Handbook of Clinical Nanomedicine, Volume

7/25/2019 Handbook of Clinical Nanomedicine, Volume

1/48

Pan Stanford Series on Nanomedicine Vol. 1

Handbook of

Clinical NanomedicineNanoparticles, Imaging, Therapy, andClinical Applications

edited by

Raj Bawa

Gerald F. Audette

Israel Rubinstein


2/48

Handbook of

Clinical Nanomedicine

Vol. 1


3/48

Published

Vol. 1

Handbook of Clinical

N: N,

I, T, C

A

Raj Bawa, Gerald F. Audee, andIsrael Rubinstein, eds.

2016

978-981-4669-20-7 (Hardcover)

978-981-4669-21-4 (eBook)

Vol. 2

Handbook of Clinical

N: Lw, B,R, Sf, Rk

Raj Bawa, ed., Gerald F. Audette

and Brian E. Reese, asst. eds.

2016

978-981-4669-22-1 (Hardcover)

978-981-4669-23-8 (eBook)

Forthcoming

Vol. 3

I E f

B

N

Raj Bawa, Jnos Szebeni,

Thomas J. Webster, andGerald F. Audee, eds.

2017

Vol. 4

I f Nb

F f M

Pz M

Shaker A. Mousa andRaj Bawa, eds.

2017

P Sf S N

Series Editor

Raj Bawa

Titles in the Series


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Pan Stanford Series on Nanomedicine Vol. 1

Handbook of

Clinical NanomedicineNanoparticles, Imaging, Therapy,and Clinical Applications

edited by

Raj Bawa, MS, PhDPatent Agent, Bawa Biotech LLC, Ashburn, Virginia, USA

Adjunct Professor, Department of Biological Sciences

Rensselaer Polytechnic Institute, Troy, New York, USA

Scientific Advisor, Teva Pharmaceutical Industries, Ltd., Israel

Gerald F. Audette, PhDAssociate Professor, Department of Chemistry

Acting Director, Centre for Research on Biomolecular Interactions

York University, Toronto, Canada

Israel Rubinstein, MDProfessor, Department of Medicine

University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USAAssociate Chief of Staff for Research and Development

Jesse Brown VA Medical Center, Chicago, Illinois, USA


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Published by

Pan Stanford Publishing Pte. Ltd.

Penthouse Level, Suntec Tower 38 Temasek BoulevardSingapore 038988Email: [email protected]: www.panstanford.com

Note from the Series Editor and Publisher

It should be noted that knowledge and best practices in the various ields

represented in this handbook (such as medicine, pharmacology, biotechnology,toxicology, pharmaceutical sciences, materials science, etc.) are constantly

changing. As new research and experience broaden our knowledge base,changes in research methods, legal and business practices or medical treatmentsmay become necessary. Therefore, the reader is advised to consult the mostcurrent information regarding: (i) various products, companies or proceduresfeatured; (ii) recommended doses, methods, duration of administration andcontraindications; and (iii) legal, business or commercial information provided.It is imperative that researchers, physicians, lawyers, policymakers and businessprofessionals always rely on their own experience and knowledge in evaluatingand using any information, procedures, formulations or experiments describedherein. To the fullest extent of the law, neither the publisher nor the authorsor editors, make any representations or warranties, express or implied, with

respect to information presented in this book. They assume no liability forany injury and/or damage to persons or property as a matter of productsliability, negligence or otherwise, or from any use or operation of any methods,products, drugs, medical procedures, instructions, legal opinions or ideaspresented in this handbook.

A catalogue record for this book is available from the Library of Congress and

the British Library.

Handbook of Clinical Nanomedicine: Nanoparticles, Imaging, Therapy,and Clinical Applications

Copyright 2016 Pan Stanford Publishing Pte. Ltd. All rights reserved. Thisbook, or parts thereof, may not be reproduced in any form or by any means,electronic or mechanical, including photocopying, recording or by anyinformation storage and retrieval system now known or to be invented, withoutwritten permission from the publisher. For photocopying of material in thisvolume, please pay a copying fee through the Copyright Clearance Center, Inc.,222 Rosewood Drive, Danvers, MA 01923, USA. In this case, permission tophotocopy is not required from the publisher.

ISBN 978-981-4669-20-7 (Hardcover)

ISBN 978-981-4669-21-4 (eBook)ISBN 978-981-4316-17-0 (Set, Hardcover)ISBN 978-981-4411-66-0 (Set, eBook)

Printed in the USA


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This book is dedicated with love to my father,

Dr. S. R. Bawa,

on his 85th birthday,dad, grandfather, inspiration, anatomist,

electron microscopist, department founder,

professor and head, university dean

the best teacher I ever had.

R.B.


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Ab E

Raj Bawa, MS, PhD, is president of BawaBiotech LLC, a biotech/pharma consultancy

and patent law irm based in Ashburn, VA, USA

that he founded in 2002. He is an inventor,

entrepreneur, professor and registered patent

agent licensed to practice before the U.S. Patent

& Trademark Ofice. Trained as a biochemist

and microbiologist, he has been an active researcher for over two

decades. He has extensive expertise in pharmaceutical sciences,

biotechnology, nanomedicine, drug delivery and biodefense, FDA

regulatory issues, and patent law. Since 1999, he has held various

adjunct faculty positions at Rensselaer Polytechnic Institute in

Troy, NY, where he is currently an adjunct professor of biological

sciences and where he received his doctoral degree in three years(biophysics/biochemistry). Since 2004, he has been an adjunct

professor of natural and applied sciences at NVCC in Annandale,

VA. He is a scientiic advisor to Teva Pharmaceutical Industries,

Ltd., Israel. He has served as a principal investigator of National

Cancer Institute SBIRs and reviewer for both the National

Institutes of Health and the National Science Foundation. In

the 1990s, Dr. Bawa held various positions at the US Patent &

Trademark Ofice, including primary examiner for 6 years. He is

a life member of Sigma Xi, co-chair of the Nanotech Committee ofthe American Bar Association and serves on the global advisory

council of the World Future Society. He has authored over 100

publications, co-edited four texts and serves on the editorial

boards of 17 peer-reviewed journals, including serving as a special

associate editor of Nanomedicine (Elsevier) and an editor-in-chiefof the Journal of Interdisciplinary Nanomedicine (Wiley). Some ofDr. Bawas awards include the Innovations Prize from the

Institution of Mechanical Engineers, London, UK (2008);Appreciation Award from the Undersecretary of Commerce,

Washington, DC (2001); the Key Award from Rensselaers Ofice of

Alumni Relations (2005); and Lifetime Achievement Award from

the American Society for Nanomedicine (2014).


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viii

Gerald F. Audette, PhD, has been a faculty memberat York University in Toronto, Canada, since 2006.

Currently, he is an associate professor in the

Department of Chemistry and acting director of the

Centre for Research on Biomolecular Interactions at

York University. He received his doctorate in 2002

from the Department of Biochemistry at the

University of Saskatchewan in Saskatoon, Canada. Working with Drs.

Louis T. J. Delbaere and J. Wilson Quail (19952001), Dr. Audettes

research focused on the elucidation of the proteincarbohydrate

interactions that occur during blood-group recognition (in particular

during the recognition of O blood type) using high-resolution X-raycrystallography. Dr. Audette conducted his postdoctoral research

at the University of Alberta (20012006) in Edmonton, Canada.

Working with Drs. Bart Hazes and Laura Frost; his research again

utilized high-resolution protein crystallography to examine the

correlation between protein structure and biological activity of

type IV pilins that are assembled into pili used by bacteria for

multiple purposes, including cellular adhesion during infection.

It was during these studies that Dr. Audette identiied the

generation of protein nanotubes from engineered pilin monomers.

Dr. Audette also studied the process of bacterial conjugation (or

lateral gene transfer) using the F-plasmid conjugative system of

Escherichia coli. Current research directions include: structure/function studies of proteins involved in bacterial conjugation

systems, the structural and functional characterization of

several type IV pilins (the monomeric subunit of the pilus), their

assembly systems, and adapting these unique protein systems for

applications in bionanotechnology. Dr. Audette has previouslyserved as co-editor-in-chief of the Journal of Bionanoscience(20072010).

Israel Rubinstein, MD, is professor of medicineat the College of Medicine, University of Illinois

at Chicago, USA. He is member of the section of

pulmonary, critical care, allergy and sleep medicine

in the Department of Medicine, University of Illinois

at Chicago. He is an attending physician at theUniversity of Illinois Hospital and Health Sciences

System and Jesse Brown VA Medical Center in Chicago. Dr. Rubinstein

About the Editors


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ix

is also the associate chief of staff for research and development at

the Jesse Brown Veterans Administration Medical Center. Prior

to his appointment at the University of Illinois at Chicago, he was

associate professor of medicine at the University of Nebraska

Medical Center in Omaha, Nebraska, USA. Dr. Rubinstein received

his medical degree from the Hebrew University-Hadassah School of

Medicine in Jerusalem, Israel. He was a medical resident in Israel,

fellow in respirology at the University of Toronto and a research

fellow at the Cardiovascular Research Institute, University of

California at San Francisco. Dr. Rubinstein holds 18 issued and

pending patents and has authored close to 200 peer-reviewed

papers in scientiic journals. Dr. Rubinsteins funded researchendeavors center around nanomedicine and targeted drug delivery

with speciic focus on lipid-based products and repurposing.

