Nanomaterials in Drug Delivery, Imaging, and Tissue Engineering

Ashutosh Tiwari is an assistant professor of nanobioelectronics at the Biosensors and Bioelectronics Centre, IFM-Linköping University, Editor-in-Chief of Advanced Materials Letters, and a materials chemist. He graduated from the University of Allahabad, India. He has published more than 125 articles and patents as well as authored/edited in the field of materials science and technology. Dr.Tiwari received the 2011 "Innovation in Materials Science Award and Medal" during the International Conference on Chemistry for Mankind: Innovative Ideas in Life Sciences. Atul Tiwari is an associate researcher at the Department of Mechanical Engineering in the University of Hawaii, USA. He received his PhD in Polymer Science and earned the Chartered Chemist and Chartered Scientist status from the Royal Society of Chemistry, UK. His areas of research interest include the development of silicones and graphene materials for various industrial applications. Dr. Tiwari has invented several international patents pending technologies that have been transferred to industries. He has been actively engaged in various fields of polymer science, engineering, and technology and has published more than fifty peer-reviewed journal papers, book chapters, and books related to material science.

Preface xv Part I: Biomedical nanomaterials

1 Nanoemulsions: Preparation, Stability and Application in Biosciences 1
Thomas Delmas, Nicolas Atrux-Tallau, Mathieu Goutayer, SangHoon Han, Jin Woong Kim, and Jérôme Bibette

1.1 Introduction 2

1.2 Nanoemulsion:A Thermodynamic Definition and Its Practical Implications 5

1.2.1 Generalities on Emulsions 5

1.2.2 Nanoemulsion vs. Microemulsion, a Thermodynamic Definition 6

1.3 Stable Nanoemulsion Formulation 9

1.3.1 Nanoemulsion Production 9

1.3.2 Nanoemulsion Stability Rules 11

1.3.3 Nanoemulsion Formulation Domain 16

1.3.4 Conclusion on the Formulation of Stable Nanoemulsions 21

1.4 Nanoencapsulation in Lipid Nanoparticles 21

1.4.1 Aim ofActive Encapsulation 21

1.4.2 Lipid Complexity and Influence of Their Physical State 23

1.4.3 Amorphous Lipids for a Large Range of Encapsulated Molecules 27

1.4.4 Lipids Viscosity and Release 31

1.4.5 Conclusion on the Use ofAmorphous Lipid Matrices for Control OverActive Encapsulation and Release 34

1.5 Interactions between Nanoemulsions and the Biological Medium: Applications in Biosciences 35

1.5.1 Nanoemulsion Biocompatibility 35

1.5.2 Classical TargetingApproach by Chemical Grafting – Example of Tumor Cell Targeting by Crgd Peptide for Cancer Diagnosis and Therapy 38

1.5.3 New ‘No Synthesis Chemistry’Approach – Example of Pal-KTTKS andAsiaticoside Targeting for CosmeticActives Delivery 41

