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Withania Somnifera As a Topical Anti- Melanoma Agent

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Withania Somnifera As a Topical Anti- Melanoma Agent Withania somnifera as a topical anti- melanoma agent TN Chinembiri 20945175 Thesis submitted for the degree Doctor Philosophiae in Pharmaceutics at the Potchefstroom Campus of the North-West University Promoter: Prof J du Plessis Co-Promoters: Dr M Gerber Prof LH du Plessis November 2016 DEDICATED TO MY DAUGHTER TALIA RUTENDO MAPAMBA “Our eyes are in front because it’s more important to look ahead than to look back. Don’t dwell on things in the past. Learn from them and keep MOVING forward” Unknown ii Table of Contents Table of Contents iii List of Figures xvi List of Tables xxii Abbreviations xxv Acknowledgements xxviii Abstract xxx Uittreksel xxxiv Foreword xxxviii CHAPTER 1: INTRODUCTION AND PROBLEM STATEMENT 1 References 7 CHAPTER 2: REVIEW ARTICLE PUBLISHED IN MOLECULES 8 1. Introduction 10 2. Natural Sources of Anti-Cancer Compounds 11 2.1 Marine sources 13 2.2 Microbial sources 13 2.3 Plant sources 14 3. Anti-Cancer Dietary Components and Phytochemicals 14 3.1 Flavonoids 15 3.1.1 Quercetin 16 3.1.2 Kaempferol 17 3.1.3 Epigallocatechin-3-gallate 17 3.1.4 Apigenin 18 3.1.5 Daidzein 19 3.1.6 Biflavonoids 19 3.2 Carotenoids 20 3.2.1 β-carotene 21 iii 3.2.2 Lycopene 22 3.2.3 Fucoxanthine 22 3.3 Vitamins 22 3.3.1 Vitamin A (retinol) 23 3.3.2 Vitamin C (ascorbic acid) 24 3.3.3 Vitamin D 24 3.3.4 Vitamin E 25 3.4 Terpenoids 26 3.5 Resveratrol 27 3.6 Curcumin 28 3.7 Sulforaphane 29 4. Anti-melanoma activity of crude plant extracts 30 4.1 Hypericum perforatum 30 4.2 Withania somnifera 30 4.3 Melaleuca alternifolia 30 4.4 Zingiber officinale 31 4.5 Viscum album 31 4.6 Calendula officinalis 31 4.7 Rosmarinus officinalis 32 4.8 Aloe species 32 4.9 Artemisia species 33 4.10 Alpinia species 33 5. Conclusions 33 Acknowledgments 35 Author Contributions 35 Conflicts of Interest 35 References 35 CHAPTER 3: RESEARCH ARTICLE SUBMITTED TO PHARMACOGNOSY MAGAZINE 52 Introduction 55 iv Materials and Methods 56 Materials 56 Preparation of plant extracts 57 Chemical characterisation of Withania somnifera extracts with nuclear magnetic resonance spectroscopy 57 Chemical characterisation of Withania somnifera extracts with high performance liquid chromatography 57 Formulation of niosomes and solid lipid nanoparticles 58 Physico-chemical characterisation of formulations 59 Stability testing of formulations 60 Skin preparation for skin diffusion studies 60 Franz cell diffusion studies 61 Tape-stripping studies 62 Statistical analysis 62 Results and Discussion 63 Chemical characterisation of Withania somnifera crude extracts 63 Physico-chemical characterisation of formulations 63 Stability testing of formulations 65 Franz cell diffusion studies 67 Tape-stripping studies 67 Conclusion 70 Acknowledgements 71 References 71 Abbreviations 85 Table legend 86 Figure legend 87 CHAPTER 4: ARTICLE FOR PUBLICATION IN PLOS – ONE JOURNAL 88 Introduction 90 Materials and Methods 93 v Materials 93 Preparation and characterisation of W. somnifera leaf extracts 93 Formulation of solid lipid nanoparticles 94 Cell propagation and assay preparation 94 Conventional