Currently, he serves as editor-in-chief of Nanotechnology, Scienceand Applications, associate editor of the International Journal ofNanomedicine, and editorial board member of several scientiicjournals. Dr. Rubinstein is member of the scientiic advisory board

of the International Academy of Cardiology. He is a fellow of the

American Heart Association as well as the American College

of Physicians and the American College of Chest Physicians. In

addition, he is a member of the American Thoracic Society, American

Physiological Society, American Society for Pharmacology and

Experimental Therapeutics, and American Microbiology Society.

Dr. Rubinstein is a board member and director of Advanced Life

Sciences, a publicly traded biopharmaceutical company based

in Woodridge, Illinois, USA. He is a co-founder of ResQ Pharma,

an emerging clinical stage pharmaceutical company focusing

on repurposing FDA-approved drugs for cardiopulmonaryresuscitation and drug overdoses.

About the Editors


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C

List of Corresponding Authors xxix

Foreword xxxiii

Small Is Beautiful: Preface by the Series Editor xxxvii

Acknowledgements xlv

SectionI: General Introduction and Beginnings

1. S N: I H

P 3

Chin Wee Shong, PhD, Sow Chorng Haur, PhD,

and Andrew T. S. Wee, PhD

1.1 The Development of Nanoscale Science 3

1.2 The Nanoscale 9 1.3 Examples of Interesting Nanoscience Applications 12

2. N: D I f N

w B S 21

Ki-Bum Lee, PhD, Aniruddh Solanki, PhD, John Dongun Kim, PhD,and Jongjin Jung, PhD

2.1 Introduction 21

2.2 Designing Nanomaterials for Biology andMedicine 22

2.3 Application of Nanomaterials in BiomedicalResearch 29

2.4 Nanosystematic Approach for Cell Biology 39

2.5 Conclusion 43

3. A S I W f N 61

Rutledge Ellis-Behnke, PhD

3.1 Introduction 61

3.2 Size Medicine 62

3.3 Newer Areas of Emerging Therapeutics 64


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xii Contents

3.4 Safety 66

3.5 Fad, Promises, or Reality? 67

4. T T R N R A 73

Melanie Swan, MBA

4.1 Introduction 73

4.2 Top 10 Areas of Recent Advance in Nanomedicine,Bio-Nanomaterials, and Nanodevices 76

4.3 Conclusion 93

5. T C E f N 103

Fritz Allhoff, JD, PhD

5.1 Introduction 103

5.2 The Rise of Nanomedicine 105

5.3 Diagnostics and Medical Records 109

5.4 Treatment 114

5.5 Moving Forward 119

6. W N? Df N Cx

f D D 127

Raj Bawa, MS, PhD


6.2 Brief Historical Background 133

6.3 What is Nano? 136

6.4 Physical Scientists versus Pharmaceutical Scientists:Different Views of the Nanoworld 146

6.5 Is Drug Delivery at the Nanoscale Special?Does Size Matter? 149

6.6 Summary and Future Prospects 161

SectionII: Nanoparticles, Nanodevices, and Imaging

7. P f N M 171

Takuya Tsuzuki, PhD

7.1 Introduction 171 7.2 Nanoparticulate Materials 174

7.3 Common Characteristics of All Types ofNanoparticulate Materials 175


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xiiiContents

7.4 Characteristics of Speciic Types ofNanoparticulate Materials 190

7.5 Summary 202

8. S D N: M f P

Pk Bf 211

Andrew Owen, PhD, and Steve P. Rannard, DPhil


8.2 Physical Properties of Solid Drug Nanoparticles 212

8.3 Approaches for Solid Drug Nanoparticle

Manufacture 214 8.4 Pharmacokinetic Advantages 217

8.5 Conclusions 223

9. D D f A

N P 233

Heidi M. Mansour, PhD, RPh, Chun-Woong Park, PhD,and Raj Bawa, MS, PhD

9.1 Introduction 233 9.2 Approved Nanopharmaceutical Products:

Parenteral Drug Delivery 242

9.3 Approved Nanopharmaceutical Products:Oral Drug Delivery 246

9.4 Approved Nanopharmaceutical Products:Dermal and Transdermal Drug Delivery 249

9.5 Approved Nanopharmaceutical Products:Pulmonary Drug Delivery 250

9.6 Conclusions and Future Prospects 252

10. Nz A D D 273

Sandip Chavhan, PhD, Kailash Petkar, PhD, andKrutika Sawant, PhD


10.2 Current Nanonization Strategies 277

10.3 Conversion to Solid Dosage Forms 286

10.4 Pharmaceutical Applications andCommercialization Aspects 287

10.5 Conclusions 291


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xiv Contents

11. M N f Pz M:

T C Mk 299

Dania Movia, PhD, Craig Poland, PhD, Lang Tran, PhD,Yuri Volkov, PhD, and Adriele Prina-Mello, PhD


11.2 Multilayered Engineered Nanoparticles 300

11.3 The Risk Assessment of Multilayered ENP 302

11.4 The Translation of Multilayered ENPin Clinical Markets 305


12. N f P A 319

Brigitta Loretz, PhD, Ratnesh Jain, PhD, Prajakta Dandekar, PhD,Carolin Thiele, PhD, Yamada Hiroe, PhD, Babak Mostaghaci, PhD,Lian Qiong, MSc, and Claus-Michael Lehr, PhD


12.2 Therapeutic Needs and Opportunities forNanopharmaceuticals 321

12.3 Current Arsenal of Nanocarriers 330 12.4 Translation of Nanopharmaceuticals into Clinics 333

12.5 Challenges for Developing FutureNanopharmaceuticals 343

12.6 Conclusions and Future Perspectives 349

13. P N f T 365

Shoshy Mizrahy, MSc,and Dan Peer, PhD


13.2 Polysaccharides 366

13.3 Main Mechanisms of Nanoparticle Preparationfrom Polysaccharides 372

13.4 Polysaccharide-Based Nanoparticles 376

13.5 Polysaccharide-Coated Nanoparticles 388

13.6 Summary 393

14. T S f C60Bkf 409

Harold W. Kroto, PhD

14.1 Carbon Cluster Studies 414

14.2 Carbon Chains in Space and Stars 415


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xvContents

14.3 Carbon in Space Dust and the Diffuse

Interstellar Bands 416

14.4 C60Pre-discovery Experiments 417 14.5 The Discovery of C60 419

14.6 C60Theoretical Prehistory 422

14.7 The Circumstantial Supporting Evidence 424

14.8 Skeptical Studies 427

14.9 Spectroscopic Theory 428

14.10 Extraction and Structure Proof 428

14.11 Aftermath Studies 431

14.12 Mechanism 433 14.13 Epilogue: Detection of C60in Space 434

15. A f N M I 443

Jason L. J. Dearling, PhD, and Alan B. Packard, PhD


15.2 Contrast Media for Computed Tomography 445

15.3 Ultrasound 454

15.4 Summary 459

16. N f N 465

Yuri L. Lyubchenko, PhD, DSc, Yuliang Zhang,

Alexey V. Krasnoslobodtsev, PhD,and Jean-Christophe Rochet, PhD


16.2 Basic Principles of AFM 466

16.3 AFM: Imaging of Biological Samples 467

16.4 Dynamic Biological Events: Time-lapse AFM 470

16.5 AFM Force-Spectroscopy and Intermolecular

Interactions 472

16.6 Concluding Remarks 482

17. N f M-M D

I D D 493

Catherine M. Lockhart, PharmD, and Rodney J. Y. Ho, PhD

17.1 Imaging 493

17.2 Multi-Modality Imaging 498

17.3 Nanoparticles 501


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xvi Contents

17.4 Targeted Nanoparticles for Multi-ModalityMolecular Imaging 505

17.5 Conclusions and Future Prospects 51318. M N f M R

I: A T P w T 521

Ryan A. Ortega,Thomas E. Yankeelov, PhD,and Todd D. Giorgio, PhD


18.2 Properties of Iron Oxide Nanoparticles 523

18.3 Fabrication 526

18.4 Clinically Available Diagnostic Materials 530 18.5 Potential Future Clinical Applications 534


19. F--H M T C

I U U D-M C D 549

Michelle S. Bradbury, MD, PhD, and Ulrich Wiesner, PhD


19.2 Pre-Clinical Studies 553 19.3 Clinical Trial Design 554

19.4 Particle Tracer PK and Metabolic Analyses 555

19.5 Clinical Multimodal Imaging with124I-cRGDY-PEG-C Dots in Melanoma Patients 557


20. A F M f N 567

Shivani Sharma, PhD, and James K. Gimzewski, PhD


20.2 AFM for Cancer Diagnosis 572

20.3 Summary and Conclusions 581

21. A F M I Pb f

A N 589

Yuri L. Lyubchenko, PhD, DSc, and Luda S. Shlyakhtenko, PhD

21.1 Introduction 589 21.2 Protein Misfolding and Diseases 590


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xviiContents

21.3 AFM Characterization of the Nanoscale Structureof Amyloid Aggregates 592

21.4 AFM Visualization of Dynamic Biological Events 596 21.5 AFM Force Spectroscopy and Intermolecular

Interactions 599


22. I-B H-C A, S C

N: A N S f D D 617

Leonardo J. Solmesky, PhD, Yonatan Adalist, MSc,

and Miguel Weil, PhD


22.2 Image-Based High-Content Screening 619

22.3 Stem Cells Used for Lead Discovery 622

22.4 Personalized Medicine Platforms 627

22.5 Stem Cells as Tools for Improvement of Safetyand Toxicology 628

22.6 Advances in Nanomedicine for Drug Discovery

Using HCS 629 22.7 Conclusions 631

23. V N: T f M S

B 641

Nicole F. Steinmetz, PhD, and Marianne Manchester, PhD

23.1 What Is Nano? 642

23.2 Where Did it all Begin? A History of VNPs:

From Pathogens to Building Blocks 643 23.3 Why VNPs? Materials Properties of VNPs 647

