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

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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

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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

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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

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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

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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