Preface...xv Contributors...xvii 1 Reviewing the Gaps in the Safety and Risk Assessment of Nanoparticles and Nanomaterials... 1 1.1 Introduction... 1 1.2 Risk Assessment and Sustainability... 2 1.2.1 Effect of Nanosized Particles... 3 1.2.2 Integrated Platforms for Nanoparticle Toxicity Analysis... 6 1.3 Conclusions... 9 References... 9 2 Lipid Nanoparticles in Cancer Therapy: Past, Present and Future... 11 2.1 Introduction... 11 2.2 Concepts and Definitions of Lipid Nanoparticles... 11 2.3 In Vitro Properties and In Vivo Features of Lipid Nanoparticles... 15 2.4 Lipid Nanoparticles for Cancer Chemotherapeutics... 19 2.4.1 Delivery of Poorly Water-soluble Compounds... 20 2.4.2 Delivery of Water-soluble Ionic Salts... 21 2.4.3 Delivery of Water-soluble Nonionic Drug Molecules... 22 2.5 Conclusions... 23 References... 23 v
3 Multifunctional Lipid Nanocarriers for Cancer Prevention and Therapy... 29 3.1 Introduction... 29 3.1.1 Cancer Vaccines and Chemoprevention... 29 3.1.2 Cancer Treatment Strategies... 30 3.1.3 Delivery Challenges in Cancer Prevention and Therapy... 31 3.2 Lipid-based Nanotechnology for Cancer... 32 3.2.1 Nanotechnology Applications in Medicine... 32 3.2.2 Cancer Nanomedicine... 33 3.2.3 Passive and Active Targeting Strategies... 33 3.2.4 Multifunctional Nanotechnology... 38 3.3 Illustrative Examples in Cancer Prevention... 39 3.3.1 Lipid Nanocarriers for Cancer Vaccines... 39 3.3.2 Lipid Nanocarriers for Cancer Prevention... 41 3.4 Illustrative Examples in Cancer Therapy... 42 3.4.1 Multifunctional Liposomal Formulations... 42 3.4.2 Multifunctional Nanoemulsion Formulations... 43 3.5 Illustrative Examples of Lipid Nanocarriers for Nucleic Acid Delivery... 44 3.6 Conclusions... 46 Acknowledgements... 46 References... 47 4 Targeting Solid Lipid Nanoparticles for Drug Delivery in Cancer Therapy... 55 4.1 Introduction... 55 4.2 Chemotherapy and Its Limitations... 55 4.2.1 Need for Targeted Drug Delivery Systems... 56 4.2.2 Particulate Carriers for Anti-cancer Drug Delivery... 56 4.3 Solid Lipid Nanoparticles... 58 4.3.1 Encapsulation of Hydrophobic Drugs... 59 4.3.2 Encapsulation of Hydrophilic Drugs... 63 4.4 Modifications to Improve Encapsulation Efficiency and Release Characteristics... 65 4.5 Modifications to Improve Multidrug Resistance... 66 4.6 Modifications to Improve Cellular Uptake and Targetability... 68 vi
4.7 Modifications to Achieve Brain Targeting... 71 4.8 Toxicity Concerns... 74 4.9 Conclusions... 75 References... 76 5 Targeting Liposomes for Drug Delivery in Cancer Therapy... 85 5.1 Introduction... 85 5.2 Types of Liposomal Anti-cancer Drugs and Their Clinical Use... 86 5.2.1 Anthracyclines: Liposomal Doxorubicin and Daunorubicin... 87 5.2.2 Pyrimidine Analogues: Liposomal Cytarabine and Gemcitabine... 87 5.2.3 Vinca Alkaloids: Liposomal Vincristine and Vinorelbine... 91 5.2.4 Taxanes: Liposomal Paclitaxel and Docetaxel... 94 5.2.5 Platinum Compound: Liposomal Cisplatin and Oxaliplatin... 96 5.2.6 Liposomal Camptothecin Analogues... 98 5.2.7 Podophyllotoxin Derivatives: Liposomal Etoposide... 101 5.2.8 Nitrogen Mustard Analogues: Liposomal Chlorambucil... 103 5.3 Ligand-mediated Targeting Liposomes... 104 5.3.1 Antibody-mediated Targeting Liposomes... 106 5.3.2 Peptide-mediated Targeting Liposomes... 109 5.3.3 Folate-mediated Targeting Liposomes... 112 5.3.4 Transferrin-mediated Targeting Liposomes... 112 5.4 Future Directions of Liposome-based Anti-cancer Drugs... 113 5.5 Conclusions... 114 Acknowledgements... 115 References... 115 6 Cationic Liposomes and Tumour Vasculature Targeting: A Therapeutic Approach that has Potential for Solid Tumours...137 6.1 Introduction... 137 6.2 Tumour Cell Targeting versus Tumour Vasculature Targeting... 138 6.3 Tumour Angiogenesis... 139 6.3.1 Formation of Tumour Vessels... 139 6.3.2 Structure and Function of Tumour Vessels... 140 vii