23.4 Summary 651

24. B S S: N f

If G D 657

Agnesa Shala, PhD, Michele Ferraro, MSc,and Gerald F. Audette, PhD

24.1 Introduction 657 24.2 Bacterial Secretion Systems 659


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xviii Contents

24.3 The Type IV Secretion System 665


25. T V C S N 687

Frank J. Boehm


25.2 Vascular Cartographic Scanning Nanodevice 689

25.3 Overview of Envisaged VCSN Capabilities 690

25.4 Summary of VCSN Components 692

25.5 Discussion 694

25.6 VCSN Advantages 697 25.7 The Gastrointestinal Micro Scanning Device 698

25.8 Description of Scanning Procedure 701

25.9 Additional Issues 702

26. A O G N

f Db M 707

Angelika Domschke, PhD

26.1 Introduction: Importance of DiabetesManagement 707

26.2 Current Continuous Glucose Monitoring

Devices 708

26.3 Noninvasive Continuous Glucose

Monitoring Devices 709

26.4 Advantages of Noninvasive and Continuous

Ophthalmic/Contact Lens Glucose Sensors 710

26.5 Requirements for Ophthalmic/ContactLens Glucose Sensors 710

26.6 Fluorescence-Based Glucose Sensing 713

26.7 Colorimetric Sensors Based on Periodic

Optical Nanostructures 722

26.8 Holographic Glucose Sensors 724

26.9 Photonic Crystal Glucose Sensors 727

26.10 Microelectromechanical-Based Sensors 730

26.11 Progress and Remaining Challenges toward theDevelopment of Ophthalmic Glucose Sensors 736

26.12 Outlook 738


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xixContents

Section III: Therapy and Clinical Applications

27. Tw N f B If 749

Georgette B. Salieb-Beugelaar, PhD, and Patrick R. Hunziker, MD


27.2 Diagnostics for Bacterial Infections: From theState of the Art to Nanodiagnostics 751

27.3 Future Challenges for in vitroDiagnosticsSuited for Infectious Diseases 767

27.4 Conclusion 769

28. Cx E f B N 783

Jill B. Conner, MS, PhD, Raj Bawa, MS, PhD, J. Michael Nicholas, PhD,

and Vera Weinstein, PhD


28.2 Non-Biologic Complex Drugs and RegulatoryPathway for Follow-On Products 791

28.3 Nanomedicines and Regulatory Pathway forNanosimilars 796

28.4 Colloidal and Nanomedicine Properties ofCopaxone 797

28.5 Immunogenicity 810


29. Dx: T F FDA-A NF

I P (J 2015 U) 827

Yechezkel Barenholz, PhD

29.1 Historical Perspective 828

29.2 First-Generation Liposomal Doxorubicin:Liver-Directed Liposomal Doxorubicin 833

29.3 OLV-DOX Clinical Trials 846

29.4 DoxilDevelopment 857

29.5 Doxil Performance in Humans 876

29.6 What Is New about Doxil since 2011 883

29.7 Conclusions, Take Home Lessons,and What Is Next? 884

29.8 Doxil Historical Perspectives 886

29.9 Personal Touch 886


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xx Contents

30. N Sk B: T

T N-B D 907

Hagar I. Labouta, PhD,and Marc Schneider, PhD 30.1 Introduction 907

30.2 Enhancement of Drug Penetration viaEncapsulation in Nanocarriers 910

30.3 Skin Penetration/Permeation of Nanoparticles 915

30.4 Conclusion 926

31. A f N N-I

T G T 937

Mahmoud Elsabahy, PhD,MariaJimena Loureiro, MSc,

and Marianna Foldvari,PhD,DPharmSci


31.2 Topical Delivery as an Alternative Routeof Administration 939

31.3 Biological Barriers toward Topical Gene Therapy 939

31.4 Nanomedicines for Non-Invasive Topical Gene

Delivery Applications 941 31.5 Toward Needle-Free Future Nanomedicines 960


32. N T f If D 973

Alf Lamprecht, PhD


32.2 Rheumatoid Arthritis 974

32.3 Inlammatory Bowel Disease 978 32.4 Uveitis 982

33. A 3D N/Mfb Tq

f T O R 989

Benjamin Holmes, MSc, Thomas J. Webster, PhD,and Lijie Grace Zhang, PhD


33.2 Electrospinning 991 33.3 3D Printing 1002

33.4 Other Current Methodology 1011

33.5 Summary 1013


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xxiContents

34. N f A L Ij/A

R D S: A Sf

P? 1027

Ruxana T. Sadikot, MD, and Israel Rubinstein, MD


34.2 ALI and ARDS 1029

34.3 Nanomedicine for ALI and ARDS 1030

34.4 Nanomedicine for Drug Delivery to the Lung 1032


35. N: T A-V N 1039

Randall W. Barton, PhD, Jayant G. Tatake, PhD,

and Anil R. Diwan, PhD


35.2 Nanoviricides Polymeric Micelle Technology 1040

35.3 The Nanoviricide Antiviral Technology 1043

35.4 Nanoviricides Antiviral Effects 1046

36. N T E fO 1053

Lesley M. Hamming, PhD, JD, and Mark G. Hamming, MD


36.2 Beneits of Nanometer-Scale Features 1056

36.3 Commercialization 1057

36.4 Tissue Engineering for Bone 1060

36.5 Tissue Engineering for Cartilage 1063 36.6 Conclusion 1065

37. A f N D 1073

Karolina Jurczyk, DDS, PhD, and Mieczyslaw Jurczyk, PhD, DSc

37.1 Bulk Nanostructured Titanium 1074

37.2 Bulk TitaniumBioceramic Nanocomposites 1079

37.3 Dental Implants with Nanosurface 1089

37.4 Nanostructured Materials for Permanentand Bioresorbable Medical Implants 1095

37.5 Nanostructured Dental Composite RestorativeMaterials 1098


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xxii Contents

38. B A R M:

Sff, T M, T H

D, S C 1109

David W. Green, PhD,and Besim Ben-Nissan, PhD


38.2 Biomimetic Stem-Cell Scaffolds 1111

38.3 Electrospun Polysaccharide Core-Shell Fibres 1123

38.4 Self-Adjusting Bioscaffolds 1125

38.5 Transplantation and Biocargo Modules 1126

38.6 Polysaccharide Chitosan Coated Alginate

Nanocapsules 1130

38.7 Native Extracellular Matrix Equivalents 1132

38.8 Tissue Homing Devices 1134

38.9 Summary 1134


39. P A f N

N S 1141

Shu Wang, MD, PhD, and Jia Zhang, MS


39.2 Nanoparticles 1142

39.3 Phytochemicals 1144


40. D N f Eff T

f C D 1167

Bhuvaneshwar Vaidya, MPharm, PhD, and Suresh P. Vyas,

MPharm, PhD


40.2 Nanocarriers for the Treatment ofMyocardial Infarction 1168

40.3 Novel Carriers for the Treatment ofThromboembotic Diseases 1174

40.4 Nanocarriers for the Treatment ofRestenosis 1179

40.5 Concluding Remarks 1185


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xxiiiContents

41. Cb Nb Sb f N

Gw 1197

Ccilia Mnard-Moyon, PhD


41.2 Effects of Carbon Nanotubes on Neuronal

Cells Adhesion, Growth, Morphology andDifferentiation 1199

41.3 Electrical Stimulation of Neuronal CellsGrown on Carbon Nanotube-Based Substrates 1209

41.4 Investigation of the Mechanisms of the Electrical

Interactions Between CNTs and Neurons 1223 41.5 Conclusions and Perspectives 1228

42. P N f C T 1239

MohitS. Verma, Joshua E. Rosen, Ameena Meerasa,

Serge Yoffe, MEng, and Frank X. Gu, PhD


42.2 Biological Interactions of Nanomaterials 1241

42.3 Nanoparticle Targeting 1246 42.4 Classes of Polymeric Nanosystems for

Cancer Therapy 1249

42.5 Synthesis Methods 1255


43. N f R O 1273

Srinivas Sridhar, PhD, Ross Berbeco, PhD, Robert A. Cormack,

PhD, and G. M. Makrigiorgos, PhD 43.1 Gold Nanoparticles for Radiation Therapy 1274

43.2 Nanoparticles as Delivery Agents for

Radiation Sensitizers 1279

43.3 Nano-Coated Drug-Loaded Implants for

Biologically in situEnhanced, Image-GuidedRadio Therapy 1280

43.4 Nanoparticles as Imaging Agents for Radiation

Therapy 1284 43.5 Nanotechnology for Radiation Sources 1285



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xxiv Contents

44. G N C 1293

Joan Comenge, PhD, Francisco Romero, PhD, Aurora Conill, MS,

and Vctor F. Puntes, PhD 44.1 Historical Perspective on the Medical Use of Gold 1294