cell culture 94 Cell culture in Matrigel® 94 Cytotoxicity assays 94 MTT and XTT assays 94 Apoptosis assays 95 DNA fragmentation, caspase 3/7 activity, membrane permeability and mitochondrial membrane potential 95 Annexin V FITC apoptosis assay of cells in Matrigel® 96 Confocal microscopy assessment of cells in Matrigel® 97 Statistical analysis 97 Results and Discussion 97 Characterisation of plant extracts 97 Cytotoxicity assays 97 Apoptosis assays 99 DNA fragmentation 99 Membrane permeability 100 Caspase 3/7 activity 100 Mitochondrial membrane potential 101 Annexin V FITC apoptosis assay of cells in Matrigel® 102 Confocal microscopy assessment of cells in Matrigel® 102 Conclusion 103 Acknowledgements 104 Funding information 104 Competing interests 104 References 104 vi CHAPTER 5: FINAL CONCLUSION AND FUTURE RECOMMENDATIONS 116 References 120 APPENDIX A: PREPARATION OF WITHANIA SOMNIFERA CRUDE EXTRACTS AND EXTRACT CHARACTERISATION 121 A.1 Introduction 121 A.2 Withania somnifera 121 A.3 Materials and Methods 122 A.4 Preparation of W. somnifera crude extracts 122 A.5 HPLC method for W. somnifera extracts and standard compounds 126 A.5.1 Chromatographic conditions 126 A.5.2 Preparation of standard 127 A.5.3 Linearity 127 A.5.4 Lower limit of quantification (LLOQ) 129 A.5.5 HPLC analysis of W. somnifera crude extracts 130 A.6 Nuclear magnetic resonance (NMR) fingerprinting of W. somnifera crude extracts 133 A.6.1 NMR spectra of pure compounds and crude extracts 133 A.7 Conclusion 138 References 139 APPENDIX B: FORMULATION OF NIOSOMES AND SOLID LIPID NANOPARTICLES FOR TOPICAL DELIVERY OF WITHANIA SOMNIFERA CRUDE EXTRACTS 140 B.1 Background 140 B.2 Vesicles for topical drug delivery 140 B.2.1 Niosomes 140 B.2.2 Solid lipid nanoparticles (SLN) 141 B.3 Formulation of niosomes and solid lipid nanoparticles 143 B.3.1 Excipients used in the formulation of niosomes and solid lipid nanoparticles 143 B.3.1.1 Tween® 80 143 B.3.1.2 Span® 60 144 vii B.3.1.3 Cholesterol 144 B.3.1.4 Compritol® 888 ATO 144 B.3.1.5 Precirol® ATO 5 145 B.3.1.6 Sodium cholate 145 B.3.1.7 Phosphatidylcholine 145 B.3.2 Method for formulation of solid lipid nanoparticles and niosomes 145 B.4 Physicochemical characterisation of formulations 146 B.5 Optimisation of formulations 147 B.5.1 Results for optimisation of formulations 148 B.5.2 Results for the physicochemical characterisation of the final formulations 150 B.5.2.1 Size and polydispersity of niosomes and solid lipid nanoparticles 151 B.5.2.2 Zeta-potential of niosomes and solid lipid nanoparticles 154 B.5.2.3 pH of the niosomes and solid lipid nanoparticles 155 B.5.2.4 Encapsulation efficiency of niosomes and solid lipid nanoparticles 156 B.5.2.4.1 Withaferin A 156 B.5.2.4.2 Withanolide A 157 B.6 Conclusion 158 References 159 APPENDIX C: PHYSICO-CHEMICAL STABILITY TESTING OF WITHANIA SOMNIFERA NIOSOMES AND SOLID LIPID NANOPARTICLES 162 C.1 Introduction 162 C.2 Materials and methods 163 C.2.1 Preparation of freeze-dried formulations 164 C.2.2 pH 164 C.2.3 Particle size, polydispersity index and zeta-potential 164 C.2.4 Encapsulation efficiency 164 C.3 Results and discussion 165 C.3.1 pH 165 viii C.3.2 Zeta-potential 167 C.3.3 Particle size 169 C.3.4 Polydispersity index 171 C.3.5 Encapsulation efficiency 173 C.3.5.1 