6.3.3 Lack of Functional Lymphatics... 141 6.3.4 Methods for Evaluating Angiogenesis... 141 6.4 Tumour Vascular Targeting with Cationic Liposomes... 142 6.4.1 Development of Cationic Liposomes Homing to Tumour Vasculature... 143 6.4.2 Cationic Liposomes and Encapsulated Drug Behaviour... 145 6.4.3 Effect of Dosing Schedule on the Anti-tumour Efficacy of Cationic Liposomal Formulations... 147 6.4.4 Pharmacokinetics of Cationic Liposomes... 147 6.5 Dual Targeting Approach of Both Tumour Endothelial Cells and Tumour Cells... 150 6.6 Effect of Sequential Administration on the Anti-tumour Efficacy of Cationic Liposomal Formulations... 152 6.7 Clinical Applications of Cationic Liposomes: Promise and Obstacles... 154 6.7.1 Safety of Cationic Liposomes in Preclinical and Clinical Use... 154 6.7.2 Clinical Applications of Cationic Liposomes in Cancer Therapy... 156 6.8 Conclusions... 157 Acknowledgements... 158 References... 158 7 Lipid-based Nanocarriers for Cancer Gene Therapy...169 7.1 Introduction... 169 7.2 Preclinical Studies Testing Lipid-based Nanocarriers for Cancer Gene Therapy... 170 7.3 Clinical Studies Testing Lipid-based Nanocarriers for Cancer Gene Therapy... 178 7.4 Conclusions... 181 Acknowledgements... 182 References... 182 8 Lipid-based Biomimetics: General Perspectives in Drug and Vaccine Delivery...189 8.1 Introduction... 189 8.2 Intermolecular Interactions... 195 viii
8.3 Carriers in the Biological Milieu... 204 8.4 Lipid Coating on Particles and Its Applications... 212 8.5 Conclusions... 225 References... 226 Acknowledgements... 226 9 Advances in Liposomal Formulations for Targeting Lung Cancer...257 9.1 Introduction... 257 9.2 Targeting Lung Cancer Cells... 258 9.2.1 Physical Targeting... 258 9.2.2 Biological Targeting... 260 9.3 Lipid-based Targeted Therapies... 262 9.3.1 Ligand-targeted Liposomes... 262 9.3.2 Drug Release from Liposomes... 263 9.4 Therapeutic Agents Delivered by Liposomes... 264 9.5 Clinical Use of Liposomes for Lung Cancer... 264 9.5.1 Liposomal Formulations of Anthracyclines... 269 9.5.2 Liposomal Formulations of Topoisomerase I Inhibitors and Taxanes... 270 9.5.3 Liposomal Formulations of Cancer Vaccines and Gene Therapy Agents... 271 9.5.4 Liposomal Formulations of Cisplatin... 271 9.6 Conclusions... 272 References... 273 10 Nanocarriers Targeting Breast Cancers to Deliver Modulators of Oestrogen Receptor...279 10.1 Introduction... 279 10.2 Oestrogen Receptor in the Mammary Gland... 280 10.2.1 Oestrogen Receptors in the Normal Breast... 280 10.2.2 Oestrogen Receptor in Breast Cancers... 282 10.3 Oestrogen Receptor-mediated Signalling... 282 10.3.1 Oestradiol-dependent Transcription... 282 10.3.2 Oestrogen Receptor Activation through Phosphorylations... 284 ix