1.5.4 Conclusion on Nanoemulsions Application in Biosciences 46

1.6 General Conclusion 47

References 48

2 Multifunctional Polymeric Nanostructures for Therapy and Diagnosis 57
Angel Contreras-García and Emilio Bucio

2.1 Introduction 58

2.2 Polymeric-based Core-shell Colloid 61

2.3 Proteins and Peptides 64

2.4 Drug Conjugates and Complexes with Synthetic Polymers 65

2.5 Dendrimers, Vesicles, and Micelles 67

2.5.1 Dendrimers 67

2.5.2 Vesicles 68

2.5.3 Micelles 70

2.6 Smart Nanopolymers 71

2.6.1 Temperature and pH Stimuli-responsive Nanopolymers 72

2.6.2 Hydrogels 72

2.6.3 Stimuli Responsive Biomaterials 73

2.6.4 Interpenetrating Polymer Networks 74

2.7 Stimuli Responsive Polymer-metal Nanocomposites  75

2.8 Enzyme-responsive Nanoparticles 78

Acknowledgements 83

References 83

3 Carbon Nanotubes: Nanotoxicity Testing and Bioapplications 97
R. Sharma and S. Kwon

3.1 Introduction 98

3.1.1 What is Nanotoxicity of Nanomaterials? 98

3.2 Historical Review of Carbon Nanotube 99

3.3 Carbon Nanotubes (CNTs) and Other Carbon Nanomaterials 100

3.3.1 Physical Principles of Carbon Nanotube Surface Science 102

3.4 Motivation – Combining Nanotechnology and Surface Science with Growing Bioapplications 104

3.5 Cytotoxicity Measurement and Mechanisms of CNT Toxicity 111

3.1.6 In Vivo Studies on CNT Toxicity 113

3.1.7 Inflammatory Mechanism of CNT Cytoxicity 114

3.1.8 Characterization and Toxicity of SWCNT and MWCNT Carbon Nanotubes 116

3.6 MSCs Differentiation and Proliferation on Different Types of Scaffolds 120

3.6.1 An In Vivo Model CNT-Induced Inflammatory Response in Alveolar Co-culture System 122

3.6.2 Static Model: 3-Dimensional Tissue Engineered Lung 124

3.6.3 Dynamic Model: Integration of 3D Engineered Tissues into Cyclic Mechanical Strain Device 126

3.6.4 In Vivo MR Microimaging Technique of Rat Skin Exposed to CNT 127

3.7 New Lessons on CNT Nanocomposites 130

3.8 Conclusions 135

Part II: Advanced nanomedicine

4 Discrete Metalla-Assemblies as Drug Delivery Vectors 149
Bruno Therrien

4.1 Introduction 149

4.2 Complex-in-a-Complex Systems 150

4.3 Encapsulation of Pyrenyl-functionalized Derivatives 155

4.4 Exploiting the Enhanced Permeability and Retention Effect 159

4.5 Incorporation of Photosensitizers in Metalla-assemblies 162

4.6 Conclusion 165

Acknowledgments 165

References 166

5 Nanomaterials for Management of Lung Disorders and Drug Delivery 169
Jyothi U. Menon, Aniket S. Wadajkar, Zhiwe iXie, and Kytai T. Nguyen

5.1 Lung Structure and Physiology 170

5.2 Common Lung DiseasesAnd Treatment Methods 171

5.2.1 Lung Cancer 171

5.2.2 PulmonaryArterial Hypertension 172

5.2.3 Obstructive Lung Diseases 173

5.3 Types of Nanoparticles (NPs) 173

5.3.1 Liposomes 174

5.3.2 Micelles 176

5.3.3 Dendrimers 177

5.3.4 Polymeric Micro/Nanoparticles 177

5.4 Methods for Pulmonary Delivery 179

5.4.1 Nebulization 179

5.4.2 Metered Dose Inhalation (MDI) 182

5.4.3 Dry Powder Inhalation (DPI) 183

5.4.4 IntratrachealAdministration 183

5.5 Targeting Mechanisms 184

5.5.1 Passive Targeting 184

5.5.2 Active Targeting 185

5.5.3 Cellular Uptake Mechanisms 188

5.6 TherapeuticAgents Used for Delivery 188

5.6.1 ChemotherapeuticAgents 188

5.6.2 Bioactive Molecules 190

5.6.3 Combinational Therapy 190

5.7 Applications 191

5.7.1 Imaging/DiagnosticApplications 191

5.7.2 TherapeuticApplications 193

5.7.3 Lung Remodeling and Regeneration 194

5.8 Design Considerations of NPs 195

5.8.1 Half-life of NPs 195

5.8.2 Drug Release Mechanisms 195

5.8.3 Clearance Mechanisms in the Lung 196

5.9 Current Challenges and Future Outlook 197

6 Nano-Sized Calcium Phosphate (CaP) Carriers for Non-Viral Gene/Drug Delivery 199
Donghyun Lee, Geunseon Ahn and Prashant N. Kumta

