Nanotechnology in Therapeutics

Costas Demetzos is Professor of Pharmaceutical Nanotechnology at the National and Kapodistrian University of Athens. Currently, Prof. Demetzos serves as Director of the Laboratory of Pharmaceutical Technology, and since 2008 he serves as President of the Hellenic Pharmaceutical Society (HPS). His research interests include pharmaceutical nanotechnology, nanomedicine, and thermodynamics.

About the Author ix

Foreword xiii

Advances in Pharmaceutical Technology: Series Preface xv

Preface xvii

Acknowledgments xxi

List of Abbreviations xxiii

List of Figures xxix

List of Tables xxxv

Part A Nanotechnology: Introduction and Brief Historical Overview 1

1 Introduction and Applications of Nanotechnology 3

1.1 Nanotechnology: Introduction and Brief Historical Overview 3

1.2 An Overview of Nanomedicines 9

1.3 Nanomedicine 10

1.4 The Strategic Research and Innovation Agenda for Νanomedicine (SRIA) 2016– 2030 (www.etp- nanomedicine.eu) 31

2 Biophysics, Thermodynamics, and Stability of Colloidal Dispersion Nanosystems 37

2.1 The Eukaryotic Cell Membranes 37

2.1.1 Structure and Function of Cell Membranes 38

2.1.2 Thermodynamic Properties of the Lipid Bilayers of Cell Membranes 40

2.2 Liquid Crystals (LCs) 43

2.2.1 Thermotropic and Lyotropic Liquid Crystals 45

2.3 Liquid Crystals in Biological Systems 46

2.4 The Role of Lipidic Domains in Cell Membranes 51

2.4.1 Lipid Conformational and Motional Properties 56

2.5 Dispersion Nanosystems 57

2.6 Stability of Nanocolloidal Dispersion Systems 62

2.6.1 Fundamentals of DLVO Theory 62

2.7 The DLVO Theory 64

2.7.1 Historical Background in Brief 64

2.7.2 Extension of the Classic DLVO Theory 66

2.7.3 Classification of Hydration Forces During the Interaction of Nanoparticles of a Colloidal Dispersion System 67

2.7.4 Entropic Effect 70

2.7.5 Osmotic Effect 71

2.7.6 Enthalpic Stabilization 71

2.8 Introduction to Applied Thermodynamics and Biothermodynamics 72

2.8.1 Introduction to Thermodynamics 72

2.8.2 Small System Thermodynamics 73

2.8.3 Comparison of Thermal Analysis with Other Analytical Techniques 75

2.8.4 Classification of Thermal Analysis Techniques 75

2.8.5 Differential Scanning Calorimetry: Basic Principles 76

2.8.6 Polymorphism – Lyotropism 77

2.8.7 Differential Scanning Calorimetry (DSC) Types 78

2.9 Light Scattering Techniques 80

2.9.1 Photon Correlation Spectroscopy (PCS) 80

2.10 Microscopy 82

2.10.1 Optical Microscopy 83

2.10.2 Electron Microscopy 83

2.10.3 Scanning Probe Microscopy 83

Part B Lipid and Polymeric Nanostructures in Medicine 87

3 Liposomes: An Overview 89

3.1 Introduction and Historical Issues of Liposomal Technology 89

3.2 Types of Liposomes 99

3.3 Entrapment of Bioactive Molecules in Multilamellar Lipid Vesicles and Liposomes 101

3.4 Advantages of Liposomes 103

3.5 Liposomes as Model of the Cell Membrane and Properties of Their Liquid Crystalline State of Matter 105

3.6 Liposome Physicochemical Characterization and Their Physical Stability 106

3.6.1 Summary of Liposome Preparation Methods 110

3.7 Liposomes as Analytical Tool 114

3.7.1 Biosensors Based on Liposome Technology 115

3.7.2 Future Perspectives in Lipidic Drug Delivery Nanosystems 118

4 Lipidic and Polymeric Nanomedicines in Clinical Applications 123

4.1 Liposomal Nanomedicines 123

4.1.1 Anticancer Liposomal Medicines 123

4.1.2 Antifungal Liposomal and Lipidic- based Nanomedicines. Case Study of Liposomal and Lipidic- based Amphotericin B 131

4.1.3 Lipid Nanoparticles 133

4.2 Advanced Liposomal Nanomedicines 138

4.2.1 Stimuli- responsive Liposomal Nanosystems 138

4.2.2 Immunoliposomes 139

4.2.3 Mitochondria as Target Domain 140

4.3 Polymers 144

4.3.1 Polyelectrolytes 146

4.4 Polymersomes 147

4.4.1 Polymersome Size and Size Distribution Evaluation 148

4.4.2 Polymersome Properties and Applications 149

4.4.3 Polymersome Surface Chemistry 150

4.4.4 Polymerosome Applications 150

4.5 Biodegradable Polymeric Nanoparticles 151

4.6 Polymeric Micelles 151

4.7 Dendrimers 152

4.7.1 Dendrimer Use in Biomedicine 154

4.7.2 Dendrimer Applications 155

4.7.3 Dendrimer Application in Diagnostics with Magnetic Resonance Imaging Technique 156

5 Applied Nanotechnology 161

5.1 Nanotechnology in Therapeutics 161

5.2 Nanotechnology and Cancer 165

5.3 Nanooncology and Gene Transfer 167

5.4 Nanobiotechnology 170

5.5 Nanogenomics and Nanoproteomics 171

5.6 Delivery Nanosystems for Therapeutic Biological Products 172

5.7 New Therapies Based on Nanotechnology 173

5.8 Theranostics 176

5.8.1 Theranostics: Applications in the Treatment, Diagnosis of Diseases, and Tissue Monitoring 176

6 Nanotechnology in Vaccines 181

6.1 Introduction to Vaccines 181

6.2 Development of Novel Nanovaccines 187

6.3 Liposomes, Lipid Nanoparticles, and Nonviral Lipid Nanoparticles (Virosomes) 189

6.4 Vaccines Against SARS‐CoV‐2 Virus 198

6.4.1 Stability of Nanovaccines as Nanocolloids 201

6.5 Future Perspectives and the Concept of the “Thermodynamic Epitope” 203

6.6 LNPs‐based Nanovaccines in Clinical Applications 213

6.6.1 Comirnaty® 213

6.6.2 Spikevax 214

Part C Nanotechnology and Nanomedicine: The Regulatory Landscape 217

7 New Health Technologies and Regulatory Approaches 219

7.1 New Health Technologies and the Regulatory Landscape for the Approval Process 219

7.2 Nanoinformatics 221

7.2.1 Artificial Intelligence (AI) 223

7.3 Complex Systems, Complexity, and Artificial Bionanosystems 226

7.4 Chaos and Nonlinear Dynamics in Nanocolloids 230

7.4.1 Chaotic Dynamic Systems 232

7.4.2 Lyapunov Approximation 232

7.4.3 Linking Lyapunov Exponents to Information 234

7.5 Nanocolloids. Complexity, Chaos, and Stability 234

7.6 Regulatory Agencies 236

7.6.1 Medicine Approval Processes 238

7.7 Advanced Therapy Medicinal Products (ATMPs) 239

7.8 Approval Process for Advanced Therapy Medicinal Products 242

7.9 The Regulatory Framework for the Nanobiotechnological Products in the United States and the Role of the FDA 244

7.10 Regulatory Issues for Biotechnological Medicines. The Role of the EMA 246

7.11 Committee for Advanced Therapies (CAT) 249

7.12 Nanosimilars 249

7.13 Generics and Biosimilar Therapeutic Products 255

Index 261