44.2 Gold in the ERA of Nanotechnology:New Properties for a Known Material 1294

44.3 Synthesis of Gold Nanoparticles 1295

44.4 Gold Nanoparticles to Target Cancer 1298

44.5 Challenges of Using Gold Nanoparticlesin Therapy 1300

44.6 Examples of Gold Nanoparticles in CancerTherapy 1304


45. S L N N

L C f C T 1315

Melike ner, PhD


45.2 Principles of Drug Incorporation into SLNand NLC, and Drug Release 1317

45.3 Targeting of SLN and NLC in the Treatmentof Cancer 1320

45.4 Incorporation of Anti-Neoplastic Drugsand Genes into SLN and NLC for CancerTreatment 1328

45.5 NSAIDs as Adjuvant to Cancer Chemotherapy 1333


46. N T Ab C

S E 1347

Archana Retnakumari, MTech, Parwathy Chandran, MTech,Ranjith Ramachandran, MSc, Giridharan L. Malarvizhi, MTech,Shantikumar Nair, PhD, and Manzoor Koyakutty, PhD


46.2 Protein Nanomedicine Targeted to Aberrant

Kinome Involved in Refractory Cancer 1348 46.3 ProteinProtein CoreShell Nanomedicine

Targeted to Multiple Kinases in Refractory Cancer 1351


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xxvContents

46.4 PolymerProtein Nanomedicine TargetingAberrant Kinome in Acute Myeloid Leukemia 1355

46.5 PolymerProtein CoreShell NanomedicineTargeted to Cancer Metastasis 1357

46.6 Protein Nanomedicine Targeted to AberrantEpigenome 1362


47. Bb N-B A

T B-B B 1379

Supriya D. Mahajan, PhD, Yun Yu, PhD, Ravikumar Aalinkeel, PhD,

Jessica L. Reynolds, PhD,Bindukumar B. Nair, PhD,Manoj J. Mammen, MD, Tracey A. Ignatowski, PhD,Chong Cheng, PhD, and Stanley A. Schwartz, PhD, MD


47.2 Methods 1382

47.3 Results 1388

47.4 Discussion 1392


48. HIV-Sf I w S

P-Lk N 1407

Orsolya Lorincz, PhD, and Julianna Lisziewicz, PhD


48.2 Nanomedicines for Immunotherapy 1409

48.3 Pathogen-Like DNA-Nanomedicines forImmunotherapy 1411

48.4 DermaVir Immunotherapy for the Cureof HIV/AIDS 1420


49. B E N:

F Lb O R 1433

Mario Ganau, MD, PhD, Roberto I. Foroni, PhD,Andrea Soddu, PhD, and Rossano Ambu, MD

49.1 Neurosurgery at the Crossroads ofNanotechnology, Biomedical Engineering

and Neuroscience 1433


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49.2 Applications in Neurovascular Surgery 1434

49.3 Applications in Pediatric Neurosurgery 1435

49.4 Applications in Neuro-Oncology 1436 49.5 Applications in Epilepsy and Functional Surgery 1437

49.6 Applications in Spinal Surgery 1438

49.7 Hemostasis in Brain and Spine Surgery 1438

49.8 New Horizons in Nanoneurosurgery 1439

49.9 Conclusion 1440

50. N-B S f Mb

D 1445

Rute Nunes, Carole Sousa, Bruno Sarmento, PhD,

and Jos das Neves, PhD


50.2 Limitations of Microbicide ProductsCurrently under Development 1446

50.3 Why Nanotechnology-Based Microbicides?Potential and Perils 1448

50.4 Nanosystems Presenting Intrinsic Activityagainst HIV/Competing with the Virus forHost Targets 1450

50.5 Nanosystems Acting as Carriers forMicrobicide Agents 1453

50.6 Mucoadhesive or Mucus-PenetratingMicrobicide Nanosystems? 1465

50.7 Nanotechnology-Based Rectal Microbicides 1471


51. N-B S Cb

E T f Sb: C S

F P 1493

Nisha C. Kalarickal, PhD, and Yashwant R. Mahajan, PhD


51.2 The Discovery and Consequent Developmentof Antibiotic Resistance 1494

51.3 Nanotechnology-Based Solutions againstSuperbugs 1498



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52. N B R V D 1517

Inbal Tsarfati-BarAd and Levi A. Gheber, PhD

52.1 The Need for Portable Biochips for Viral Detection 1517

52.2 Arrayed Biosensors: Biochips 1518

52.3 The Need for Miniaturization 1519

52.4 Nanolithography 1519

52.5 SPM-Based Nanolithography Methods 1520

52.6 Problems Associated with Miniaturization 1523


53. L N-T D D 1529

Anita Gupta, MSc, PhD, and G. S. Gupta, MSc, PhD


53.2 Lectins 1530

53.3 CarbohydrateLectin Interactions 1536

53.4 Nanotechnology and Drug Targeting Strategies 1538

53.5 Nanocarriers Used in Drug Delivery Systems 1538

53.6 Lectins as Drug Carriers 1547 53.7 Reverse Lectin Targeting 1548

53.8 Carbohydrate-Directed Targeting 1556


54. D f Eb H F V 1577

Ariel Sobarzo, PhD, Robert S. Marks, PhD,and Leslie Lobel, MD, PhD

54.1 Ebola Virus 1577 54.2 Etiology and Epidemiology 1578

54.3 Disease Transmission and Clinical Behavior 1579

54.4 Therapy 1579

54.5 The Fear of Ebola 1580

54.6 Current Methods in Ebola Diagnostics 1580

54.7 Nucleic Acid-Based Techniques 1584

54.8 Engineered Recombinant Proteins 1585

54.9 New Trends in Ebola Diagnostics 1587

54.10 Future Diagnostics 1590

54.11 The Effort Continues 1594


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55. N S FTb D 1611

Mariana Varna, PhD, Maya Juenet, MSc, Richard Bayles, PhD,Mikael Mazighi, MD, PhD, Cdric Chauvierre, PhD,and Didier Letourneur, PhD


55.2 Composition of Nano- and MicrocarriersUsed in Thrombolytic Therapy 1617

55.3 Thrombolytic Therapy Using Nanocarriers andMicrobubbles in Preclinical Development 1620

55.4 Microbubbles Associated with ThrombolyticDrugs and/or Ultrasound for Clinical Applications 1628

55.5 Discussion and Conclusion 1629

55.6 Future Perspective 1631

Index 1639


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L f C A

Fritz Allhoff Department of Philosophy, 3004 Moore Hall, Western MichiganUniversity, 1903 W. Michigan Avenue, Kalamazoo, MI 49008, USA,

Email: [email protected]

Gerald F. Audette Department of Chemistry and the Centre for Research onBiomolecular Interactions, York University, Life Sciences Building 327C,

4700 Keele Street, Toronto, Ontario M3J 1P3, Canada, Email: audette@

yorku.caYechezkel Barenholz Laboratory of Membrane and Liposome Research,

Department of Biochemistry and Molecular Biology, Institute of Medical

Research Israel-Canada, The Hebrew University-Hadassah Medical

School, POB 12272, Jerusalem 9112102, Israel, Email: chezyb@ekmd.

huji.ac.il

Randall Barton NanoViricides, Inc., One Controls Drive, Shelton, CT 06484,USA, Email: [email protected]

Raj Bawa Bawa Biotech LLC, 21005 Starlower Way, Ashburn, VA 20147,

USA, Email: [email protected] J. Boehm NanoApps Medical, Inc., 141 Empress Avenue South,

Thunder Bay, ON, Canada P7B 4N6, Email: [email protected]

Michelle S. Bradbury Department of Radiology, Memorial Sloan KetteringCancer Center, 1275 York Avenue, New York, NY 10065, USA, Email:

[email protected]

Jill B. Conner Teva Pharmaceutical Industries, Ltd., Specialty Life CycleInitiatives, 11100 Nall Avenue, Overland Park, KS 66211, USA, Email:

[email protected]

Jos das Neves INEB-Instituto de Engenharia Biomdica, University ofPorto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal, Email:[email protected]

Jason L. J. Dearling Division of Nuclear Medicine and Molecular Imaging,Department of Radiology, Boston Childrens Hospital and Harvard

Medical School, 300 Longwood Avenue, Boston, MA 02115, USA, Email:

[email protected]

Angelika Domschke Angelika Domschke Consulting LLC, 3379 EnnieldWay, Duluth, GA 30096, USA, Email: [email protected]

Rutledge Ellis-Behnke Department of Brain and Cognitive Sciences,Massachusetts Institute of Technology, Cambridge, MA 02139, USA,


Marianna Foldvari School of Pharmacy, University of Waterloo, 200University Avenue West, Waterloo, ON, Canada N2L 3G1, Email:

[email protected]
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


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Mario GanauDepartment of Surgical Science, Asse Didattico di Medicina,Cittadella Universitaria, S.S. 554. 09042 Monserrato (CA), Italy, Email:

[email protected]

Howard E. Gendelman Department of Pharmacology and ExperimentalNeuroscience, College of Medicine, University of Nebraska Medical

Center, Omaha, NE 68198, USA, Email: [email protected]

Levi A. Gheber Department of Biotechnology Engineering, Ben-GurionUniversity of the Negev, PO Box 653, Beer-Sheva 84105, Israel, Email:

[email protected]

