q 2006 by Taylor & Francis Group, LLC

q 2006 by Taylor & Francis Group, LLC

q 2006 by Taylor & Francis Group, LLC
 Dedication

To the loving memory of my dad,

Mustafa Amiji, and to my mom, Shirin Amiji

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Foreword
We are at the threshold of a new era in cancer treatment and diagnosis, brought about by the
convergence of two disciplines—materials engineering and life sciences—that 30 years ago might
have been difficult to envision. The product of this curious marriage, nanobiotechnology, is yielding
many surprises and fostering many hopes in the drug-development space. Nanoparticles,
engineered to exquisite precision using polymers, metals, lipids, and carbon, have been combined
with molecular targeting, molecular imaging, and therapeutic techniques to create a powerful set of
tools in the fight against cancer. The unique properties of nanomaterials enable selective drug
delivery to tumors, novel treatment methods, intraoperative imaging guides to surgery, highly
sensitive imaging agents for early tumor detection, and real-time monitoring of response to
treatment.
Using nanotechnology, it may be possible to leap over many of the hurdles of cancer drug
delivery that have confounded conventional drugs. These hurdles include hindered access to the
central nervous system through the blood–brain barrier, sequestration by the reticulo-endothelial
system, inability to penetrate the interior of solid tumors, and overcoming multi-drug resistance
mechanisms. These obstacles can be mitigated by manipulating the size, surface charge,
hydrophilicity, and attached targeting ligands of a therapeutic nanoparticle.
The novelty of using nanotechnology for medical applications presents its own challenges,
similar in many ways to the challenges faced by the introduction of the first synthetic protein-based
drugs. In the early 1980s, protein-based drugs offered an entirely new approach to targeting and
treating disease. They could be “engineered” to be highly specific and even offered the capability of
separating the targeting and therapeutic functions of a drug, such as when monoclonal antibodies
are conjugated to cytotoxic agents. But monoclonal antibodies and recombinant protein-based
drugs necessitated a different approach to lead optimization, metabolism, and toxicity screening
from that of small-molecule drugs. Factors such as stability, immunogenicity, and species
specificity had to be considered and tested in ways that were not familiar to the developers of
traditional drugs.
Nanotechnology-based drugs will catalyze a reevaluation of optimization, metabolism, and
toxicity-screening protocols. Interactions between novel materials and biological pathways are
largely unknown but are widely suspected to depend heavily on physical and chemical
characteristics such as particle size, particle size distribution, surface area, surface chemistry
(including charge and hydrophobicity), shape, and aggregation state—features not usually
scrutinized for traditional drugs. Standard criteria for physicochemical characterization will have to
be established before safety testing can yield interpretable and reproducible results.
Would nanotechnology-based drugs be successful? All drugs have to run an obstacle course
through physiological and biochemical barriers. For monoclonal antibody drugs, only a minute
portion of an intravenously administered drug reaches its target. However, drugs based on
nanomaterials, including nanoparticles, have unique properties that enable them to specifically bind
to and penetrate solid tumors. Size and surface chemistries can be manipulated to facilitate
extravasation through tumor vasculature, or the therapeutic agent can be encapsulated in polymer
micelles or liposomes to prevent degradation and increase circulation half-life to improve the odds
of it reaching the target.
This level of functional engineering has not been available to either small-molecule or protein-
based drugs. For these drugs, modification of one characteristic, such as solubility or charge, can
have dramatic effects on other essential characteristics, such as potency or target specificity.
Nanoparticles, however, introduce a much higher degree of modularity and offer at least four
advantages over the antibody conjugates: (1) the delivery of a larger therapeutic payload per target
recognition event, enhancing potency; (2) the ability to carry multiple targeting agents, enhancing

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selectivity; (3) the ability to carry multiple therapeutic agents, enabling targeted combination
therapies; and (4) the ability to bypass physiological and biological barriers.
We would all like to hasten the day when chemotherapy—the administration of non-specific,
toxic anti-cancer agents—is relegated to medical history. Improvements in diagnostic screening
and the development of drugs that target specific biological pathways have begun to turn the tide
and contribute to a slow, yet consistent decline in death rates. While confirming that early diagnosis
and targeted therapies are pointing us in the right direction, the progress is still incremental.
Nanotechnology may be our best hope for overcoming many of the barriers faced by today’s drugs
in the battle against cancer. The combined creative forces of engineering, chemistry, physics, and
biology will beget new and hopefully transformative options to old, intractable problems.

