mounted in Franz diffusion cells. The receptor solution was sampled at 30 min, analyzed for 3H
and 14C content, and the correlation between water and octanol absorption was determined by
statistical tests suitable for non-normally distributed data. This study was conducted on skin from 37
donors with from 3 to 30 replicate skin sections per donor (a total of 426 sections).
Results: The correlation between 3H2O and 14C-octanol absorption was low (Pearson correlation
coefficient = 0.3485). The 3H2O absorption cutoff used in this study to select for a normal skin barrier
rejected some sections in which 14C-octanol absorption was within normal limits and accepted others
in which 14C-octanol absorption was abnormally high. The converse was true for 3H2O absorption
when the 14C-octanol-based cutoff was used.
Conclusions: The results of the 3H2O test or of similar tests that primarily assess the permeability of
polar pathways through the skin may not necessarily provide information relevant to the absorption of
highly lipophilic compounds. Octanol, or another molecule that more closely matches the
physicochemical attributes of the test compound, may characterize properties of the skin barrier that
are more relevant to compounds of low water solubility.
16
Photo-oxidation of IgG1 and Model Peptides: Detection and Analysis of Triply Oxidized His and
Trp Side Chain Cleavage Products
Jessica BaneOlivier MozziconacciLi YiY. John WangAlavattam Sreedhara Christian Schöneich
ABSTRACT
Purpose: Triply oxidized histidine in an IgG1 monoclonal antibody was noticed when exposed to ICH
light conditions. In order to understand the role of light source, irradiation wavelengths and primary
sequence, specifically those of a nearby tryptophan, we synthesized and exposed several peptides to
ICH light conditions and analyzed the products using LC-MS analysis.
Methods: Protein and peptide samples were photo-irradiated under ICH conditions as well as with
monochromatic light at λ = 254 nm and analyzed using either LTQ Orbitrap or a LTQ-FT ion
cyclotron resonance mass spectrometer respectively.
Results: A triply oxidized His residue was detected along with a second doubly oxidized His residue
in an IgG1. Both of these oxidized His residues are located near Trp residues. In order to investigate
the role of Trp photosensitization in His oxidation we synthesized model peptides and Ala mutants.
Peptides exposed to ICH light stress conditions revealed a small percent of triply oxidized His in the
Trp-containing peptide sequences but not in their corresponding Ala mutants.
Conclusions: The differences in product formation under different photo-irradiation conditions
underline the importance of light source, irradiation wavelengths and primary sequence in the
photosensitivity of proteins.
Volume 34, Issue 2, February 2017
Role of Knowledge Management in Development and Lifecycle Management of
Biopharmaceuticals
Anurag S. RathoreOscar Fabián Garcia-AponteAydin GolabgirBibiana Margarita Vallejo-
DiazChristoph Herwig
ABSTRACT
Knowledge Management (KM) is a key enabler for achieving quality in a lifecycle approach for
production of biopharmaceuticals. Due to the important role that it plays towards successful
implementation of Quality by Design (QbD), an analysis of KM solutions is needed. This work
provides a comprehensive review of the interface between KM and QbD-driven biopharmaceutical
production systems as perceived by academic as well as industrial viewpoints. A comprehensive set of
356 publications addressing the applications of KM tools to QbD-related tasks were screened and a
query to gather industrial inputs from 17 major biopharmaceutical organizations was performed. Three
KM tool classes were identified as having high relevance for biopharmaceutical production systems
and have been further explored: knowledge indicators, ontologies, and process modeling. A proposed
categorization of 16 distinct KM tool classes allowed for the identification of holistic technologies
supporting QbD. In addition, the classification allowed for addressing the disparity between industrial
and academic expectations regarding the application of KM methodologies. This is a first of a kind
attempt and thus we think that this paper would be of considerable interest to those in academia and
industry that are engaged in accelerating development and commercialization of biopharmaceuticals.
17
Triple Drug Combination of Zidovudine, Efavirenz and Lamivudine Loaded Lactoferrin
Nanoparticles: an Effective Nano First-Line Regimen for HIV Therapy
Prashant KumarYeruva Samrajya LakshmiAnand K Kondapi
ABSTRACT
Purpose: To enhance efficacy, bioavailability and reduce toxicity of first-line highly active anti-
retroviral regimen, zidovudine + efavirenz + lamivudine loaded lactoferrin nanoparticles were prepared
(FLART-NP) and characterized for physicochemical properties, bioactivity and pharmacokinetic
profile.
Methods: Nanoparticles were prepared using sol-oil protocol and characterized using different sources
such as FE-SEM, AFM, NanoSight, and FT-IR. In-vitro and in-vivo studies have been done to access
the encapsulation-efficiency, cellular localization, release kinetics, safety analysis, biodistribution and
pharmacokinetics.