James K. Gimzewski Department of Chemistry and Biochemistry, Universityof California, 607 Charles E. Young Drive East, Los Angeles, CA 90095-

1569, USA, Email: [email protected]

Todd Giorgio Department of Biomedical Engineering, VanderbiltUniversity, VU Station B 351620, Nashville, TN 37235-1620, USA,


D. W. Green Department of Oral Biosciences, Faculty of Dentistry,University of Hong Kong, The Prince Philip Dental Hospital, 34 Hospital

Road, Sai Ying Pun, Hong Kong, Email: [email protected]

Frank X. Gu Department of Chemical Engineering, University of Waterloo,200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada,


G. S. Gupta Department of Biophysics, Panjab University, Chandigarh160014, India, Email: [email protected]

Lesley M. Hamming Winston & Strawn LLP, 35 W. Wacker Drive, Chicago, IL60601-9703, USA, Email: [email protected]

Karolina Jurczyk University of Medical Sciences, Conservative Dentistryand Periodontology Department, Bukowska 70 Str., 60-812 Poznan,

Poland, Email: [email protected]

Manzoor Koyakutty Cancer Nanomedicine, Amrita Centre for Nanosciencesand Molecular Medicine, Amrita Institute of Medical Sciences and

Research Centre, Amrita Vishwa Vidyapeetham University, Ponekkara

PO, Kochi, Kerala 682041, India, Email: [email protected]

Alexey Krasnoslobodtsev Department of Physics, University ofNebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA, Email:

[email protected]

Harold W. Kroto Department of Chemistry & Biochemistry, Florida StateUniversity, 95 Chieftan Way, Tallahassee, FL 32306-4390, USA, Email:

[email protected]

Alf Lamprecht Laboratory of Pharmaceutical Engineering, Faculty ofMedicine and Pharmacy, University of Franche-Comt Besanon, France,


Ki-Bum Lee Department of Chemistry and Chemical Biology, Rutgers NewBrunswick-Busch Campus, Rutgers, 610 Taylor Road, Piscataway, NJ

08854, USA, Email: [email protected]

List of Corresponding Authors
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


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Claus-Michael Lehr Helmholtz-Institute for Pharmaceutical ResearchSaarland, Department of Drug Delivery, Saarland University, 66123Saarbrcken, Universittscampus E8 1, Germany, Email: Claus-Michael.

[email protected] LetourneurINSERM U1148, LVTS, Cardiovascular Bio-Engineering,

X. Bichat Hospital, Paris, France, Email: [email protected]

Julianna Lisziewicz eMMUNITY Inc., 4400 East West Hwy, Bethesda, MD20814, USA, Email: [email protected]

Catherine M. Lockhart Department of Pharmaceutics, University ofWashington, Box 357610, H272 Health Science Building, 1959 NE Paciic

Street, Seattle, WA 98195 USA, Email: [email protected]

Yuri Lyubchenko Department of Pharmaceutical Sciences, University of

Nebraska Medical Center, 601 S. Saddle Creek Road, Omaha, NE 68106,USA, Email: [email protected]

Supriya Mahajan Department of Medicine, Division of Allergy,Immunology, and Rheumatology, State University of New York atBuffalo, 6074 UBs Clinical and Translational Research Center, 875Ellicott Street, Buffalo, NY 14203, USA, Email: [email protected]

Yashwant R. Mahajan Centre for Knowledge Management of Nanoscienceand Technology, 12-5-32/8, Vijaypuri Colony, Tarnaka, Secunderabad

500017, Telangana, India, Email: [email protected]

Heidi M. Mansour The University of Arizona, College of Pharmacy, 1703 E.Mabel Street, Tucson, AZ 85721-0207, USA, Email: [email protected]

Ccilia Mnard-Moyon CNRS, Institut de Biologie Molculaire et Cellulaire,Laboratoire dImmunopathologie et Chimie Thrapeutique (UPR 3572),15 Rue Ren Descartes, 67084 Strasbourg, Cedex, France, E-mail:[email protected]

Andrew Owen Department of Molecular and Clinical Pharmacology,Institute of Translational Medicine, University of Liverpool, 70 PembrokePlace, Liverpool L69 3GF, UK, Email: [email protected]

Dan Peer Laboratory of NanoMedicine, Britannia Building, 2nd Floor Room226, Tel Aviv University, Tel Aviv 69978, Israel, Email: [email protected]

Adriele Prina-Mello School of Medicine and Centre for Research onAdaptive, Nanostructures and Nanodevices, Institute of MolecularMedicine, Trinity College, Dublin D8, Ireland, Email: [email protected]

Vctor F. Puntes Inorganic Nanoparticles Group, Catalan Institute ofNanotechnology (ICN-2), 08193 Bellaterra, Barcelona, Spain, Email:[email protected]

Steve Rannard Department of Chemistry, University of Liverpool, LiverpoolL697ZD, United Kingdom, Email: [email protected]

Ruxana T. Sadikot Emory University School of Medicine, Section ofPulmonary and Critical Care Medicine, 201 Dowman Drive, Atlanta, GA30322, USA, Email: [email protected]

List of Corresponding Authors
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:mailto:mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:mailto:mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


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Fw

Major medical advances that emerged during the nineteenth and

early twentieth century were based on either bottom-up or top-

down type particle dimensions. In this regard, the importance of

early pico/sub-nanoscale (i.e., 0.0011 nm) elemental/small

molecule bottom-up therapies is well known. Examples include

therapies based on elemental mercury or arsenic compounds (i.e.,treatment of syphilis), radium (i.e., cancer therapy) or nineteenth

century pharma (i.e., antipyrine, quinine, aspirin, etc.). On the

other hand, signiicant medical insights emerged concurrently with

Louis Pasteurs germ theory of disease (1862) that emphasized

top-down type particle dimensions. Speciically, this theory

emphasized that microbes such as bacteria possessed macro-/

micron scale (i.e., micron to mm) dimensions and caused diseases.

Additionally, in 1928, Alexander Fleming was the irst to report the

therapeutic beneits of controlling infection by the use of antibioticmolds (i.e., small-molecule penicillin). Until recent times however,

very little attention has been devoted to the role of nano-sized

(i.e., 11000 nm) particles and phenomena residing between these

two upper and lower hierarchical extremes. Progress toward this

new perspective irst required critical insights into life sustaining

nanoparticles (proteins, DNA, RNA) developed by Linus Pauling,

Max Perutz et al. and Francis Crick/James Watson, respectively.

Pioneering structural characterization, vaccines and insights

developed by Alex Klug, Jonas Salk and others concerning life-

threatening nanoparticles such as viruses clearly demonstrated

the important role that good and bad nanoparticles could

play in deining the human conditions of either health ordisease. These pioneering scientists laid the groundwork forunderstanding life processes and, more importantly, the critical

role that nanometric dimensions might play in future medicaladvancements. In fact, it was Linus Paulings deep insights into the

nanoscale dimensions and dynamics of proteins (i.e., Hemoglobin)that undoubtedly allowed him to diagnose and propose the

irst rational therapies for sickle cell anemia as early as 1949.

Paulings seminal work on sickle cell anemia may represent the

very irst example of nanomedicine in practice. That withstanding,


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it was Richard Feynmans famous California Institute of Technology

lecture in 1959 titled There is Plenty of Room at the Bottomthat oficially launched the present nanotechnology explosion/

revolution. Since that time, the recognized impact of nanoscale

complexity on biology and traditional medicine has grown

dramatically as witnessed by an exponential increase in

publications/patents, establishment of national/global scientiic

societies and the emergence of several mainstream journals/

publishersall focusing on the new emerging frontier of

nanomedicine and bionanotechnology. My earliest connections to nanomedicine began with

industrial/academic activities (19902005) which focused on theuse of abiotic, nanoscale particles called dendrimers for a variety

of biological/medical applications. It was found that, by properly

modifying these synthetic nanoparticles as a function of size,

shape, surface chemistry, lexibility, architecture or composition,

it was possible to selectively mimic, intervene, complex or control

the in vivo inter/intracellular dynamics of many importantbiological nanoparticles such as proteins, DNA, and RNA with

minimal cytotoxicity. These strategies provided some of the early

working examples of rational in vivo protein mimicry, gene/viralcomplexation, immuno-diagnostics and targeted drug-delivery by

design. Not only did these lead to many successful gene transfection,

cardio-diagnostic, antiviral/bacterial and pending targeted drug-

delivery products, but they also provided an unbridled personal

optimism for the unlimited future possibilities expected in the

ield of nanomedicine.

It is from this broad perspective, that I have had the pleasure

to review the Handbook of Clinical Nanomedicine: Nanoparticles,Imaging, Therapy, and Clinical Applications, which is the irst inthe series on clinical nanomedicine texts edited by Dr. Raj Bawa.