Piotr Grodzinski, Ph.D.

National Cancer Institute

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Preface
With parallel breakthroughs occurring in molecular biology and nanoscience/technology, the newly
recognized research thrust on “nanomedicine” is expected to have a revolutionary impact on the
future of healthcare. To advance nanotechnology research for cancer prevention, diagnosis, and
treatment, the United States National Cancer Institute (NCI) established the Alliance for
Nanotechnology in Cancer in September 2004 and has pledged $144.3 million in the next five years
(for details, visit http://nano.cancer.gov). Among the approaches for exploiting developments in
nanotechnology for cancer molecular medicine, nanoparticles offer some unique advantages as
sensing, delivery, and image enhancement agents. Several varieties of nanoparticles are available,
including polymeric conjugates and nanoparticles, micelles, dendrimers, liposomes, and
nanoassemblies.
This book focuses specifically on nanoscientific and nanotechnological strategies that are
effective and promising for imaging and treatment of cancer. Among the various approaches
considered, nanotechnology offers the best promise for targeted delivery of drugs and genes to the
tumor site and alleviation of the side effects of chemotherapeutic agents. Multifunctional
nanosystems offer tremendous opportunity for combining more than one drug or using drug and
imaging agents. The expertise of world-renowned academic and industrial researchers is brought
together here to provide a comprehensive treatise on this subject.
The book is composed of thirty-eight chapters divided into seven sections that address the
specific nanoplatforms used for imaging and delivery of therapeutic molecules. Section 1 focuses
on the rationale and fundamental understanding of targeting strategies, including pharmacokinetic
considerations for delivery to tumors in vivo, multifunctional nanotherapeutics, boron neutron
capture therapy, and the discussion on nanotechnology characterization for cancer therapy, as well
as guidance from the U.S. Food and Drug Administration on approval of nanotechnology products.
Section 2 focuses on polymeric conjugates used for tumor-targeted imaging and delivery, including
special consideration on the use of imaging to evaluate therapeutic efficacy. In Section 3, polymeric
nanoparticle systems are discussed with emphasis on biodegradable, long-circulating nanoparticles
for passive and active targeting. Section 4 focuses on polymeric micellar assemblies, where
sophisticated chemistry is applied for the development of novel nanosystems that can provide
efficient delivery to tumors. Many of the micellar delivery systems are undergoing clinical trials in
Japan and other countries across the globe. Dendritic nanostructures used for cancer imaging and
therapy are discussed in Section 5. Section 6 focuses on the oldest nanotechnology for cancer
therapy—liposome-based delivery systems—with emphasis on surface modification to enhance
target efficiency and temperature-responsive liposomes. Lastly, Section 7 focuses on other lipid
nanosystems used for targeted delivery of cancer therapy, including nanoemulsions that can cross
biological barriers, solid-lipid nanoparticles, lipoprotein nanoparticles, and DQAsomes for
mitochondria-specific delivery.
Words cannot adequately express my admiration and gratitude to all of the contributing authors.
Each chapter is written by a world-renowned authority on the subject, and I am deeply grateful for
their willingness to participate in this project. I am also extremely grateful to Dr. Piotr Grodzinski
for providing the Foreword. Drs. Fredika Robertson and Mauro Ferrari have done a superb job in
laying the foundation by providing a chapter entitled “Introduction and Rationale for
Nanotechnology in Cancer.” I am grateful to Professor Kinam Park at Purdue University,
Professor Robert Langer at MIT, and Professor Vladimir Torchilin at Northeastern University, who
have been my mentors and collaborators, as well as many other researchers from academia and
industry. Special thanks are due to the postdoctoral associates and graduate students in my
laboratory at Northeastern University who have been the “soldiers in the trenches” in our quest to
use nanotechnology for the targeted delivery of drugs and genes to solid tumors. Lastly, I am deeply

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grateful to the wonderful people at Taylor & Francis-CRC Press, including Stephen Zollo, Patricia
Roberson, and many others, who have made the concept of this book into reality.
Any comments and constructive criticisms of the book can be sent to the editor at
m.amiji@neu.edu.

