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This page intentionally left blank
CRC Press
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© 2012 by Taylor & Francis Group, LLC
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Version Date: 20120710

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 To the fond memory of my parents,
who taught me to seek enlightenment and knowledge
and strive for excellence.

Dearest souls,
although you have departed and moved far away,
your perpetual memory in our hearts
makes us feel that you are ever near us, with us.

—N.V.
This page intentionally left blank
 Contents

Contributors xv
Preface xxi
Acknowledgments xxiii

1. Theranostic Applications of Nanotechnology in Chronic

Obstructive Lung Diseases 1
Neeraj Vij and Aakruti Gorde
1.1 Pulmonary Physiology and Pathogenesis of Chronic
Obstructive Lung Diseases 1
1.2 Application of Nano-Based Systems in Treating Chronic
Obstructive Lung Diseases 3
1.2.1 Therapeutic and Diagnostic Challenges in Chronic
Obstructive Lung Diseases 6
1.2.2 Nanosystems to Overcome Challenges in Chronic
Obstructive Lung Diseases 6
1.3 Nanotheranostics 7
1.3.1 Theranostic Nanoparticles for Chronic Obstructive
Lung Diseases 8
1.3.2 Perspective 9
2. Multifunctional Tumor-Targeted Nanoparticles
for Lung Cancer 15
Shinji Kuroda, Tomohisa Yokoyama, Justina O. Tam, Ailing W. Scott,
Li Leo Ma, Manish Shanker, Jiankang Jin, Corbin Goerlich,
David Willcutts, Jack A. Roth, Konstantin Sokolov, Keith P. Johnston,
and Rajagopal Ramesha
2.1 Introduction 16
2.2 Biomarkers for Tumor Targeting 18
2.3 Nanotechnology in Medicine 20
2.3.1 Development of Nanoparticles for Lung
Cancer and Other Medical Applications 20
2.3.2 Classes of Nanoparticles 23
2.3.3 Delivery Methods of Nanoparticles to
Targeted Regions 26
viii Contents

2.3.3.1 Systemic Administration 26

2.3.3.2 Local Administration via Inhalation 27
2.3.3.3 Toxicity of Nanoparticles 28
2.4 EGFR-Targeted Hybrid Plasmonic Magnetic
Multifunctional Nanoparticles 29
2.4.1 Structure of Nanoparticles 29
2.4.2 Therapeutic Function of EGFR-Targeted
Nanoparticles 30
2.4.2.1 Inhibition of EGFR signaling pathway 30
2.4.2.2 Induction of DNA damage 32
2.4.3 Diagnostic Function of EGFR-Targeted
Nanoparticles 33
2.5 Conclusions 34
3. Nasal and Pulmonary Delivery of Macromolecules
to Treat Respiratory and Nonrespiratory Diseases 45
Durga Paturi, Mitesh Patel, Ranjana Mitra, and Ashim K. Mitra
3.1 Introduction 45
3.2 Nasal Drug Delivery 46
3.2.1 Nasal Anatomy 47
3.2.2 Mechanisms of Nasal Absorption 48
3.2.3 Factors Affecting Nasal Absorption 50
3.2.3.1 Physiological factors 50
3.2.3.2 Pathological conditions 50
3.2.3.3 Biochemical changes 52
3.2.3.4 Physicochemical properties of
the permeant 52
3.2.3.5 Properties of the formulation 53
3.2.3.6 Drug distribution 54
3.2.3.7 Device-related factors 54
3.2.4 Strategies to Enhance Nasal Absorption 55
3.2.4.1 Cyclodextrins 56
3.2.4.2 Fusidic acid derivatives 56
3.2.4.3 Phospholipids 56
3.2.4.4 Bile salt derivatives 56
3.2.4.5 Peptidase and protease inhibitors 57
3.2.5 Nasal Formulations 57
 Contents ix

