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Contents

Preface............................................................................................................................................. vii
Cover Art Credits���������������������������������������������������������������������������������������������������������������������������ix
Editor................................................................................................................................................xi
Contributors.................................................................................................................................. xiii

1. Nanotechnology Applications for Infectious Diseases...................................................1

Ellis H. Tobin, MD

2. Nanotechnology Applications in Dermatology.............................................................. 85

David Schairer, MD; Jason Chouake, MD; Adnan Nasir, MD; and Adam Friedman, MD

3. Nanotechnology Applications in Ophthalmology....................................................... 195

Eman Elhawy, MD and John Danias, MD, PhD

4. Nanotechnology Applications in Urology...................................................................... 213

Himanshu Aggarwal, MD and Barry A. Kogan, MD

5. Nanotechnology Applications in Preventive Medicine and Public Health............ 235

Julielynn Wong, MD, MPH and Sara Brenner, MD, MPH

6. Nanotechnology Applications in Vascular Medicine and Surgery.......................... 249

Manish Mehta, MD; Philip S.K. Paty, MD; W. John Byrne, MD; Yaron Sternbach, MD;
John B. Taggert, MD; and Kathleen J. Ozsvath, MD

7. Therapeutic Applications and Targeted Delivery of Nanomedicines and

Nanopharmaceutical Products.......................................................................................... 321
Heidi M. Mansour, PhD and Chun-Woong Park, PhD

© 2008 Taylor & Francis Group, LLC v

Preface

Nanomedicine is the medical application of nanotechnology in the prevention, diagnosis,

and treatment of diseases. The Clinical Nanomedicine Handbook is intended to serve as an
­authoritative reference for clinicians, including physicians, nurses, healthcare ­providers,
dentists, scientists, and researchers involved in clinical applications of n ­ anotechnology.
Although many texts and publications have been released on various topics at the
intersection of nanotechnology, biology, and medicine, none have approached the
­
­convergence of these fields from a distinctly clinical vantage point.
The American Society for Nanomedicine and the National Institutes of Health (NIH)
highlight the emergence of nanomedical innovations as a necessary enabler in the
­development and deployment of preventive, diagnostic, and therapeutic medical tools of
the twenty-first century. These will be driven by the application of nanotechnology and
engineering principles to clinical interventions, which manipulate single molecules or
molecular assemblies in cells, drugs, or medical devices.
At the intersection of traditionally siloed disciplines, nanomedicine is blazing a path for
truly innovative, cutting edge, preventive interventions, rapid diagnostics, and ­effective
treatments. Current research and applications in specialties are covered in this handbook,
which is sure to expand in the coming years. Potential applications, as cited by the NIH,
include nanotechnologies that enable physicians to identify and destroy primary cancer
cells before metastasis, molecular procedures that can remove a dysfunctional ­cellular
component and replace it with an engineered biological machine, and nanoscale pumps
that deliver targeted drug therapy. The NIH also predicts that nanomedicine will enable
the development of novel tools that will allow scientists to build synthetic biological
devices, such as high-throughput sensors to scan for the presence of infectious agents or
metabolic imbalances, as well as nano-enabled therapeutics aimed at rapidly addressing
the identified problem.
From an economic perspective, nanotechnology and its affiliated applications are pro-
jected to impact every known industry and create entirely new industrial clusters such as
nanomedicine and nanobioscience. Nanotechnology accounted for nearly $300 billion in
2009 and is projected to hit $2.6 trillion by 2014. It is predicted that the economic impact of
nanotechnology will approach the size of the information technology and telecom indus-
tries combined with the potential to be 10 times larger than the biotechnology economy in
the next 5 years. In terms of revenue, 16% of goods in healthcare and life sciences will
incorporate nanotechnology. In other words, nanobioscience products alone are expected
to be a $416 billion industry by 2014.