6.1 Introduction 200

6.2 Vectors for Gene Delivery 202

6.2.1 Viral Vectors 203

6.2.2 Non-viral Vectors 203

6.2.3 Calcium Phosphate Vectors 205

6.3 Modulation of Protection and Release Characteristics of Calcium Phosphate Vector 213

6.4 Calcium Phosphate Carriers for Drug Delivery Systems 219

6.4.1 Antibiotics Delivery 219

6.4.2 Growth Factor Delivery 221

6.5 Variants of Nano-calcium Phosphates: Future Trends of the CaPDelivery Systems 221

Acknowledgements 223

References 223

7 Organics ModifiedMesoporous Silica for Controlled Drug Delivery Systems 233
Jingke Fu, Yang Zhao, Yingchun Zhu and Fang Chen

7.1 Introduction 233

7.2 Controlled Drug Delivery Systems Based on Organics Modified

7.2.1 MSNs-based Drug Delivery Systems Controlled by Physical Stimuli 238

7.2.2 MSNs-based Drug Delivery Systems Controlled by Chemical Stimuli 246

7.3 Conclusions 258

References 259

Part III: Nanotheragnostics

8 Responsive Polymer-Inorganic Hybrid Nanogels for Optical Sensing, Imaging, and Drug Delivery 263
Weitai Wu and Shuiqin Zhou

8.1 Introduction 264

8.2 Mechanisms of Response 268

8.2.1 Reception of an External Signal 268

8.2.2 Volume Phase Transition of the Hybrid Nanogels 275

8.2.4 Regulated Drug Delivery 282

8.3 Synthesis of Responsive Polymer-inorganic Hybrid Nanogels 285

8.3.1 Synthesis of the Hybrid Nanogels from Pre-synthesized Polymer Nanogels 285

8.3.2 Synthesis of the Hybrid Nanogels from Pre-synthesized Inorganic NPs 289

8.3.3 Synthesis of the Hybrid Nanogels by a Heterogeneous Polymerization Method 292

8.4 Applications 293

8.4.1 Responsive Polymer-inorganic Hybrid Nanogels in Optical Sensing 293

8.4.2 Responsive Polymer-inorganic Hybrid Nanogels in Diagnostic Imaging 299

8.4.3 Responsive Polymer-inorganic Hybrid Nanogels in Drug Delivery 301

References 306

9 Core/Shell Nanoparticles for Drug Delivery and Diagnosis 315
Hwanbum Lee, Jae Yeon Kim, Eun Hee Lee, Young In Park, Keun Sang Oh, Kwangmeyung Kim, Ick Chan Kwonand Soon Hong Yuk

9.2 Core/Shell NPs from Polymeric Micelles 319

9.2.1 Polymeric Micelles with Physical Drug Entrapment 319

9.2.2 Polymeric Micelles with Drug Conjugation 321

9.2.3 Polymeric Micelles Formed by Temperature-Induced Phase Transition 323

9.3 Phospholipid-based Core/Shell Nanoparticles 325

9.4 Layer-by-Layer-Assembled Core/Shell Nanoparticles 329

9.5 Core/Shell NPs for Diagnosis 330

9.4 Conclusions 331

Acknowledgments 331

References 331

10 Dendrimer Nanoparticles and Their Applications in Biomedicine 339
Arghya Paul, Wei Shao, Tom J. Burdon, Dominique Shum-Tim and Satya Prakash