3.2.5.1 Nasal drops 59

3.2.5.2 Nasal sprays 59
3.2.5.3 Nasal powders 60
3.2.5.4 Nasal ointments and emulsions 60
3.2.5.5 Nasal gels 61
3.2.5.6 Liposomes 62
3.2.5.7 Nanoparticles 63
3.2.5.8 Microparticles 65
3.2.6 Nasal Delivery of Vaccines 66
3.2.7 Intranasal Gene Delivery 67
3.3 Pulmonary Drug Delivery 69
3.3.1 Anatomy of the Lungs 70
3.3.2 Pulmonary Absorption 72
3.3.3 Barriers in Pulmonary Drug Delivery 73
3.3.4 Formulations 74
3.3.4.1 Micelles 74
3.3.4.2 Liposomes 75
3.3.4.3 Microparticles 76
3.3.4.4 Nanoparticles 77
3.3.4.5 Microemulsions 79
3.3.5 Inhalation Devices 82
3.3.5.1 Pressurized metered-dose
inhaler (pMDI) 83
3.3.5.2 Nebulizers 84
3.3.5.3 Dry powder inhalers 85
3.3.6 Factors Affecting Pulmonary Deposition 85
3.3.7 Vaccines 86
3.3.8 Nucleic Acids 87
3.3.9 Oligonucleotides 91
3.4 Conclusions 92
4. In vitro and in vivo Diagnosis of Pulmonary Disorders
Using Nanotechnology 103
Indrajit Roy
4.1 Introduction 103
4.2 Nanoparticles 104
x Contents

4.2.1 Quantum Dots 105

4.2.2 Rare Earth-Doped Nanophosphors 105
4.2.3 Dye-Doped Silica/ORMOSIL Nanoparticles 106
4.2.4 Gold Nanoparticles 106
4.2.5 Iron Oxide Nanoparticles 107
4.2.6 Carbon Nanotubes 107
4.3 In vitro Diagnosis, Techniques, and Challenges 108
4.3.1 Flow Cytometry 108
4.3.2 Multiplexed Microarray ELISA 110
4.3.3 Molecular Beacon Technology 110
4.3.4 Plasmonic Biosensing 111
4.3.5 Magnetic Biosensing 112
4.3.6 Electrochemical Biosensing 112
4.4 In vivo Diagnosis, Challenges, and Techniques 112
4.4.1 Optical Imaging, Including
Confocal Endomicroscopy 113
4.4.2 Magnetic Resonance Imaging 114
4.4.3 Radiographic Imaging 115
4.4.4 Multimodal Imaging 115
4.5 Specific Examples of Lung Disorders 116
4.5.1 ALI/ARDS 117
4.5.2 Pneumocystis Pneumonia 118
4.5.3 Cystic Fibrosis 118
4.5.4 Tuberculosis 119
4.5.5 Lung Cancer 121
4.6 Toxicological Studies Using Nanoparticles 122
4.7 Conclusions 123
5. Nanoparticles for Targeting T Cells in Allergy and
Inflammatory Airway Conditions 135
Adham Bear, Laura B. Carpin, Conrad R. Cruz, Rebekah A. Drezek,
and Aaron E. Foster
5.1 Introduction 135
5.2 Role of T Cells in the Pathogenesis of Asthma 136
5.3 Treatment Strategies for Asthma 139
5.3.1 Nanosteroids for the Treatment of Asthma 139
 Contents xi

5.3.2 Nanocarrier Vaccines as Immune Modulators

to Promote TH1 Responses 142
5.4 Potential T Cell–Targeted Strategies for
Nanoparticle-Based Therapies 144
5.5 T Cell-Targeting Ligands 148
5.5.1 Large Targeting Ligands 148
5.5.1.1 Antibody conjugates to target
T cell surface molecules 148
5.5.1.2 TCR-targeted strategies 151
5.5.2 Small Targeting Ligands 152
5.5.2.1 Aptamers 152
5.5.2.2 Peptides 153
5.6 Alternative Approaches 154
5.6.1 Chemokine Receptor-Targeted Strategies 154
5.7 Summary 155
6. Multifunctional Chitosan Nanocarriers for Respiratory
Disease Gene Therapy 167
Shyam S. Mohapatra, Subhra Mohapatra, Gary Hellermann,
and Rhonda R. Wilbur
6.1 Introduction 167
6.1.1 What Are Chitosan Nanoparticles? 169
6.2 Therapeutic Effects and Safety of Chitosan in
Human Disease 171
6.2.1 Chitosan as Gene Therapy 175
6.2.2 Toxicity and Safety of Chitosan Gene Therapy 177
6.3 Safety and Efficacy Studies in Dogs 178
6.4 Safety of Chitosan-Gene Nanocomplexes in
Nonhuman Primates 181
6.5 Respiratory Disease Applications 182
6.5.1 Examples of Chitosan Nanoparticle
Applications to Treat Allergic Disease 183
6.5.1.1 Food allergy and anaphylaxis 183
6.5.1.2 Experimental asthma 183
6.5.1.3 RSV infection 184
6.5.2 Nano-Immunotherapy for Allergies 185
6.6 Future of Immunotherapy 186
6.7 Concluding Remarks 187
xii Contents