The distinguished editors (Raj Bawa, PhD, Gerald F. Audette, PhD,

and Israel Rubinstein, MD) have successfully organized critical

contributions from an international team of experts into three

important sections that constitute this handbook. Throughout

all three sections, the editors and authors remain loyal to the

handbook theme. They provide a systematic and rational coverage

of major issues and challenges encountered in the progression ofnanomedical concepts to working prototypes, clinical applications,

nanodevices and imaging tools. More speciically, Section Iprovidesa general introduction to nanomedicine, along with historical/

Foreword


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xxxv

background information and ten, recent signiicant nanomedical

advancements. The important chapter on nanotechnology

nomenclature and deinitional issues of nanotherapeutics highlights

the fact that nanomedicines cannot be pigeonholed into any speciic

numerical range or dimension, especially in the context of drug

delivery. Section II consists of a balanced discussion of severalnanosystems, nanodevices and imaging tools including magnetic

resonance imaging, atomic force microscopy, multi-modal imaging/

diagnostics, in vivo imaging techniques, image-based analysisrelated to stem cells, and bacterial/viral nanomachines as tools for

biomedicine. Of particular interest is the chapter on the irst-in-

human molecular targeting and cancer imaging via ultrasmall dual-modality C-dots. The inspirational story of C60Buckminsterfullerene

by Nobel Laureate Dr. Kroto reveals the unique perspectives of many

scientists who made major contributions to its discovery. SectionIII overviews important clinical applications of nanotherapeuticsfor topical/transdermal delivery; targeted cancer and antiviral

therapies; and inlammatory, cardiovascular, respiratory and

neuronal diseases. Applications of bionanomaterials for orthopedics

and dentistry are relected in two excellent chapters. This section

also provides suitable attention to more specialized topics suchas nanolithography and biochips for viral detection, 3D nano/

microfabrication techniques for tissue and organ regeneration,

solutions to combat emerging superbugs, diagnostics of Ebola,

HIV-speciic immunotherapy, and nanoneurosurgery. A superb

chapter on the irst FDA-approved nanodrug product (Doxil) by

its inventor, Dr. Yechezkel (Chezy) Barenholz, is a fascinating read.

The important chapter on the blockbuster MS drug, Copaxone,

by experts from Teva Pharmaceutical Industries, highlights thenew era of biosimilars, nanosimilars and NBDCs.

The Handbook provides a well-edited, reader-friendly,multidisciplinary roadmap that clearly communicates essential

nanomedical information in a style that is attractive to both the

novice and expert. It offers the appropriate advice required to

advance nanomedical innovations from the concept stage to working

prototypes, clinical applications and, inally, to commercial reality.

The diversity and expertise of the authors has produced a well-

balanced, comprehensive reference resource which successfullybridges communication and terminology gaps often encountered

in such multi-disciplinary efforts. As a result, the Handbookshould be of interest to individuals from academia, industry and

Foreword


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xxxvi

government in ields ranging from medicine, biotechnology, drug

development, pharmaceutical sciences, engineering, policy, FDA

law and commercialization. This authoritative and comprehensive

reference bridges the gap between basic biomedical research,

engineering, medicine and law while providing a thorough

understanding of nanos potential to address (i) medical problems

from both the patient and health providers perspective, and (ii)

current applications and their potential in a healthcare setting.

I view the Handbook of Clinical Nanomedicine: Nanoparticles,Imaging, Therapy, and Clinical Applicationsas an essential referenceasset that should be invaluable to all who are interested in the

explosive growth and future promise of this new emerging area.

Donald A. Tomalia, PhDDecember 2015

Dr. Donald Tomalia received his Bachelor of Arts

degree in chemistry from the University of Michigan

and his PhD in physical organic chemistry from

Michigan State University in 1968 while working

at The Dow Chemical Company. In 1990, he movedto Michigan Molecular Institute as professor and

director of Nanoscale Chemistry and Architecture. He has

subsequently founded three dendrimer-based nanotechnology

companies: Dendritech, Inc.; Dendritic Nanotechnologies, Inc.;

and NanoSynthons LLC. Dr. Tomalia is currently director of the

National Dendrimer & Nanotechnology Center, CEO/founder of

NanoSynthons LLC, distinguished visiting professor at Columbia

University, adjunct professor in the department of chemistry at the

University of Pennsylvania and afiliate professor in the department

of physics at Virginia Commonwealth University. He is famous

for his discovery of dendrimers and has received several awards

for his accomplishments and contributions to science, including

the 2012 Wallace H. Carothers Award. He has authored over 250

publications and is the inventor or coinventor of 128 patents.

He currently serves as an associate editor of the Journal ofNanoparticle Research (Springer); as member of the Executive

Advisory Board of the European Foundation for ClinicalNanomedicine; and as a faculty member of Faculty 1000 Biology.

In 2011, Dr. Tomalia was inducted into the Thomas Reuters Hall

of Citation Laureates in Chemistry, a listing of the 40 most

highly cited international scientists in the ield of chemistry.

Foreword


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S I BfPf b S E

Back in 2002, I presented on nanomedicine at the Canadian Space

Agency, a few hours drive from Montreal. The audience was

primarily composed of materials scientists and engineers. After a few

excellent questions from the audience, I realized that physical

scientists and pharmaceutical scientists view the nanoworld quitedifferently and that there is tension between the two camps. This

was back then, but the state of affairs is the same today, maybe

even more profound. Since then, nanohas become more sectorized,with nanomedicine1 at the forefront along with nanoelectronics.2

1Nanomedicine, an offshoot of nanotechnology, may be deined as the science and

technology of diagnosing, treating and preventing disease and improving human

health via nano. This exciting and interdisciplinary arena is driven by collabora-tive research, patenting, commercialization, business development and technol-

ogy transfer within diverse areas such as biomedical sciences, chemical engineering,biotechnology, physical sciences, and information technology. Optimists see nano as

an enabling technology, a sort of next industrial revolution that could enhance the

wealth and health of nations. They promise that at least within the medical sector

of nano, nanodrugs will be a healthcare game-changer by offering patients access

to personalized medicine. Pessimists, on the other hand, take a cautionary position,

preaching instead a go-slow approach, pointing to a lack of suficient scientiic

information on health risks and general failure on the part of regulatory agencies

and patent ofices. As usual, the reality is somewhere between such extremes.

Whatever your stance, nano has already permeated virtually every sector of the global

economy, with potential applications consistently inching their way into the market-

place. Nano continues to evolve and play a pivotal role in various industry segments,spurring new directions in research and development and translational efforts.

2The preix nano in the SI measurement system denotes 109or one-billionth. There

is no irm consensus over whether the preix nano is Greek or Latin. While the

term nano is often linked to the Greek word for dwarf, the ancient Greek word for

dwarf is actually spelled nanno (with a double n) while the Latin word for dwarf

is nanus (with a single n). While a nanometer refers to one-billionth of a meter

in size (109m = 1 nm), a nanosecond refers to one billionth of a second (10 9 s =

1 ns), a nanoliter refers to one billionth of a liter (109l = 1 nl) and a nanogram re-

fers to one billionth of a gram (109g = 1 ng). The diameter of an atom ranges from

about 0.1 to 0.5 nm. Some other interesting comparisons: ingernails grow around

a nanometer/second; in the time it takes to pick a razor up and bring it to your

face, the beard will have grown a nanometer; a single nanometer is how much the

Himalayas rise in every 6.3 seconds; a sheet of newspaper is about 100,000

nanometers thick; it takes 20,000,000 nanoseconds (50 times per second) for a hum-

mingbird to lap its wings once; a single drop of water is ~50,000 nanoliters; a grain of

table salt weighs ~50,000 nanograms.


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However, there is still a clear need for true interdisciplinarily

because of the different approaches of physical scientists versus

pharmaceutical scientists with respect to generation, examination,

analysis and discussion of nanomedicine data. I have been extremely

cognizant of this fact as I have developed this book series so that

everyoneinds it relevant and useful.Each stand-alone volume in this series is focused broadly

on nanomedicine, pharma and various branches of medicine.

It is essential reading for both the novice and the expert in ields

ranging from medicine, pharmaceutical sciences, biotechnology,

immunology, engineering, FDA law, intellectual property, policy,

future studies, ethics, licensing, commercialization, risk analysis andtoxicology. Each volume is intended to serve as a useful reference

resource for professionals but also to provide supplementary

readings for advanced courses for graduate students and

medical fellows. Diversity within the broad and evolving arena

of nanomedicine is relected in the expertise of the distinguished

contributing authors. All chapters contain key words, igures in

full-color and an extensive list of references. As compared to other

texts on the market, each volume in the series is comprehensive,

truly multidisciplinary and intended to be a stand-alone referenceresourceall presented in an easily accessible, user-friendly format.

The editors have skillfully curated each chapter to relect the most

relevant and current information possible. The range of topics

covered in each volume as well as the interdisciplinary approach of

the volumeswill attract a global audience and serve as a deinitiveresource, reference and teaching supplement. My purpose in

constructingeach volume is to provide chapters that give the reader

a better understanding of the subject matter presented therein butalso to provoke relection, discussion and catalyze collaborations

between the diverse stakeholders. Each volume is essentially a

guided tour of critical topics and issues that should arouse the

readers curiosity so that they will engage more profoundly with

the broader theme relected.