10.3.3 Nongenomic Action of Oestrogen Receptor... 285 10.3.4 The Intriguing Role of Oestrogen Receptor β... 285 10.4 Classical Therapeutics used in Breast Cancer... 286 10.4.1 Chemotherapy and Radiotherapy... 286 10.4.2 Hormone Therapy... 286 10.5 Nanocarriers Targeting Oestrogen Receptor-dependent Breast Cancer... 288 10.5.1 General Considerations... 288 10.5.2 Conventional Nanoparticles... 290 10.5.3 Stealth Nanoparticles... 290 10.6 Active Targeted Nanoparticles... 293 10.6.1 Small Molecule-targeted Liposomes... 294 10.6.2 Magneto-liposomes... 295 10.6.3 Immuno-targeted Liposomes... 295 10.7 Novel Molecular-targeted Approaches for Liposomal Delivery... 297 10.7.1 Silencing Ribonucleic Acids and Antisense Oligonucleotides... 297 10.7.2 Heat Shock Protein 90 Inhibitors... 298 10.7.3 Histone Deacetylase Inhibitors... 298 10.7.4 PI3K/Akt Inhibitors... 302 10.7.5 Tyrosine Kinase Inhibitors... 304 10.7.6 Inhibitors of the Ras Family... 305 10.7.7 Ubiquitin-proteasome Inhibitors... 306 10.7.8 Gene Therapy... 306 10.8 Conclusions... 307 Acknowledgements... 308 References... 309 11 Lipid Nanocarriers Targeting Adrenocortical Tumour Cells: Genetics, Clinical Implications, Treatment Strategies and Molecular Targets...331 11. 1 Introduction... 331 11.2 Aetiology of Adrenocortical Carcinoma... 332 11.2.1 Li-Fraumeni Syndrome, the TP53 Gene and the 17p13 Locus... 332 x
11.2.2 Beckwith-Wiedemann Syndrome, the IGF2 Gene and the 11p15 Locus... 333 11.2.3 Multiple Endocrine Neoplasia Type 1, MEN1 Gene and 11q13 Locus... 334 11.2.4 Carney s Complex, Protein Kinase A R1A and 17q22 24 Locus... 334 11.3 Clinical Implications... 334 11.3.1 Recognising Familial or Syndromic Adrenocortical Tumours... 334 11.3.2 Evaluating the Prognosis of Patients with Adrenocortical Tumours... 335 11.4 Current Therapies for Adrenocortical Carcinoma... 335 11.4.1 Mechanism and Biotransformation of Mitotane... 336 11.4.2 Emerging Technologies in the Treatment of Adrenocortical Carcinoma... 337 11.5 Emerging Molecular Targets in Adrenocortical Carcinoma... 338 11.6 Challenges in Lipid-based Drug Delivery Systems for Adrenocortical Carcinoma... 338 11.7 Conclusions... 340 References... 341 12 Advances in Microemulsions and Nanoemulsions for Improved Therapy in Brain Cancer... 347 12.1 Introduction... 347 12.2 Brain Cancer... 347 12.2.1 Primary Brain Tumours... 347 12.2.2 Metastatic Brain Tumours... 348 12.3 Blood-brain Barrier... 348 12.3.1 Transport across the Blood-brain Barrier... 349 12.4 Blood-brain Barrier in Brain Cancer... 353 12.5 Drug Delivery Strategies... 354 12.5.1 Local Delivery... 354 12.5.2 Systemic Delivery... 355 12.5.3 Nano Drug Delivery Approaches for Brain Cancer... 357 12.6 Microemulsions and Nanoemulsions... 361 12.6.1 Preparation of Microemulsions and Nanoemulsions... 363 12.6.2 Components of Microemulsions and Nanoemulsions... 365 xi
12.7 Microemulsions and Nanoemulsions for Cancer Therapy... 367 12.8 Functional Microemulsions and Nanoemulsions to Cross the Blood-brain Barrier... 368 12.8.1 Functional Oils... 368 12.8.2 Functional Surfactants and Cosurfactants... 370 12.9 Multifunctional Microemulsions and Nanoemulsions... 372 12.10 Characterisation of Microemulsion and Nanoemulsion... 374 12.11 Evaluation In Vitro and In Vivo... 375 12.12 Advantages of Microemulsions and Nanoemulsions as Drug Delivery Systems... 376 12.13 Conclusions... 376 Acknowledgements... 377 References... 377 13 Bioavailability Enhancement and Brain Targeting of Curcumin: A Potential Anti-tumour Agent... 395 13.1 Introduction... 395 13.2 Chemistry of Curcumin... 397 13.3 Brain Tumour... 398 13.4 Blood-brain Barrier... 400 13.5 Role of Curcumin in Cancer... 402 13.5.1 Contribution of Curcumin in the Induction of Apoptotic Mechanism... 405 13.5.2 In Vitro Anti-cancer Effects of Curcumin... 406 13.5.3 Preclinical Pharmacodynamic Studies... 407 13.5.4 Combinatorial Chemoprevention by Curcumin... 409 13.5.5 Pharmacokinetic Studies in Animals... 410 13.5.6 Pharmacokinetic Studies in Humans... 410 13.5.7 Alleviation of Chemotherapy-induced Symptoms... 414 13.6 Therapeutic Strategies for Bioavailability Enhancement of Curcumin... 415 13.6.1 Adjuvants... 415 13.6.2 Self-microemulsifying Drug Delivery System... 416 13.6.3 Liposomes, Micelles and Phospholipid Complexes... 417 13.6.4 Nanoparticulate Delivery System... 418 13.6.5 Solid Lipid Nanoparticles... 419 xii