Encapsulation efficiency of Withaferin A 173 C.3.5.2 Encapsulation efficiency of withanolide A 175 C.4 Conclusion 177 References 179 APPENDIX D: FRANZ CELL DIFFUSION STUDIES 181 D.1 Introduction 181 D.2 Materials and methods 183 D.2.1 HPLC method for sample analysis 183 D.2.2 Preparation of receptor phase 184 D.2.3 Preparation of donor phase 184 D.2.4 Skin preparation 185 D.2.5 Franz cell diffusion studies 185 D.2.5.1 Membrane release studies 186 D.2.5.2 Skin diffusion studies 186 D.2.6 Tape-stripping studies 187 D.2.7 Statistical and data analysis 188 D.3 Results and discussion 188 D.3.1 Membrane release studies 188 D.3.2 Skin diffusion studies 195 D.3.3 Tape-stripping studies 195 D.3.4 Statistical analysis 198 D.3.4.1 Membrane release studies 198 D.3.4.2 Tape-stripping 202 D.4 Conclusion 203 References 205 ix APPENDIX E: IN VITRO ANTI-MELANOMA EFFICACY OF WITHANIA SOMNIFERA 208 E.1 Introduction 208 E.1.1 Flow cytometry 209 E.1.2 Confocal microscopy 210 E.2 Materials and Methods 211 E.2.1 Materials 211 E.2.2 Cell line selection and cell maintenance 212 E.2.3 Seeding cells in Corning® Matrigel® Matrix 212 E.2.4 MTT and XTT cytotoxicity assays (2D) 213 E.2.4.1 Day one 213 E.2.4.2 Day two 214 E.2.4.3 Day three 214 E.2.5 XTT cytotoxicity assay in Matrigel® 214 E.2.6 Apoptosis assays – 2D 215 E.2.6.1 APO-BrdU TUNEL assay 215 E.2.6.1.1 Day one 215 E.2.6.1.2 Day two 215 E.2.6.1.3 Day three 216 E.2.6.2 Membrane permeability/dead cell assay 216 E.2.6.3 Caspase-3/7 green flow cytometry assay 217 E.2.6.4 Mitochondrion membrane potential assay 217 E.2.7 Apoptosis determination in 3D 218 E.2.7.1 Annexin V FITC apoptosis assay 218 E.2.7.2 Seeding cells in Matrigel® in 4-well dish for microscopy analysis 219 E.3 Results and Discussion 220 E.3.1 MTT and XTT 220 E.3.2 Apo BrdU TUNEL assay 224 E.3.3 Caspase 3/7 apoptosis assay 229 E.3.4 Membrane permeability 233 x E.3.5 Mitochondrion Membrane Potential 236 E.3.6 Annexin V FITC apoptosis assay 237 E.3.7 Confocal microscopy imaging 239 E.4 Statistical analysis 240 E.5 Conclusion 242 References 244 APPENDIX F: MOLECULES SUBMISSION GUIDELINES 256 F.1 Manuscript Submission Overview 256 F.1.1 Types of Publications 256 F.2 Submission Process 256 F.2.1 Accepted File Formats 257 F.2.2 Cover Letter 257 F.2.3 Note for Authors Funded by the National Institutes of Health (NIH) 257 F.3 Preparation of a Manuscript 257 F.3.1 General Considerations 257 F.3.2 Front Matter 260 F.3.3 Research Manuscript Sections 261 F.3.4 Back Matter 262 F.3.5 Preparing Figures, Schemes and Tables 264 F.4 Qualification for Authorship 264 F.5 Research Ethics Guidelines 265 F.5.1 Research Involving Animals 265 F.5.2 Research Involving Human Subjects 266 F.5.3 Research Involving Cell Lines 266 F.5.4 Research Involving Plants 267 F.6 Correct Identification of Components of Natural Products 267 F.7 Potential Conflicts of Interest 268 F.8 Editorial Procedures and Peer-Review 268 F.8.1 Initial Checks 268 xi F.8.2 Peer-Review 268 F.8.3 Editorial Decision and Revision 269 F.8.4 Author Appeals 269 F.8.5 Production and Publication 269 F.9 Suggesting Reviewers 270 F.10 English Corrections 270 F.11 Publication Ethics Statement 270 F.12 Supplementary Materials and Data Deposit 272 F.13 Guidelines
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