Since 2002, I have been involved in almost all aspects of nano-

science, nanomedicine and nanotechnologypatent prosecution,

teaching and research, FDA regulatory ilings, and conference

organizer and speaker. I have intimately seen the evolution ofnanomedicine. I have cheered on the cutting-edge discoveries

and inventions but also stood up to criticize inept governmental

regulatory policies, spotty patent examination at patent ofices,

Preface by the Series Editor


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xxxix

hyped-up press releases from eminent university labs and inaccurate

depiction of nano by the press.3

While the nano die was cast long ago, it is well entrenched

now and there is no turning back. Although the air may be thick

with news of nano-breakthroughs and a hot topic for discussion in

industry, pharma, patent ofices and regulatory agencies, the average

citizen on the street knows very little about what constitutes a

nanoproduct, a nanomaterial or a nanodrug. This was apparent to

me early on when the CBS station in Albany, NY, while interviewing

me for a story on nanotechnology, approached people on the street

and asked them to deine nano. Amazingly, no one could come up

with even a functional description of the term or nomenclature. Thisissue persists. Mind you, these interviews were taking pace a few

blocks away from the highly publicized billions-of-dollar investment

in the behemoth, Albany Nanotech (now SUNY Polytechnic Institutes

Colleges of Nanoscale Science and Engineering). Recognizing that

the so-called nano-revolution will have limited impact unless all

stakeholders, especially the public, are fully on board, I immediately

initiated an annual nano-conference that continues to this day. This

annual conference is free to all attendees and for the irst dozen

years was held at Rensselaer Polytechnic Institute in Troy, NY, while

the latest one was held this fall at Albany College of Pharmacy and

Health Sciences.

Louis Pasteur famously said:Science knows no country, becauseknowledge belongs to humanity, and is the torch which illuminatesthe world. Science is the highest personiication of the nation because

that nation will remain the irst which carries the furthest the works

of thought and intelligence. Perhaps, nothing is truer in this regard

than nanoscience, nanotechnology and nanomedicine. We are ina rapidly changing worldpolitically, economically, societally,

environmentally and technologically. At the present time in our

history, global boundaries are artiicial or eroding, there are few

true global leaders, the world power dynamics are shifting and the

3Too often though, start-ups, academia and companies exaggerate basic research

developments as potentially revolutionary advances and claim these early-stage

discoveries as conirmation of downstream novel products and applications to come.

Nanotechnologys potential beneits are frequently overstated or inferred to be very

close to application when clear bottlenecks to commercial translation exist. Manyhave desperately tagged or thrown around the nano preix to suit their purpose,

whether it is for federal research funding, patent approval of the supposedly novel

technologies, raising venture capital funds, running for ofice or seeking publication

of a journal article.



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outdated bureaucratic structures irmly in place are unable to deal

effectively with the emerging knowledge economy. There is also a

certain degree of chaos in the world of nano. From my perspective,there is a combination of excitement, potential, confusion, hype,

and misinformation in this regardall of this seen more than in

other ields when they were evolving. It is true that in the heady

days of any new, emerging technology, deinitions tend to abound

and only gradually documented via reports, journals, books and

dictionaries. Ultimately, standard-setting organizations like the

International Organization for Standardization (ISO) and American

Society for Testing and Materials (ASTM) International produce

technical speciications. This evolution is typical and essential as thedevelopment of terminology is a prerequisite for creating a common

language needed for effective communication in any ield. Clearly, a

similar need for an internationally agreed deinition for key terms like

nanotechnology, nanoscience, nanomedicine, nanobiotechnology,

nanodrug, nanotherapeutic, nanopharmaceutical and nanomaterial,

has gained urgency.4 Nomenclature, technical speciications,

standards, guidelines and best practices are critically needed

to advance nanotechnologies in a safe and responsible manner.

Contrary to a few commentators, terminology does matter because

it prevents misinterpretation and confusion. It is essential for

research activities, harmonized regulatory governance, accurate

patent searching and prosecution, standardization of procedures,

manufacturing and quality control, assay protocols, granting

agencies, policymakers, ethicists, public dialogue, safety assessment,

and more. All deinitions of nanotechnology based on size or

dimensions must be dismissed, especially in the context of medicine

and pharmaceutical science, for the reasons elaborated in chapter 6of this volume.5Viablesui generisdeinition of nano having a bright-4Similar disagreements over terminology and nomenclature are seen in other ields

as well. For example, the term super resolution microscopy, the subject of the 2014

Nobel Prize, is considered an inaccurate description of the technique.5Nanoscale therapeutics may have unique properties (nanocharacter) that can be

beneicial for drug delivery but there is no speciic size or dimensional limit where

superior properties reside. Hence, a size limitation below 100 nm cannot be touted

as the basis of novel properties of nanotherapeutics. In fact, properties other than

size can also have a dramatic effect on the nanocharacter of nanodrugs: shape/

geometry, zeta potential, speciic nanomaterial class employed, composition, deliveryroute, crystallinity, aspect ratio, surface charge, etc. See: Bawa, R. (2016). Whats in

a name? Deining nano in the context of drug delivery. In: Bawa, R., Audette, G.

and Rubinstein, I. eds. Handbook of Clinical Nanomedicine: Nanoparticles, Imaging,Therapy, and Clinical Applications, Chapter 6, Pan Stanford Publishing, Singapore.



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line size range as applied to nanodrugs blurs with respect to what

is truly nanoscale; it is unnecessary, misleading, and in fact, may

never be feasible. Since the 100 nm boundary has no solid scientiic

or legal basis, this series will avoid using the sub-100 nm inaccurate

and random deinition of nano.6

The volumes in this series will extensively cover advances in

drug delivery7as this is leading all developments in nanomedicine.

The following points serve to highlight the major impact of

nanotechnology to drug delivery:

Novel nanodrugs and nanocarriers are being developed that

address fundamental problems of traditional drugs because

of the ability of these compounds to overcome poor watersolubility issues, alter unacceptable toxicity proiles, enhance

bioavailability, and improve physical/chemical stability.

Additionally, via tagging with targeting ligands, these nanodrug

formulations can serve as innovative drug delivery systems

for enhanced cellular uptake or localization of therapeutics

into tissues of interest (i.e., site-speciic targeted delivery).

Various FDA-approved liposomal, solid nanoparticle-based,

antibody-drug conjugate (ADC) and polymer-drug conjugate

delivery platforms overcome associated issues such as

6Deinitions along these lines will instead be employed in this book series:

The design, characterization, production, and application of structures, devices, andsystems by controlled manipulation of size and shape at the nanometer scale (atomic,molecular, and macromolecular scale) that produces structures, devices, and systemswith at least one novel/superior characteristic or property. See: Bawa, R. (2007).Patents and nanomedicine.Nanomedicine (London), 2(3), 351374.

7Although numerous nanodrugs have been routinely used in medicinal products

for decades without any focus or even awareness of their nanocharacter, it is only

within the past two decades that they have been highlighted due to their potential

of revolutionizing drug delivery. Obviously, the Holy Grail of any drug delivery

system is to deliver the correct dose of a particular active agent to a speciic disease

or tissue site within the body while simultaneously minimizing toxic side effects

and optimizing therapeutic beneit. This is often not achievable via conventional

drugs. However, the potential to do so may be greater now via engineered

nanodrugs. Often, nanodrugs transport active agents to their target binding sites

(ligands, receptors, active sites, etc.) to impart maximum therapeutic activity with

maximum safety (i.e., protect the body from adverse reactions) while preventing

the degradation/denaturation/inactivation of the active agent during delivery/

transit. Targeting can be achieved or enhanced by (i) linking speciic ligands or

molecules (e.g., antibodies, glycoproteins, etc.) to the carrier, or (ii) by alteringthe surface characteristics of the carrier. Furthermore, therapeutics that have side

effects due to triggering an immune response (e.g., complement activation) or

cleared by the reticuloendothelial (RES) system can be entrapped, encapsulated or

embedded within a nanoparticle coat or matrix.



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(i) low solubility (Abraxane), (ii) extremely high drug toxicity

(Brentuximab vedotin and Trastuzumab emtansine), and

(iii) side effects related to high doses of free drug (Doxil,

Marqibo, DaunoXome).

Reformulation of old, shelved therapeutics into nanosized

dosage forms could offer the possibility of adding new life to

old therapeutic compounds. Classic examples include drugs

developed as nanocrystalline products (Rapamune, Emend,

Triglide).

Coupled with advances in pharmacogenomics, smart

nanomachines, information technology and personalized

medicine, upcoming innovations in nanomedicine may evengenerate multifunctional entities enabling simultaneous

diagnosis, delivery and monitoring of APIs.

Emerging technologies are particularly problematic for

governmental regulatory agencies, given their independent nature,

slow response rate, signiicant inertia and a general mistrust of

industry. Major global regulatory systems, bodies and regimes

regarding nanomedicines are not fully mature, hampered in part

by a lack of speciic protocols for preclinical development andcharacterization. Additionally, in spite of numerous harmonization

talks and meetings, there is a lack of consensus on the different

procedures, assays and protocols to be employed during pre-

clinical development and characterization of nanomedicines. On

the other hand, there is a rise of diverse nanospeciic regulatory

arrangements and systems, contributing to a dense global

regulatory landscape, full of gaps and devoid of central coordination.

It is often observed that governmental regulatory bodies lack

technical and scientiic knowledge to support risk-based regulation,thereby leaving a signiicant regulatory void. In fact, the baby

steps undertaken by the FDA over the past decade have led to

regulatory uncertainty. There are potentially serious and inhibitory

consequences if nanomedicine is overregulated. A balanced

approach is required here, at least on a case-by-case basis, which

addresses the needs of commercialization against mitigation of

inadvertent harm to patients or the environment. Obviously, not

everything nanomedical needs to be regulated. However, moreis clearly needed from regulatory agencies like the FDA and EMA

than a stream of guidance documents that are generally in

draft format, position papers that lack any legal implication,



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presentations that fail to identify key regulatory issues and policy

papers that are often short on speciics. There is a very real need

for regulatory guidelines that follow a science-based approach

(not policy-based) that are responsive to the associated shifts in

knowledge and risks. Other critically important and interrelated

regulatory law themes that will permeate this series will include

transnational regulatory harmonization, FDA law, generic

biowaivers, nanosimilars, combination products (nanotheranostics)

and non-biologic complex drugs (NBCDs).