© 2008 Taylor & Francis Group, LLC vii

Cover Art Credits

Silver np 4 (Blue image wedges): Cluster of green-route

synthesized silver nanoparticles under a TEM. Center for
Converging Technologies, University of Rajasthan, Jaipur,
India. Photographed by Sahil Tahiliani & Abhijeet Mishra.
2011.

Silver np 1 (Green image wedges): Electron micrograph

of chemically synthesized silver nanoparticles of various
shapes i.e. rods, sphere, pyramidical etc. Center for
Converging Technologies, University of Rajasthan,
Jaipur, India. Photographed by Sahil Tahiliani & Ruchir
Priyadarshi. 2012.

Nci-vol-2505-300 (Orange image wedges): Electron

micrograph of macrophages in the brain before and after
in vitro infection by HIV-I. Laboratory of Tumor Cell
Biology. National Cancer Institute. Dr. Suzanne Gartner
(photographer). 1990.

SEM blood cells (Red image wedges): Scanning electron

microscope image of normal circulating human blood
cells. National Cancer Institute. Bruce Wetzel and Harry
Schaefer (photographers). 1982.

© 2008 Taylor & Francis Group, LLC ix

Editor

Dr. Sara Brenner is a preventive medicine and public health

physician at the College of Nanoscale Science and Engineering
(CNSE), State University of New York, s­ erving as the assistant
vice president for NanoHealth Initiatives and an assistant pro-
fessor of n
­ anobioscience. Her research and initiatives aim to
develop novel nanotechnology a­ pplications in the life sciences,
including medicine and public health.
She leads health and safety research related to nanoparticle
and engineered ­ nanomaterial exposures in the workplace,
consumer marketplace, and ­environment. She is chair of the
steering committee for the NanoHealth and Safety Center at
CNSE, a public–private ­partnership that is addressing gaps in
our understanding of the safety and risk associated with the
unique characteristics of nanoscale materials. Dr. Brenner’s research team incorporates
theory from many disciplines such as physics, engineering, biology, genetics, toxicology,
medicine, public health, epidemiology, industrial hygiene, and ­environmental science to
advance risk assessment and reduction strategies for ­occupational e­ xposures, monitoring
of materials that may impact population health and public safety, and the development of
­industrial practice standards for product safety. She is also the CNSE program director of
the MD/PhD program in medicine and nanoscale science or engineering, a program that
she helped cofound with SUNY Downstate Medical Center. It is the first dual-degree clini-
cal training program in nanomedicine that aims to produce a new, hybrid generation of
physician researchers.
She is also the recipient of the Albany-Colonie Chamber of Commerce Women of
Excellence Award 2012 Emerging Professional.

© 2008 Taylor & Francis Group, LLC xi

Contributors

Himanshu Aggarwal, MD Heidi M. Mansour, PhD

Division of Urology Division of Dermatology
Department of Surgery Department of Medicine
Albany Medical Center Albert Einstein College of Medicine
Albany, New York Bronx, New York
Sara Brenner, MD, MPH Manish Mehta, MD
SUNY College of Nanoscale Science and The Vascular Group, PLLC
Engineering The Institute for Vascular Health and
Albany, New York Disease
W. John Byrne, MD Albany Medical College
The Vascular Group, PLLC and
The Institute for Vascular Health and Vascular Research and Registry
Disease Albany, New York
Albany Medical College
Adnan Nasir, MD
Albany, New York
Department of Dermatology
Jason Chouake, MD The University of North Carolina at
Division of Dermatology Chapel Hill
Department of Medicine Chapel Hill, North Carolina
Albert Einstein College of Medicine
Bronx, New York Kathleen J. Ozsvath, MD
The Vascular Group, PLLC
John Danias, MD, PhD The Institute for Vascular Health and
Department of Ophthalmology Disease
SUNY Downstate Medical Center Albany Medical College
Brooklyn, New York Albany, New York
Eman Elhawy, MD Chun-Woong Park, PhD
Flushing Hospital Medical Center Division of Dermatology
Flushing, New York Department of Medicine
Albert Einstein College of Medicine
Adam Friedman, MD Bronx, New York
Division of Dermatology
Department of Medicine Philip S.K. Paty, MD
Albert Einstein College of Medicine The Vascular Group, PLLC
Bronx, New York The Institute for Vascular Health and
Disease
Barry A. Kogan, MD Albany Medical College
Division of Urology Albany, New York
Department of Surgery
Albany Medical Center David Schairer, MD
and Division of Dermatology
Urological Institute of Northeastern Department of Medicine
New York Albert Einstein College of Medicine
Albany, New York Bronx, New York