7. Targeted Delivery to the Pulmonary Endothelium 193

Yifei Zhang, Jiang Li, Xiang Gao, and Song Li

7.1 Introduction 193

7.2 Pulmonary Endothelium as a Target for
Drug Delivery 194
7.2.1 Physiological Functions of Lung ECs 194
7.2.2 Pulmonary Endothelium as a Drug
Delivery Target 195
7.2.2.1 Passive targeting 195
7.2.2.2 Active targeting via surface antigens 196
7.2.3 Physiological Barriers for Intravenous Drug
Delivery to the Pulmonary Endothelium 199
7.2.3.1 In vivo barriers 200
7.2.3.2 Cellular barriers 201
7.3 Targeting the Pulmonary Endothelium for Imaging
and Therapeutic Applications 206
7.3.1 Imaging Applications 206
7.3.2 Therapeutic Applications 207
7.3.2.1 Targeted delivery of protein
therapeutics 207
7.3.2.2 Targeted gene delivery to the
pulmonary endothelium 212
7.4 Conclusion 218
8. Nanosystems for Selective Epithelial Barrier
Targeting in Chronic Airway Diseases 235
Heather A. Parsons, Rachel L. Damico,
and Venkataramana K. Sidhaye
8.1 Introduction 235
8.2 Obstructive Lung Diseases 238
8.2.1 Airway Inflammation in COPD 240
8.2.2 Airway Inflammation in Asthma 242
8.2.3 Role of the Airway Epithelial Barrier 242
8.2.3.1 Epithelial barrier in asthma 243
8.2.3.2 Epithelial barrier in COPD 244
8.3 NP Delivery of Airway Diseases 244
 Contents xiii

8.3.1 Local Delivery 244

8.3.2 Existing Studies for the Treatment of
Chronic Airway Diseases 246
8.4 Toxicity of NPs 248
8.5 Conclusions and Future Directions 250
9. Potential Respiratory Health Risks of Engineered
Carbon Nanotubes 259
James C. Bonner, Jeffrey W. Card, Stavros Garantziotis,
and Darryl C. Zeldin
9.1 Introduction 259
9.2 Immune Cell Interaction with CNTs 261
9.3 Fibrogenic Reactions to CNTs 262
9.4 CNTs and Preexisting Allergic Asthma 263
9.5 CNTs and LPS-Induced Airway Inflammation 266
9.6 Effects of CNTs on Other Organ Systems 266
9.7 DNA Damage and Aneuploidy Caused by CNTs 267
9.8 Pleural Toxicity of CNTs 268
9.9 Conclusions 269
This page intentionally left blank
 Contributors

James C. Bonner received his PhD in physiology

from Mississippi State University in 1987,
completed his postdoctoral training at the
National Institute of Environmental Health
Sciences (NIEHS) in 1990, and served as a
principal investigator at NIEHS and at the
Hamner Institutes for Health Sciences. He joined
the Department of Environmental and Molecular
Toxicology at NC State University as an associate professor in 2007.
Dr. Bonner has over 20 years of experience in respiratory
toxicology and lung disease pathogenesis. He has published more
than 80 peer-reviewed research articles on environmental lung
disease, numerous review articles, and several textbook chapters on
respiratory toxicology.
He is the lead author of Chapter 9, on the potential respiratory
health risks of engineered carbon nanotubes.

Aaron E. Foster received his BA in biology

from the University of Puget Sound in Tacoma,
Washington, in 1994 and his PhD in chemical
engineering from the University of Sydney,
Australia, in 2003. Currently, he is an assistant
professor at the Center for Cell and Gene Therapy
at Baylor College of Medicine.