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Editor
Dr. Mansoor M. Amiji received his undergraduate degree in pharmacy from Northeastern
University in 1988 and his PhD in pharmaceutics from Purdue University in 1992. His areas of
specialization include polymeric biomaterials, advanced drug delivery systems, and nanomedical
technologies.
Dr. Amiji’s research interests include the synthesis of novel polymeric materials for medical and
pharmaceutical applications; surface modification of cationic polymers by the complexation-
interpenetration method to develop biocompatible materials; the preparation and characterization
of polymeric membranes and microcapsules with controlled permeability properties for medical
and pharmaceutical applications; target-specific drug and vaccine delivery systems for
gastrointestinal tract infections; localized delivery of cytotoxic and anti-angiogenic drugs for
solid tumors in novel biodegradable polymeric nanoparticles; intracellular delivery systems for
drugs and genes using target-specific, long-circulating, biodegradable polymeric nanoparticles; and
gold and iron-gold core-shell nanoparticles for biosensing, imaging, and delivery applications. His
research has received sustained funding from the National Institutes of Health (NIH), the National
Science Foundation (NSF), foundations, and local industries.
Dr. Amiji is Professor and Associate Chair of the Pharmaceutical Sciences Department and Co-
Director of the Northeastern University Nanomedicine Education and Research Consortium
(NERC). The NERC oversees a doctoral training grant in nanomedicine science and technology
that was co-funded by the NIH and NSF. He has two published books, Applied Physical Pharmacy
and Polymeric Gene Delivery: Principles and Applications, along with numerous manuscript
publications. He has also received a number of awards, including the 2003 Eurand Award for
Innovative Oral Drug Delivery Research, Third Prize.
Dr. Amiji has supervised the research efforts of over 50 postdoctoral associates, doctoral and
master’s level graduate students, and undergraduate honors students over the last 13 years. His
teaching responsibilities include the Doctor of Pharmacy (PharmD) program and graduate
programs (MS and PhD) in pharmaceutical sciences, biotechnology, and nanomedicine.

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Contributors
Hamidreza Montazeri Aliabadi Rolf F. Barth
Department of Pharmacy and Pharmaceutical Department of Pathology
Sciences The Ohio State University
University of Alberta Columbus, Ohio
Edmonton, Alberta, Canada
Reina Bendayan
Department of Pharmaceutical Sciences
Christine Allen University of Toronto
Department of Pharmaceutical Sciences Toronto, Ontario, Canada
and
Department of Chemical Engineering and Tania Betancourt
Applied Chemistry The University of Texas at Austin
University of Toronto Austin, Texas
Toronto, Ontario, Canada
D. Bhadra
Department of Pharmaceutical Sciences
Ashootosh V. Ambade Dr. H.S. Gour University
Department of Chemistry Sagar, India
University of Massachusetts at Amherst
Amherst, Massachusetts S. Bhadra
Department of Pharmaceutical Sciences
Dr. H.S. Gour University
Mansoor M. Amiji
Sagar, India
Department of Pharmaceutical Sciences
Northeastern University Sangeeta N. Bhatia
Boston, Massachusetts Harvard–MIT Division of Health Sciences
and Technology
Joseph M. Backer Massachusetts Institute of Technology
SibTech, Inc. Cambridge, Massachusetts
Newington, Connecticut
Sarathi V. Boddapati
Department of Pharmaceutical Sciences
Marina V. Backer
Northeastern University
SibTech, Inc.
Boston, Massachusetts
Newington, Connecticut
Lisa Brannon-Peppas
You Han Bae The University of Texas at Austin
Department of Pharmaceutics and Austin, Texas
Pharmaceutical Chemistry
University of Utah Mark Butler
Salt Lake City, Utah Department of Chemical Engineering
and Applied Chemistry
University of Toronto
Lajos P. Balogh Toronto, Ontario, Canada
Department of Radiation Medicine
and John C. Byrd
Department of Cellular Stress and Division of Hematology–Oncology
Cancer Biology NCI Comprehensive Cancer Center
Roswell Park Cancer Institute The Ohio State University
Buffalo, New York Columbus, Ohio

