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Transcript of Handbook of Clinical Nanomedicine, Volume
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7/25/2019 Handbook of Clinical Nanomedicine, Volume
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Pan Stanford Series on Nanomedicine Vol. 1
Handbook of
Clinical NanomedicineNanoparticles, Imaging, Therapy, andClinical Applications
edited by
Raj Bawa
Gerald F. Audette
Israel Rubinstein
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Handbook of
Clinical Nanomedicine
Vol. 1
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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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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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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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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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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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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
6.1 Introduction 128
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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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
8.1 Introduction 211
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
10.1 Introduction 273
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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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
11.1 Introduction 299
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
11.5 Conclusions 311
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
12.1 Introduction 319
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
13.1 Introduction 365
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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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
15.1 Introduction 443
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
16.1 Introduction 465
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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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
18.1 Introduction 521
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
18.6 Conclusions 537
19. F--H M T C
I U U D-M C D 549
Michelle S. Bradbury, MD, PhD, and Ulrich Wiesner, PhD
19.1 Introduction 549
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
19.6 Conclusions and Future Prospects 559
20. A F M f N 567
Shivani Sharma, PhD, and James K. Gimzewski, PhD
20.1 Introduction 567
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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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
21.6 Conclusions 608
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
22.1 Introduction 617
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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24.3 The Type IV Secretion System 665
24.4 Conclusions 672
25. T V C S N 687
Frank J. Boehm
25.1 Introduction 687
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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Section III: Therapy and Clinical Applications
27. Tw N f B If 749
Georgette B. Salieb-Beugelaar, PhD, and Patrick R. Hunziker, MD
27.1 Introduction 749
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
28.1 Introduction 784
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
28.6 Conclusions and Future Prospects 816
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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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
31.1 Introduction 937
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
31.6 Conclusions 962
32. N T f If D 973
Alf Lamprecht, PhD
32.1 Introduction 973
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
33.1 Introduction 989
33.2 Electrospinning 991 33.3 3D Printing 1002
33.4 Other Current Methodology 1011
33.5 Summary 1013
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34. N f A L Ij/A
R D S: A Sf
P? 1027
Ruxana T. Sadikot, MD, and Israel Rubinstein, MD
34.1 Introduction 1027
34.2 ALI and ARDS 1029
34.3 Nanomedicine for ALI and ARDS 1030
34.4 Nanomedicine for Drug Delivery to the Lung 1032
34.5 Conclusions 1034
35. N: T A-V N 1039
Randall W. Barton, PhD, Jayant G. Tatake, PhD,
and Anil R. Diwan, PhD
35.1 Introduction 1039
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
36.1 Introduction 1053
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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38. B A R M:
Sff, T M, T H
D, S C 1109
David W. Green, PhD,and Besim Ben-Nissan, PhD
38.1 Introduction 1109
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
38.10 Conclusions 1135
39. P A f N
N S 1141
Shu Wang, MD, PhD, and Jia Zhang, MS
39.1 Introduction 1141
39.2 Nanoparticles 1142
39.3 Phytochemicals 1144
39.4 Conclusions and Future Prospects 1156
40. D N f Eff T
f C D 1167
Bhuvaneshwar Vaidya, MPharm, PhD, and Suresh P. Vyas,
MPharm, PhD
40.1 Introduction 1167
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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41. Cb Nb Sb f N
Gw 1197
Ccilia Mnard-Moyon, PhD
41.1 Introduction 1197
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
42.1 Introduction 1239
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
42.6 Conclusions 1260
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
43.6 Conclusions 1286
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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
44.7 Conclusions 1307
45. S L N N
L C f C T 1315
Melike ner, PhD
45.1 Introduction 1315
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
45.6 Conclusions 1334
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
46.1 Introduction 1347
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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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
46.7 Conclusions and Future Prospects 1365
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
47.1 Introduction 1379
47.2 Methods 1382
47.3 Results 1388
47.4 Discussion 1392
47.5 Conclusions and Future Prospects 1395
48. HIV-Sf I w S
P-Lk N 1407
Orsolya Lorincz, PhD, and Julianna Lisziewicz, PhD
48.1 Introduction 1407
48.2 Nanomedicines for Immunotherapy 1409
48.3 Pathogen-Like DNA-Nanomedicines forImmunotherapy 1411
48.4 DermaVir Immunotherapy for the Cureof HIV/AIDS 1420
48.5 Conclusions 1422
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
50.1 Introduction 1445
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
50.8 Conclusions and Future Perspectives 1473
51. N-B S Cb
E T f Sb: C S
F P 1493
Nisha C. Kalarickal, PhD, and Yashwant R. Mahajan, PhD
51.1 Introduction 1493
51.2 The Discovery and Consequent Developmentof Antibiotic Resistance 1494
51.3 Nanotechnology-Based Solutions againstSuperbugs 1498
51.4 Conclusions and Future Perspectives 1509
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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
52.7 Conclusions 1524
53. L N-T D D 1529
Anita Gupta, MSc, PhD, and G. S. Gupta, MSc, PhD
53.1 Introduction 1529
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
53.9 Conclusions 1561
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
55.1 Introduction 1612
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:
Jill B. Conner Teva Pharmaceutical Industries, Ltd., Specialty Life CycleInitiatives, 11100 Nall Avenue, Overland Park, KS 66211, USA, Email:
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:
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,
Email: [email protected]
Marianna Foldvari School of Pharmacy, University of Waterloo, 200University Avenue West, Waterloo, ON, Canada N2L 3G1, Email:
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:
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:
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,
Email: [email protected]
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,
Email: [email protected]
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:
Harold W. Kroto Department of Chemistry & Biochemistry, Florida StateUniversity, 95 Chieftan Way, Tallahassee, FL 32306-4390, USA, Email:
Alf Lamprecht Laboratory of Pharmaceutical Engineering, Faculty ofMedicine and Pharmacy, University of Franche-Comt Besanon, France,
Email: [email protected]
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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xxxiv
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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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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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,
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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,