Results: FLART-NP with a mean diameter of 67 nm (FE-SEM) and an encapsulation efficiency of
>58% for each drug were prepared. In-vitro studies suggest that FLART-NP deliver the maximum of
its payload at pH5 with a minimum burst release throughout the study period with negligible toxicity
to the erythrocytes plus improved in-vitro anti-HIV activity. FLART-NP has improved the in-vivo
pharmacokinetics (PK) profiles over the free drugs; an average of >4fold increase in AUC and AUMC,
30% increase in the Cmax, >2fold in the half-life of each drug. Biodistribution data suggest that
FLART-NP has improved the bioavailability of all drugs with less tissue-related inflammation as
suggested with histopathological evaluation
Conclusions: The triple-drug loaded nanoparticles have various advantages against soluble (free) drug
combination in terms of enhanced bioavailability, improved PK profile and diminished drug-associated
toxicity.
18
Improvement in Thermal Stability of Sucralose by γ-Cyclodextrin Metal-Organic Frameworks
Nana LvTao GuoBotao LiuCaifen WangVikaramjeet SinghXiaonan XuXue LiDawei Chen Ruxandra
Gref, Jiwen Zhang
ABSTRACT
Purpose: To explain thermal stability enhancement of an organic compound, sucralose, with
cyclodextrin based metal organic frameworks.
Methods: Micron and nanometer sized basic CD-MOFs were successfully synthesized by a modified
vapor diffusion method and further neutralized with glacial acetic acid. Sucralose was loaded into CD-
MOFs by incubating CD-MOFs with sucralose ethanol solutions. Thermal stabilities of sucralose-
loaded basic CD-MOFs and neutralized CD-MOFs were investigated using thermogravimetric analysis
(TGA), differential scanning calorimetry (DSC) and high performance liquid chromatography with
evaporative light-scattering detection (HPLC-ELSD).
Results: Scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD) results showed
that basic CD-MOFs were cubic crystals with smooth surface and uniform sizes. The basic CD-MOFs
maintained their crystalline structure after neutralization. HPLC-ELSD analysis indicated that the CD-
MOF crystal size had significant influence on sucralose loading (SL). The maximal SL of micron CD-
MOFs (CD-MOF-Micro) was 17.5 ± 0.9% (w/w). In contrast, 27.9 ± 1.4% of sucralose could be loaded
in nanometer-sized basic CD-MOFs (CD-MOF-Nano). Molecular docking modeling showed that
sucralose molecules preferentially located inside the cavities of γ-CDs pairs in CD-MOFs. Raw
sucralose decomposed fast at 90°C, with 86.2 ± 0.2% of the compound degraded within only 1 h.
Remarkably, sucralose stability was dramatically improved after loading in neutralized CD-MOFs,
with only 13.7 ± 0.7% degradation at 90°C within 24 h.
Conclusions: CD-MOFs efficiently incorporated sucralose and maintained its integrity upon heating at
elevated temperatures.
19
Comparative Study of Different Nano-Formulations of Curcumin for Reversal of Doxorubicin
Resistance in K562R Cells
Tapan K. DashV. Badireenath Konkimalla
ABSTRACT
Purpose: Curcumin is very well established as a chemo-therapeutic, chemo-preventive and chemo-
sensitizing agent in diverse disease conditions. As the isolated pure form has poor solubility and
pharmacokinetic problems, therefore it is encapsulated in to several nano-formulations to improve its
bioavailability. Here in the current study, we aim to compare different nano-formulations of curcumin
for their chemo-sensitizing activity in doxorubicin (DOX) resistant K562 cells.
Methods: Four different curcumin formulations were prepared namely DMSO assisted curcumin
nano-dispersion (CurD, 260 nm), liposomal curcumin (CurL, 165 nm), MPEG-PCL micellar curcumin
(CurM, 18 nm) and cyclodextrin encapsulated curcumin (CurN, 37 nm). The formulations were
subjected to particle characterizations (size, zeta potential, release studies), followed by biological
assays such as cellular uptake, P-gp inhibitory activity and reversal of DOX resistance by co-treatment
with DOX.
Results: Curcumin uptake in K562N and K562R cells was mildly reduced when treated with CurL and
CurM, while for CurD and CurN the uptake remained equivalent. However, CurL retained P-gp
inhibitory activity of curcumin and with a considerable chemo-sensitizing effect but CurM showed no
P-gp inhibitory activity. CurN retained above biological activities, but requires a secondary carrier
under in vivo conditions.
Conclusions: From the results, CurM was found to be most suitable for solubilization of curcumin
where as CurL can be considered as most suitable nano-formulation for reversal of DOX resistance.