© 2008 Taylor & Francis Group, LLC xiii

xiv Contributors

Yaron Sternbach, MD Ellis H. Tobin, MD

The Vascular Group, PLLC Department of Medicine
The Institute for Vascular Health and Albany Medical College
Disease and
Albany Medical College Upstate Infectious Diseases
Albany, New York Associates
Albany, New York
John B. Taggert, MD
The Vascular Group, PLLC Julielynn Wong, MD, MPH
The Institute for Vascular Health and Center for Innovative Technologies and
Disease Public Health
Albany Medical College Toronto, Ontario, Canada
Albany, New York

© 2008 Taylor & Francis Group, LLC

1
Nanotechnology Applications for Infectious Diseases

Ellis H. Tobin, MD

CONTENTS
1.1 Introduction............................................................................................................................. 2
1.1.1 Basic Nanoscience Concepts.....................................................................................3
1.2 Specialty of Infectious Diseases........................................................................................... 4
1.3 Scope of Infectious Diseases................................................................................................. 7
1.4 Magnitude of Infectious Diseases........................................................................................ 8
1.5 Nanoscience Principles, Methods, and Terminology Relevant to Infectious
Diseases.................................................................................................................................. 10
1.6 Current Approach to Diagnosis of Infections.................................................................. 11
1.7 Infectious Diseases: Nanobiosensing Interface................................................................ 12
1.7.1 Photonic Biosensing: Semiconductors................................................................... 14
1.7.2 Quantum Dot Semiconductors and Infectious Diseases Biosensing................ 15
1.7.2.1 Quantum Dots and Virus Detection....................................................... 17
1.7.2.2 Quantum Dot Biosensing and Human Immunodeficiency Virus..... 17
1.7.2.3 Quantum Dot Biosensing and Respiratory Syncytial Virus............... 18
1.7.2.4 Quantum Dot Biosensing and Influenza Virus..................................... 19
1.7.2.5 Quantum Dot Biosensing and Hepatitis Viruses.................................. 20
1.7.2.6 Quantum Dot Biosensing and Other Viruses........................................ 20
1.7.3 Quantum Dots, Bacteria, and Bacterial Toxin Detection.................................... 21
1.7.3.1 Quantum Dot Biosensing and Bacteria: General Principles................ 21
1.7.3.2 Quantum Dot Biosensing and Biofilms.................................................. 23
1.7.3.3 Quantum Dot Biosensing and Food-Borne Bacteria............................ 24
1.7.3.4 Quantum Dot Biosensing and Syphilis.................................................. 25
1.7.3.5 Quantum Dot Biosensing and Mycobacteria......................................... 25
1.7.3.6 Quantum Dot Biosensing and Bacterial Toxins.................................... 26
1.7.4 Quantum Dot Biosensing and Fungi..................................................................... 27
1.7.5 Quantum Dot Biosensing and Parasites................................................................ 28
1.7.6 Quantum Dot Biosensing: Conclusions................................................................ 29
1.8 Plasmonic Nanobiosensing: Emphasis on Infectious Diseases.....................................30
1.8.1 Plasmonics: Basic Principles....................................................................................30
1.8.2 Surface Plasmon Resonance Biosensing Scheme 1: Detection of Light
Scattering................................................................................................................... 31
1.8.3 Surface Plasmon Resonance Biosensing Scheme 2: Colorimetric Detection.... 32
1.8.4 Surface Plasmon Resonance Biosensing Scheme 3: Surface Plasmon
­Wave-Based Detection.............................................................................................34
1.8.5 Surface Plasmon Resonance Biosensing Scheme 4: Surface-Enhanced
Raman Scattering-Based Detection........................................................................ 36
1.8.6 Plasmonic Nanobiosensing: Conclusions.............................................................. 37