Dr. Foster’s research interests include cancer vaccine develop-

ment, immune modulation, and gene therapy applications using
cytotoxic T lymphocytes (CTLs) as anti-tumor effector cells or as
carriers for in vivo delivery. In collaboration with Dr. Rebekah Drezek
in the Department of Bioengineering at Rice University, he is also
studying the development and use of multifunctional nanoparticles
for the treatment of cancer and infectious disease.
Dr. Foster is the main author of Chapter 5, on the use of
nanoparticles to treat airway inflammation.
xvi Contributors

Song Li received his MD in 1985 and PhD in tumor

immunotherapy in 1991 from the Fourth Military
Medical University, China. He worked with
Dr. Leaf Huang at the University of Pittsburgh
School of Medicine as a post-doc for two years and
then as a research faculty for another four years.
Dr. Li joined the faculty of the School of Pharmacy
at the University of Pittsburgh in June 2000 and
is currently an associate professor of pharmaceutical sciences. His
major research interest is focused on the development of lipid-
and polymer-based nanodelivery systems for targeted delivery
of various types of therapeutics including nucleic acids (genes,
siRNA, and peptide nucleic acids), proteins, and small molecules
(e.g., anticancer agents and antioxidants).
Dr. Li is the main author of Chapter 7, on targeted delivery to the
pulmonary endothelium.

Ashim K. Mitra received his PhD in pharma-

ceutical chemistry in 1983 from University of
Kansas. He joined the University of Missouri–
Kansas City in 1994 as chairman of Pharma-
ceutical Sciences. He is also vice provost for
Interdisciplinary Research, Curators’ Professor of
Pharmacy, and director for Translational Research
at University of Missouri–Kansas City, School of
Medicine. Dr. Mitra has over 25 years of experience in ocular drug
delivery and disposition and has authored or co-authored over 250
refereed articles and 30 book chapters in this field. He holds 8 patents
and has made well over 450 presentations, including abstracts,
at national and international scientific meetings. This work has
attracted over 6 million dollars in funding from government agencies
such as the National Institutes of Health (NIH) and Department of
Defense (DOD) and from pharmaceutical companies.
Dr. Mitra is also a recipient of several research awards from
AAPS, AACP, and various pharmaceutical organizations and serves
on numerous editorial boards. According to Biomed Experts (during
the past 10 years), he co-authored the third-highest number of
publications in the world in the area of “Prodrugs.” In April 2010, he
was ranked fifth in the world among AAPS’s Top Ten Researchers. In
February 2012, his article “Ocular Drug Delivery” was again ranked as
one of the top 5 downloaded articles in the AAPS Journal. Currently,
he is chairman of the USP Council of Experts, General Chapter
 Contributors xvii

<771> Ophthalmic Preparations Expert Panel, U.S. Pharmacopeia. His

current research interests are focused on two main areas: delivery
and targeting of antiviral agents and development of noninvasive
delivery systems for peptide and protein drugs.
Dr. Mitra is the senior author of Chapter 3, which discusses the
use of nasal and pulmonary delivery of macromolecules to treat
respiratory and nonrespiratory diseases.

Shyam S. Mohapatra is a Distinguished USF

Health Professor and director of the Division of
Translational Medicine, Nanomedicine Research
Center at the Morsani College of Medicine,
University of South Florida. He also directs the
Signature Program in Allergy, Immunology and
Infectious Diseases at the college. A PhD graduate
of the Australian National University, Prof.
Mohapatra is a recipient of two international awards: the Alexander
von Humboldt research fellowship (1984, Bonn, Germany) in
genetics and Pharmacia Allergy Research Foundation Award (1992,
Paris) for his contributions to the field of allergy and immunology.
Prof. Mohapatra’s research program focuses on the molecular
mechanisms underlying inflammation in respiratory diseases,
cancers, viral infections, and traumatic brain injury. He has used
nanotechnology approaches to advance translational research in
these disease areas.
Prof. Mohapatra is the senior author of Chapter 6, which
discusses the application of multifunctional chitosan nanocarriers
in respiratory gene therapy.

Rajagopal Ramesh received his PhD in molecular

biology in 1994 from the All India Institute of
Medical Sciences, New Delhi, India. He completed
his postdoctoral fellowships at Tulane University
School of Medicine, New Orleans, in 1998 and
later joined the faculty at M. D. Anderson Cancer
Center in Houston, USA. Currently, Dr. Ramesh is
a professor in the Department of Pathology and
director of Experimental Therapeutics and Translational Cancer
Medicine at the University of Oklahoma Health Sciences Center,
Oklahoma City, OK, USA. He holds the Jim and Christy Everest
Endowed Chair in Cancer Developmental Therapeutics and the title
of the Oklahoma TSET Cancer Research Scholar.
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