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Robert B. Campbell Jinming Gao
Department of Pharmaceutical Sciences Simmons Comprehensive Cancer Center
Northeastern University University of Texas Southwestern
Boston, Massachusetts Medical Center
Dallas, Texas
Shing-Ming Cheng
Department of Pharmaceutical Sciences Hamidreza Ghandehari
Northeastern University Department of Pharmaceutical Sciences
Boston, Massachusetts University of Maryland
Baltimore, Maryland
Gerard G. M. D’Souza
Department of Pharmaceutical Sciences Todd J. Harris
Northeastern University Harvard–MIT Division of Health Sciences
Boston, Massachusetts and Technology
Massachusetts Institute of Technology
Marina A. Dobrovolskaia Cambridge, Massachusetts
Nanotechnology Characterization Laboratory
NCI Frederick Mitsuru Hashida
Frederick, Maryland Department of Drug Delivery Research
Graduate School of Pharmaceutical Sciences
Amber Doiron Kyoto University
The University of Texas at Austin Sakyo-ku, Kyoto, Japan
Austin, Texas
Yuriko Higuchi
P. K. Dubey Department of Drug Delivery Research
Department of Pharmaceutical Sciences Graduate School of Pharmaceutical Sciences
Dr. H. S. Gold University Kyoto University
Sagar, India Sakyo-ku, Kyoto, Japan

Omid C. Farokhzad Kang Moo Huh

Department of Anesthesiology, Perioperative Department of Polymer Science
and Pain Medicine and Engineering
Brigham and Women’s Hospital and Harvard Chungnam National University
Medical School Yuseong-Gu, Daejeon, South Korea
Boston, Massachusetts
Edward F. Jackson
Mauro Ferrari Division of Diagnostic Imaging
The Brown Foundation Institute of The University of Texas M. D. Anderson
Molecular Medicine Cancer Center
M. D. Anderson Cancer Center Houston, Texas
and
Alliance for Nanohealth N. K. Jain
The University of Texas Department of Pharmaceutical Sciences
Houston, Texas Dr. H.S. Gour University
Sagar, India
Alberto A. Gabizon
Oncology Institute Eun-Kee Jeong
Shaare Zedek Medical Center and Department of Radiology
Hebrew University University of Utah
Jerusalem, Israel Salt Lake City, Utah

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Ji Hoon Jeong Andras G. Lacko
Department of Pharmaceutics and Departments of Molecular Biology and
Pharmaceutical Chemistry Immunology
University of Utah University of North Texas Health Science
Salt Lake City, Utah Center
Fort Worth, Texas
Sangyong Jon
Department of Life Science Robert Langer
Gwangju Institute of Science and Technology Department of Chemical Engineering
Gwangju, South Korea Massachusetts Institute of Technology
Cambridge, Massachusetts
Shigeru Kawakami
Department of Drug Delivery Research Afsaneh Lavasanifar
Graduate School of Pharmaceutical Sciences Department of Pharmacy and Pharmaceutical
Kyoto University Sciences
Sakyo-ku, Kyoto, Japan University of Alberta
Edmonton, Alberta, Canada
Mohamed K. Khan
Department of Radiation Medicine Eun Seong Lee
and Amorepacific Corporation/R&D Center
Department of Cellular Stress and Giheung-gu Yongin-si Gyeonggi-do
Cancer Biology South Korea
Roswell Park Cancer Institute
Buffalo, New York Helen Lee
Department of Pharmaceutical Sciences
Chalermchai Khemtong
University of Toronto
Simmons Comprehensive Cancer Center
Toronto, Ontario, Canada
University of Texas Southwestern
Medical Center Robert J. Lee
Dallas, Texas NCI Comprehensive Cancer Center
and
Sun Hwa Kim
NSF Nanoscale Science and
Department of Biological Sciences
Engineering Center
Korea Advanced Institute of Science
The Ohio State University
and Technology
Columbus, Ohio
Daejeon, South Korea

Tae-il Kim Sang Cheon Lee

School of Chemistry and Molecular Nanomaterials Application Division
Engineering Korea Institute of Ceramic Engineering and
Seoul National University Technology
Seoul, South Korea Guemcheon-gu, Seoul, South Korea

Sushma Kommareddy Chun Li

Department of Pharmaceutical Sciences M. D. Anderson
Northeastern University Cancer Center
Boston, Massachusetts The University of Texas
Houston, Texas
Vinod Labhasetwar
Departments of Pharmaceutical Sciences and Yongqiang Li
Biochemistry and Molecular Biology Department of Pharmaceutical Sciences
University of Nebraska Medical Center University of Toronto
Omaha, Nebraska Toronto, Ontario, Canada