10.1  Introduction 340

10.2  Dendrimers and Their Characteristics 341

10.3  Biomolecular Interactions of Dendrimer Nanocomplexes 343

10.3.1  Genes (siRNA/ANS/DNA) 344

10.3.2  Drugs and Pharmaceutics 345

10.4  PotentialApplications of Dendrimer in Nanomedicine 347

10.4.1  Delivery of Chemotherapeutics 347

10.4.2  Delivery of Biomolecules 348

10.4.3  Imaging 350

10.5  Conclusion 353

Acknowledgements 355

Indexing words 355

References 355

11 Theranostic Nanoparticles for Cancer Imaging and Therapy 363
Mami Murakami, Mark J. Ernsting and Shyh-Dar Li

11.1  Introduction 363

11.2  Multifunctional Nanoparticles for Noninvasive

11.2.1 Radiolabeled Nanoparticles 366

11.2.2 Fluorescence Imaging of Biodistribution 367

11.2.3 Multimodal Radiolabel and Fluorescence Imaging of Biodistribution 368

11.2.4 MRI Imaging of Biodistribution 369

11.2.5 Multimodal MRI and Fluorescence Imaging of Biodistribution 371

11.2.6 Multimodal Optical and CT Imaging of Biodistribution 372

11.2.7 Pharmacokinetics and Pharmacodynamics of Theranostics vs Diagnostics 373

11.3  Multifunctional Nanoparticles for Monitoring Drug Release 375

11.3.1 MRI imaging of Drug Release 375

11.3.2 Fluorescent Imaging of Drug Release 379

11.4  Theranostics to Image Therapeutic Response 380

11.5  Conclusion and Future Directions 382

Acknowledgement 383

References 383

Part IV: Nanoscaffolds technology

12 Nanostructure Polymers in Function Generating Substitute and Organ Transplants 389
S.K. Shukla

12.1  Introduction 389

12.2  Important Nanopolymers 391

12.2.1 Hydrogels 393

12.2.2 Bioceramics 394

12.2.3 Bioelastomers 395

12.2.4 Chitosan and Derivatives 396

12.2.5 Gelatine 396

12.3  MedicalApplications 397

12.3.1 Tissue Engineering for Function Generating 398

12.3.2 Tissue Engineering inArtificial Heart 400

12.3.3 Tissue Engineering in Nervous System 401

12.3.4 Bone Transplants 404

12.3.5 Kidney and Membrane Transplants 406

12.3.6 Miscellaneous 409

Acknowledgement 411

References 411

13 Electrospun Nanofiberfor Three Dimensional Cell Culture 417
Yashpal Sharma, Ashutosh Tiwari and Hisatoshi Kobayashi

13.1  Introduction 417

13.2  Nanofiber Scaffolds Fabrication Techniques 419

13.2.1 Self-Assembly 419

13.2.2 Phase Separation 421

13.2.3 Electrospinning 422

13.3  Parameters of Electrospinning Process 424

13.3.1 Viscosity or Concentration of the Polymeric Solution 424

13.3.2 Conductivity and the Charge Density 425

13.3.3 Molecular Weight of Polymer 425

13.3.4 Flow Rate 425

13.3.5 Distance from Tip to Collector 425

13.3.6 VoltageApplied 426

13.3.7 Environmental Factors 426

13.4  Electrospun Nanofibers for Three-dimensional Cell Culture 426

13.5  Conclusions 429

References 431

14 Magnetic Nanoparticles in Tissue Regeneration 435
Anuj Tripathi, Jose Savio Melo and Stanislaus Francis D’Souza

14.1  Introduction 435

14.2  Magnetic Nanoparticles: Physical Properties 438

14.3  Synthesis of Magnetic Nanoparticles 440

14.4  Design and Structure of Magnetic Nanoparticles 443

14.5  Stability and Functionalization of Magnetic Nanoparticles 445

14.6  Cellular Toxicity of Magnetic Nanoparticles 450

14.7  Tissue EngineeringApplications of Magnetic Nanoparticles 453

14.7.1 Magnetofection 455

14.7.2 Cell-patterning 458

14.7.3 Magnetic Force-induced Tissue Fabrication 461

14.8  Challenges and Future Prospects 473

Acknowledgement 474

References 474

15 Core-sheath Fibersfor Regenerative Medicine 485
Rajesh Vasita and Fabrizio Gelain

15.1  Introduction 486

15.1.1 Tissue Engineering 487

15.1.2 Scaffold Fabrication Technology 488

15.2  Core-sheath Nanofiber Technology 489

15.2.1 Co-axial Electrospinning 491

15.2.2 Emulsion Electrospinning 501

15.2.3 Melt Co-axial Electrospinning 503

15.3Application of Core-sheath Nanofibers 504

15.3.1 Delivery of Bioactive Molecules 504

15.3.2 Tissue Engineering 513

15.4  Conclusions 519

References 519