© 2008 Taylor & Francis Group, LLC 1

2 The Clinical Nanomedicine Handbook

1.9 Bio-Barcodes and Infectious Diseases–Nanobiosensing................................................ 38

1.9.1 Bio-Barcode Infectious Diseases–Nanobiosensing: Conclusions...................... 40
1.10 Magnetic Nanoparticles and Infectious Diseases Biosensing: Introduction............... 40
1.10.1 Magnetic Capture and Separation of Microorganisms....................................... 41
1.10.2 Magnetic Remanence and Infectious Diseases Nanobiosensing...................... 41
1.10.3 Magnetic Relaxation Nanoswitches and Infectious Diseases
Nanobiosensing........................................................................................................42
1.10.4 Magnetic Nanoparticles and Infectious Diseases Biosensing:
Miscellanea and Conclusions..................................................................................44
1.11 Microcantilever-Based Infectious Diseases Biosensing.................................................. 45
1.11.1 Microcantilever-Based Infectious Diseases Biosensing: Conclusions.............. 47
1.12 Miscellaneous Infectious Diseases–Nanobiosensing Strategies................................... 48
1.12.1 Fluorescent Europium Nanoparticle Biosensors.................................................. 48
1.12.2 Silica Nanoparticle Biosensors................................................................................ 48
1.12.3 Liposome Nanobiosensors...................................................................................... 48
1.12.4 Carbon Nanotube and Nanowire Biosensors....................................................... 49
1.12.5 Microbial-Based Biosensing.................................................................................... 49
1.13 Infectious Diseases Nanobiosensing: Summary and Conclusions............................... 50
1.14 Application of Nanotechnology to Antimicrobial Therapy and Prevention of
Infectious Diseases: Introduction....................................................................................... 51
1.14.1 Perspectives on Antimicrobial Therapy and Prevention of Infectious
Diseases...................................................................................................................... 51
1.14.2 Overview of Antimicrobial Pharmacology Principles........................................ 51
1.14.3 Nanoparticles Having Inherent Antimicrobial Activity.................................... 52
1.14.4 Silver Nanoparticles: Antimicrobial Activities and Anxieties...........................54
1.14.5 Nanostructures Having Inherent Antibiofilm Activity...................................... 56
1.14.6 Nanostructures as Antimicrobial Carriers........................................................... 57
1.14.7 Liposomes: Approved Antimicrobial Nanocarriers............................................ 57
1.14.8 Nanoparticles, Vaccines, and Vaccine Delivery................................................... 60
1.15 Infectious Diseases—Nano Therapeutic and Prevention Strategies: Summary......... 61
1.16 Nanotechnology–Infectious Diseases Interface: Conclusions....................................... 62
Acknowledgments......................................................................................................................... 62
References........................................................................................................................................63

1.1 Introduction
It has long been an axiom of mine that the little things are infinitely the most important.
Sir Arthur Conan Doyle (1900)

Infectious diseases (IDs) are the clinical manifestations that result from infections due
to a myriad of pathogenic viruses, bacteria, fungi, and parasites, whereas the discipline
of ID is the research and clinical practices having to do with host–pathogen interactions,
­diagnosis, treatment, and prevention of infection. The application of nanotechnology to
ID heralds a much anticipated interface, one with potentially far-reaching implications.
Indeed, some of the earliest applications of nanotechnology to medicine were in the field
of ID: the use of gold nanoparticles (GNPs) for immunolabeling of salmonella surface