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Bruce R. Line Randall J. Mrsny
Department of Radiology, and Greenebaum Center for Drug Delivery/Biology
Cancer Center Welsh School of Pharmacy
University of Maryland Cardiff University
Baltimore, Maryland Cardiff, United Kingdom

Jubo Liu
Department of Pharmaceutical Sciences R. S. R. Murthy
University of Toronto Pharmacy Department
Toronto, Ontario, Canada The M.S. University of Baroda
Vadodara, India
Zheng-Rong Lu
Departments of Pharmaceutics and Natarajan Muthusamy
Pharmaceutical Chemistry NCI Comprehensive Cancer Center
University of Utah
The Ohio State University
Salt Lake City, Utah
Columbus, Ohio
S. Mahor
Department of Pharmaceutical Sciences Anjan Nan
Dr. H. S. Gour University Department of Pharmaceutical Sciences and
Sagar, India Center for Nanomedicine and
Cellular Delivery
Walter J. McConathy University of Maryland
Department of Internal Medicine Baltimore, Maryland
University of North Texas Health Science
Center
Fort Worth, Texas Maya Nair
Departments of Molecular Biology and
Scott E. McNeil Immunology
Nanotechnology Characterization Laboratory University of North Texas Health
NCI Frederick Science Center
Frederick, Maryland Fort Worth, Texas

T. J. Miller Norased Nasongkla

Center for Drug Evaluation and Research Simmons Comprehensive Cancer Center
Food and Drug Administration University of Texas Southwestern
Silver Spring, Maryland Medical Center
Dallas, Texas
Amitava Mitra
Department of Pharmaceutical Sciences and
Center for Nanomedicine and David Needham
Cellular Delivery Department of Mechanical Engineering
University of Maryland and Materials Science
Baltimore, Maryland Duke University
Durham, North Carolina
S. M. Moghimi
Molecular Targeting and Polymer Tooru Ooya
Toxicology Group Department of Materials Science
School of Pharmacy Japan Advanced Institute of Science
University of Brighton and Technology
Brighton, United Kingdom Tatsunokuchi, Ishikawa, Japan

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Jong-Sang Park N. Sadrieh
Department of Chemistry and Molecular Center for Drug Evaluation and Research
Engineering Food and Drug Administration
Seoul National University Silver Spring, Maryland
Seoul, South Korea
Sanjeeb K. Sahoo
Kinam Park Department of Pharmaceutical Sciences
Departments of Pharmaceutics and Nebraska Medical Center
Biomedical Engineering Omaha, Nebraska
Purdue University and
West Lafayette, Indiana Institute of Life Sciences
Bhubaneswar, India
Tae Gwan Park
Department of Biological Sciences Elamprakash N. Savariar
Korea Advanced Institute of Science and Department of Chemistry
Technology University of Massachusetts at Amherst
Daejeon, South Korea Amherst, Massachusetts

Dinesh B. Shenoy
Anil K. Patri
Department of Pharmaceutical Sciences
Nanotechnology Characterization Laboratory
Northeastern University
NCI Frederick
Boston, Massachusetts and Novavax, Inc.
Frederick, Maryland
Malvern, Pennsylvania

Ana Ponce Patrick Lim Soo

Department of Biomedical Engineering Department of Pharmaceutical Sciences
Duke University University of Toronto
Durham, North Carolina Toronto, Ontario, Canada

Natalya Rapoport Stephan T. Stern

Department of Bioengineering Nanotechnology Characterization
University of Utah Laboratory
Salt Lake City, Utah NCI Frederick
Frederick, Maryland
Mike Andrew Rauth
Department of Pharmaceutical Sciences S. (Thai) Thayumanavan
University of Toronto Department of Chemistry
Toronto, Ontario, Canada University of Massachusetts at Amherst
Amherst, Massachusetts
L. Harivardan Reddy
Pharmacy Department Sandip B. Tiwari
The M.S. University of Baroda Department of Pharmaceutical Sciences
Vadodara, India Northeastern University
Boston, Massachusetts
Fredika M. Robertson
College of Medicine and Comprehensive Werner Tjarks
Cancer Center College of Pharmacy
The Ohio State University The Ohio State University
Columbus, Ohio Columbus, Ohio