20
SPECT-CT Comparison of Lung Deposition using a System combining a Vibrating-mesh
Nebulizer with a Valved Holding Chamber and a Conventional Jet Nebulizer: a Randomized
Cross-over Study
Jonathan Dugernier, Michel HesseRita VanbeverVirginie DepoortereJean RoeselerJean-Bernard
MichottePierre-François LaterreFrançois JamarGregory Reychler
ABSTRACT
Purpose: To compare in vivo the total and regional pulmonary deposition of aerosol particles
generated by a new system combining a vibrating-mesh nebulizer with a specific valved holding
chamber and constant-output jet nebulizer connected to a corrugated tube.
Methods: Cross-over study comparing aerosol delivery to the lungs using two nebulizers in 6 healthy
male subjects: a vibrating-mesh nebulizer combined with a valved holding chamber (Aerogen Ultra®,
Aerogen Ltd., Galway, Ireland) and a jet nebulizer connected to a corrugated tube (Opti-Mist Plus
Nebulizer®, ConvaTec, Bridgewater, NJ). Nebulizers were filled with diethylenetriaminepentaacetic
acid labelled with technetium-99 m (99mTc-DTPA, 2 mCi/4 mL). Pulmonary deposition of 99mTc-
DTPA was measured by single-photon emission computed tomography combined with a low dose CT-
scan (SPECT-CT).
Results: Pulmonary aerosol deposition from SPECT-CT analysis was six times increased with the
vibrating-mesh nebulizer as compared to the jet nebulizer (34.1 ± 6.0% versus 5.2 ± 1.1%, p
21
Preparation, Physicochemical Characterization and Anti-fungal Evaluation of Nystatin-Loaded
PLGA-Glucosamine Nanoparticles
Ghobad Mohammadi, Amineh ShakeriAli FattahiPardis MohammadiAli MikaeiliAlireza
AliabadiKhosro Adibkia
ABSTRACT
Purpose: Nystatin loaded PLGA and PLGA-Glucosamine nanoparticles were formulated. PLGA were
functionalized with Glucosamine (PLGA-GlcN) to enhance the adhesion of nanoparticles to Candida
Albicans (C.albicans) cell walls.
Method: Quasi-emulsion solvent diffusion method was employed using PLGA and PLGA-GlcN with
various drug–polymer ratios for the preparation of nanoparticles. The nanoparticles were evaluated for
size, zeta potential, polydispersity index, drug crystallinity, loading efficiency and release properties.
DSC, SEM, XRPD, 1H-NMR, and FT-IR were performed to analyze the physicochemical properties
of the nanoparticles. Antifungal activity of the nanoparticles was evaluated by determination of MICs
against C.albicans.
Results: The spectra of 1H-NMR and FT-IR analysis ensured GlcN functionalization on PLGA
nanoparticles. SEM characterization confirmed that particles were in the nanosize range and the
particle size for PLGA and PLGA-GlcN nanoparticles were in the range of 108.63 ± 4.5 to
168.8 ± 5.65 nm and 208.76 ± 16.85 nm, respectively. DSC and XRPD analysis ensured reduction of
the drug crystallinity in the nanoparticles. PLGA-GlcN nanoparticles exhibit higher antifungal activity
than PLGA nanoparticles.
Conclusion: PLGA-GlcN nanoparticles showed more antifungal activity with appropriate
physicochemical properties than pure Nystatin and PLGA nanoparticles.
22
Lipid Nanoparticles Loaded with an Antisense Oligonucleotide Gapmer against Bcl-2 for
Treatment of Lung Cancer
Xinwei ChengQibing LiuHong LiChen KangYang LiuTianqi GuoKe ShangChengyun YanGuang
Cheng, Robert J. Lee
ABSTRACT
Purpose: Bcl-2 is an anti-apoptotic gene that is frequently overexpressed in human cancers. G3139 is
an antisense oligonucleotide against bcl-2 that has shown limited efficacy in clinical trials. Here, we
report the synthesis of a new antisense oligonucleotide containing additional chemical modifications
and its delivery using nanoparticles.
Methods: An oligonucleotide G3139-GAP was synthesized, which has 2‘-O-methyl nucleotides at the
5‘ and 3‘ ends based on a ―gapmer‖ design. Furthermore, G3139-GAP was incorporated into lipid
nanoparticles (LNPs) composed of DOTAP/egg PC/cholesterol/Tween 80. The LNP-loaded G3139-
GAP was evaluated in A549 lung cancer cells both in vitro and in a murine xenograft model for
biological activity and therapeutic efficacy.
Results: The LNPs showed excellent colloidal and serum stability and high encapsulation efficiency
for G3139-GAP. They have a mean particle diameter and zeta potential of 134 nm and 9.59 mV,
respectively. G3139-GAP-LNPs efficiently downregulated bcl-2 expression in A549 cells, as shown
by 40% and 83% reduction in mRNA and protein levels, respectively. Furthermore, G3139-GAP-
LNPs were shown to inhibit tumor growth, prolon