© 2008 Taylor & Francis Group, LLC

Nanotechnology Applications for Infectious Diseases 3

antigens (Faulk and Taylor 1971), the encapsulation of amphotericin and doxorubicin
within liposomal nanoparticles to treat fungal infections and AIDS-associated Kaposi’s
sarcoma, respectively (Lopez-Berestein et al. 1989; Bogner et al. 1994), and the use of
pegylated interferon to treat hepatitis C (Zeuzem et al. 2000). It can even be argued that
one of the earliest examples of the application of nanotechnology to ID, although neither
were called that back then, dates to the early Renaissance, when Paracelsus used colloidal
gold to treat tuberculosis (TB) and syphilis (DeWitt 1918; Dykman and Khlebtsov 2010).
This chapter explores the nanotechnology–ID interface, two disciplines accustomed to
dealing with matter on a small scale. It endeavors to make the argument that the union
of these disciplines will have a large impact on healthcare in technologically advanced as
well as resource-limited parts of the world. The contextual framework of the chapter is one
that introduces the nanoscientist and non-ID practitioner to the profession of ID and the
ID clinician to fundamental concepts of nanoscience that have direct applications to their
medical specialties. An emphasis is placed on nanotechnology applied to the detection and
analysis of microbial pathogens and biomarkers of infection. Many of these applications,
in this study, are in the proof-of-concept stage of development, while others are in various
phases of clinical research. Several nanotechnology applications, liposomal amphotericin
for example, are in current clinical practice.
Nanotechnology is a scientifically diverse discipline that initially encompassed engi-
neering, materials science, physics, and chemistry. It has expanded to involve the biological
sciences, where the fields of nanobiotechnology and nanomedicine are rapidly emerging.
Nanotechnology exploits the complex and remarkably unique properties of matter at the
nanoscale (Planinsic, Lindell, and Remskar 2009; Kim, Rutka, and Chan 2010). Although
detailed descriptions of these fundamental physicochemical properties are beyond the
scope of this chapter, simplified illustrations are provided so that a working knowledge of
the nanobiotechnology–ID interface can be gained. There is little doubt that the practice of
medicine will be profoundly influenced by nanotechnology, and the confluence of biology
and nanotechnology will have a dramatic impact on ID.

1.1.1 Basic Nanoscience Concepts

To begin a discussion of nanotechnology with relevance to ID, it is useful to introduce a
few basic concepts pertaining to the properties of matter at the nanoscale. Nanostructures
possess a very large ratio of surface area to volume. This concept can be intuited at the
macroscopic (bulk) scale by considering the ratio of surface area to volume of a single
pad of sticky notes. Now consider the ratio when all the individual notes from the pad
are stuck to the sides of a refrigerator. Amplify that relationship a million times as you
contemplate the ratio of surface area to volume of nanosticky notes. A nanoparticle may
consist of just a few atoms, or in the case of nano-thin films and filaments, it may be just a
few atoms thick. Given the surface area-to-volume relationship discussed earlier, it is easy
to appreciate that a large fraction of the atoms that make up the nanostructure reside on
its surface (Eustis and EL-Sayed 2006). The behavior of these surface atoms confers many
of the unique properties associated with matter at the nanoscale. To give nanoscale dimen-
sions an ID perspective, it will be helpful to consider that human immunodeficiency virus
(HIV) particles have a diameter of approximately 120 nm, and the diameter of nanocrystal
quantum dots (QDs) and magnetic nanoparticles (MNPs) range between 1 and 40 nm.
Surface atoms are relatively reactive, having fewer neighbors to share chemical bonds
(Roduner 2006). This facilitates the attachment of a variety of molecules (e.g., antibiotics,
nucleotides, proteins, antibodies, and aptamers) to nanostructured surfaces by chemical

© 2008 Taylor & Francis Group, LLC