13.7 Curcumin-loaded Solid Lipid Nanoparticles for Oral Administration... 419 13.7.1 Pharmacokinetics of Curcumin-loaded Solid Lipid Nanoparticles... 422 13.7.2 Apoptotic Effect of Curcumin-loaded Solid Lipid Nanoparticles on Human Neuroblastoma Cell Lines... 424 13.7.3 Curcumin-loaded Solid Lipid Nanoparticles across Blood-brain Barrier... 425 13.8 Conclusions... 426 References... 427 14 Lipid Nanomedicines for Eye Cancer Treatment... 439 14.1 Anatomy and Physiology of the Eye... 439 14.2 Neoplastic Diseases of the Eye... 442 14.3 Treatment of Ophthalmic Cancers... 443 14.4 Ocular Pharmacokinetics: Challenges and Obstacles... 445 14.5 New Frontiers in Drug Delivery to the Eye: Lipid Nanomedicines... 448 14.6 Conclusions... 451 Acknowledgements... 451 References... 452 15 Lipid Nanocarriers for Topical Anti-cancer Therapy: An Update... 461 15.1 Introduction... 461 15.2 Introduction to Skin Anatomy and Physiology... 462 15.2.1 The Epidermis... 462 15.2.2 The Dermis... 463 15.2.3 The Skin Appendages... 463 15.2.4 Skin Pathogens, Exotoxins and Cutaneous Cellular Defence... 464 15.3 Percutaneous Absorption... 465 15.3.1 Transepidermal Absorption... 465 15.3.2 Transfollicular (Shunt Pathway) Absorption... 465 15.3.3 Intercellular Pathway... 466 15.3.4 Factors Influencing Percutaneous Absorption... 466 xiii
15.4 Lipid-based Particulate Carriers... 470 15.4.1 Class I - Based Delivery Systems... 471 15.4.2 Class II - Based Delivery Systems... 473 15.4.3 Class III - Based Delivery Systems... 477 15.5 Lipid-based Nanocarriers for Herbal Anti-cancers... 478 15.6 Lipid-based Nanocarriers for Gene Delivery for Cancer... 480 15.7 Toxicity Considerations of Nanoparticles... 482 15.8 Conclusions... 485 Acknowledgements... 485 References... 486 16 Treatment of Skin Cancer Using Sesamol-loaded Solid Lipid Nanoparticles... 493 16.1 Introduction... 493 16.2 Antioxidants in Skin Cancer... 493 16.3 Need of Suitable Delivery Systems for Antioxidant Molecules... 494 16.4 Open Sesame... 496 16.4.1 Pharmacology of Sesamol... 497 16.4.2 Preliminary Physicochemical Studies on Sesamol... 497 16.5 Solid Lipid Nanoparticles... 498 16.5.1 Solid Lipid Nanoparticles in Topical Drug Delivery... 499 16.6 In Vitro Evaluation of Sesamol... 500 16.6.1 Anti-cancer Studies in Molt-4 and HL-60 Cancer Cell Lines... 500 16.6.2 Deoxyribonucleic Acid Fragmentation Assay... 501 16.6.3 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium Bromide Assay... 502 16.7 Development and Characterisation of Sesamol-loaded Solid Lipid Nanoparticles... 506 16.7.1 Preparation of Solid Lipid Nanoparticles by Microemulsification-solidification Method... 506 16.7.2 Particle Size Analysis... 507 16.7.3 Encapsulation Efficiency... 508 16.7.4 Differential Scanning Calorimetry... 509 xiv
16.8 Skin Permeation Studies... 510 16.9 Pharmacokinetic Studies... 512 16.10 In Vivo Skin Anti-cancer Studies... 514 16.10.1 Animal Model and Treatment Groups... 515 16.10.2 Macroscopic Evaluation of Cancer... 516 16.10.3 Biochemical Analysis of Skin Homogenates... 516 16.10.4 Histopathological Analysis... 519 16.11 Conclusions... 520 References... 520 Abbreviations...527 Index...541 xv