Creating drugs today is time-consuming, expensive and

enormously challenging. De novodrug discovery and development

is a 10-17 year process from idea to marketed drug. It may takeup to a decade for a drug candidate to enter clinical trials with less

than 10% of the tested candidates in trials reaching the market. In

fact, more drugs come off patent each year than approved by the

FDA. According to a 2014 study by the Tufts Center for the Study

of Drug Development, developing a new prescription medicine that

gains marketing approval is estimated to cost nearly $2.6 billion.

It is clear to everyone that in the past decade, great strides have

been made in basic science and research. This is obviously critical

to any advanced society. However, the enormous medical advances

that should have come from the large public investment in

biomedical research are largely absent from a translation point-

of-view. All stakeholderspharma, patients, academia, NIH

have suffered and are to blame for the valley of death. Each needs

to re-examine their role and become an active, full partner in the

drug development ecosystem so that translation is more robust.

Although great strides have been made in nanomedicine generally

at the science level, especially with respect to drug delivery andimaging, it continues to be dogged by challenges and bottlenecks at

the translational level. In pharma, translational research involves

the many elements that contribute to the successful conversion

of an idea into a drug. Translation of drug products is a challenge

faced by pharma at various levels. Bridging the chasm between

drug discovery research activities and the successful translationof a drug to the market is a daunting task that requires varyingdegree of participation from key stakeholderspharma, academia,

nonproit and for-proit institutions, federal agencies and regulatory

bodies (FDA, NIH, EMA, Patent Ofices), diseases foundations

and patients. So far, the process of converting basic research



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in nanomedicine into commercially viable products has been

dificult. Securing valid, defensible patent protection from the

patent ofices along with clearer regulatory/safety guidelines from

regulatory agencies is critical to any commercialization effort.

These have been mixed bag at best and much more is warranted. If

translation of nanomedicine is to be a stellar success, it is important

that some order, central coordination and uniformity be introduced

at the transnational level. It is true that this decade has witnessed

relatively more advances and product development in nanomedicine

than the previous. In this context, many point to the inluence of

nanomedicine on the pharmaceutical, device and biotechnology

industries. One can now say that R&D is in full swing and novelnanomedical products are starting to arrive in the marketplace.

It is hoped that nanomedicine will eventually blossom into a

robust industry. We will have to see whether there will be giant

technological leaps (that can leave giant scientiic, ethical and

regulatory gaps) or paradigm-shifting advances (that necessitate

extraordinary proof and veriication). In the meantime, tempered

expectations are in order.

Key players need to come together on a global platform to

address some of these issues impacting effective translational

efforts. It is important that the publics desire for novel nanomedical

products, venture communitys modest investment, federal infusion

of funds and big pharmas lingering interest in nanomedicine

continues. In the end, the long-term prognosis and development

of nanomedicine will hinge on effective nanogovernance, issuance

of valid patents, clearer safety guidelines, public transparency and

full commitment of all the key stakeholders involvedbig pharma,

academia, governmental regulatory agencies, policy-makers, theventure community and the consumer-patient. Not only this is

possible, but it willhappen.

Raj Bawa, MS, PhD

December 15, 2015



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Acknowledgements

Richard J. Apley, Litman Law Ofices/Becker & Poliako, Washington, DC,

USA

Lajos P. Balogh, AA Nanomedicine & Nanotechnology Consulting, North

Andover, MA, USA

Yechezkel (Chezy) Barenholz, Hebrew University-Hadassah Medical School,

Israel

S. R. Bawa, Bawa Biotech LLC, Schenectady, New York, USA

Sangita Bawa, Novo Nordisk Inc., Princeton, New Jersey, USA

Nancy A. Blair-DeLeon, Institute of Electrical and Electronics Engineers,

New York, New York, USA

Sara Brenner, SUNY Polytechnic Institute, Albany, New York, USA

Stanford Chong, Pan Stanford Publishing Pte. Ltd., Singapore

Jill B. Conner, Teva Pharmaceutical Industries, Ltd., Overland Park, Kansas,

USA

Jay K. Doshi, Family Dental Care, Spring, Texas, USA

Kamal C. Doshi, Shared Towers VA LLC, McLean, Virginia, USA

Eileen S. Ewing, American Bar Association, Chicago, USA

Howard E. Gendelman, University of Nebraska Medical Center, Omaha,

Nebraska, USA

Harvinder Ghumman, Inova Health System, Reston, Virginia, USA

Susan P. Gilbert, Rensselaer Polytechnic Institute, Troy, New York, USA

Paulette Goldweber, John Wiley & Sons, Inc., Hoboken, New Jersey, USA

Neil Gordon, Guanine Inc., Montreal, Quebec, Canada

Drew Harris, Nanotechnology Law & Business, Austin, Texas, USA

Jim Hurd, NanoScience Exchange, San Francisco, California, USA

Meghana Kamath Hemphill, John Wiley & Sons, Inc., Hoboken, New Jersey,

USA

Arvind Kanswal, Pan Stanford Publishing Pte. Ltd., Singapore

Francesca Lake, Future Medicine Ltd., London, UK

Gregory Lanza, Washington University Medical School, Saint Louis, Missouri,USA

Gregory N. Mandel, Temple University Beasley School of Law, Philadelphia,

Pennsylvania, USA


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Rajesh Mehra, Chantilly Family Practice Center, Chantilly, Virginia, USA

Lucinda Miller, Northern Virginia Community College, Annandale, Virginia,

USA

Shaker A. Mousa, Albany College of Pharmacy and Health Sciences, Albany,

New York, USA

Stefan Muhlenbach, Vifor Pharma, Ltd. and University of Basel, Switzerland

J. Michael Nicholas, Teva Pharmaceutical Industries, Ltd., Overland Park,

Kansas, USA

Thurman K. Page, (formerly of) US Patent & Trademark Ofice, Alexandria,

Virginia, USA

Michael Slaughter, CRC Press/Taylor & Francis Group, Boca Raton, Florida,

USAGert Storm, Utrecht University, Utrecht, Netherlands

Robin Taylor, University of Nebraska Medical Center, Omaha, Nebraska,

USA

Mary A. Vander Maten, Northern Virginia Community College, Annandale,

Virginia, USA

Thomas J. Webster, Northeastern University, Boston, Massachusetts, USA

Vera Weinstein, Teva Pharmaceutical Industries, Ltd., Netanya, Israel

Tracy Wold, Morton Publishing, Englewood, Colorado, USA

Acknowledgements


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Dr. Bawa and his team have meticulously gathered the distilled experience of world-class

researchers, clinicians and business leaders addressing the most salient issues confronted in

product concept development and translation. Knowledge is power, particularly in nanomedicine

translation, and this handbook is an essential guide that illustrates and clarifies our way to

commercial success.

Gregory Lanza, MD, PhDProfessor of Medicine and Oliver M. Langenberg Distinguished Professor

Washington University Medical School, USA

This is an outstanding, comprehensive volume that crosscuts disciplines and topics fitting

individuals from a variety of fields looking to become knowledgeable in medical nanotech research

and its translation from the bench to the bedside.

Shaker A. Mousa, PhD, MBA

Vice Provost and Professor of Pharmacology

Albany College of Pharmacy and Health Sciences, USA

Masterful! This handbook will have a welcome place in the hands of students, educators, clinicians

and experienced scientists alike. In a rapidly evolving arena, the authors have harnessed the field

and its future by highlighting both current and future needs in diagnosis and therapies. Bravo!

Howard E. Gendelman, MD

Margaret R. Larson Professor and Chair

University of Nebraska Medical Center, USA

It is refreshing to see a handbook that does not merely focus on preclinical aspects or exaggerated

projections of nanomedicine. Unlike other books, this handbook not only highlights current advances

in diagnostics and therapies but also addresses critical issues like terminology, regulatory aspects

and personalized medicine.

Gert Storm, PhD

Professor of Pharmaceutics

Utrecht University, The Netherlands

This handbook provides a comprehensive roadmap of basic research in nanomedicine as well as

clinical applications. However, unlike other texts in nanomedicine, it not only highlights current

advances in diagnostics and therapeutics but also explores related issues like nomenclature,

historical developments, regulatory aspects, nanosimilars and 3D nanofabrication. While

bridging the gap between basic biomedical research, engineering, medicine and law, the

handbook provides a thorough understanding of nanos potential to address (i) medicalproblems from both the patient and health providers perspective and (ii) current applications

and their potential in a healthcare setting.

About the Series Editor

Dr. Raj Bawais president of Bawa Biotech LLC, a biotech/pharma consultancy

and patent law firm based in Ashburn, VA, USA. He is an entrepreneur,

professor, researcher, inventor, and registered patent agent licensed to practice

before the U.S. Patent and Trademark Office. Trained as a biochemist and

microbiologist, he is currently an adjunct professor of biological sciences at

Rensselaer Polytechnic Institute in Troy, NY, as well as a scientific advisor toTeva Pharmaceutical Industries, Israel. He has authored over 100 publications,

Documents

Handbook of Clinical Nanomedicine, Volume