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Vladimir P. Torchilin Ho Lun Wong
Department of Pharmaceutical Sciences Department of Pharmaceutical Sciences
Northeastern University University of Toronto
Boston, Massachusetts Toronto, Ontario, Canada

Gong Wu
Anagha Vaidya
Department of Pathology
Departments of Pharmaceutics and
The Ohio State University
Pharmaceutical Chemistry
Columbus, Ohio
University of Utah
Salt Lake City, Utah Xiao Yu Wu
Department of Pharmaceutical Sciences
Geoffrey von Maltzahn University of Toronto
Harvard–MIT Division of Health Sciences Toronto, Ontario, Canada
and Technology
Massachusetts Institute of Technology Xiao-Bing Xiong
Cambridge, Massachusetts Faculty of Pharmacy and Pharmaceutical
Sciences
University of Alberta
S. P. Vyas Edmonton, Alberta, Canada
Department of Pharmaceutical Sciences
Dr. H. S. Gour University Weilian Yang
Sagar, India Department of Pathology
The Ohio State University
Columbus, Ohio
Sidney Wallace
Division of Diagnostic Imaging Furong Ye
The University of Texas M. D. Anderson Departments of Pharmaceutics and
Cancer Center Pharmaceutical Chemistry
Houston, Texas University of Utah
Salt Lake City, Utah
Yanli Wang
Departments of Pharmaceutics and Guodong Zhang
Pharmaceutical Chemistry M. D. Anderson
University of Utah Cancer Center
Salt Lake City, Utah The University of Texas
Houston, Texas

Volkmar Weissig Xiaobin B. Zhao

Department of Pharmaceutical Sciences NCI Comprehensive Cancer Center
Northeastern University The Ohio State University
Boston, Massachusetts Columbus, Ohio
.

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Table of Contents
Section 1
Nanotechnology and Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Chapter 1 Introduction and Rationale for Nanotechnology

in Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Fredika M. Robertson and Mauro Ferrari

Chapter 2 Passive Targeting of Solid Tumors: Pathophysiological

Principles and Physicochemical Aspects of
Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
S. M. Moghimi

Chapter 3 Active Targeting Strategies in Cancer with a Focus on

Potential Nanotechnology Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Randall J. Mrsny

Chapter 4 Pharmacokinetics of Nanocarrier-Mediated

Drug and Gene Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Yuriko Higuchi, Shigeru Kawakami, and Mitsuru Hashida

Chapter 5 Multifunctional Nanoparticles for Cancer Therapy. . . . . . . . . . . . . . . . . . . . . . . 59

Todd J. Harris, Geoffrey von Maltzahn, and Sangeeta N. Bhatia

Chapter 6 Neutron Capture Therapy of Cancer: Nanoparticles

and High Molecular Weight Boron Delivery Agents. . . . . . . . . . . . . . . . . . . . . . 77
Gong Wu, Rolf F. Barth, Weilian Yang, Robert J. Lee, Werner Tjarks, Marina V. Backer, and
Joseph M. Backer

Chapter 7 Preclinical Characterization of Engineered Nanoparticles

Intended for Cancer Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Anil K. Patri, Marina A. Dobrovolskaia, Stephan T. Stern, and Scott E. McNeil

Chapter 8 Nanotechnology: Regulatory Perspective for Drug

Development in Cancer Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
N. Sadrieh and T. J. Miller

Section 2
Polymer Conjugates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Chapter 9 Polymeric Conjugates for Angiogenesis Targeted Tumor

Imaging and Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Amitava Mitra, Anjan Nan, Bruce R. Line, and Hamidreza Ghandehari

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Chapter 10 Poly(L-Glutamic Acid): Efficient Carrier of Cancer Therapeutics and
Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Guodong Zhang, Edward F. Jackson, Sidney Wallace, and Chun Li

Chapter 11 Noninvasive Visualization of In Vivo Drug Delivery

of Paramagnetic Polymer Conjugates with MRI. . . . . . . . . . . . . . . . . . . . . . . 201
Zheng-Rong Lu, Yanli Wang, Furong Ye, Anagha Vaidya, and Eun-Kee Jeong

Section 3
Polymeric Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Chapter 12 Polymeric Nanoparticles for Tumor-Targeted Drug

Delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Tania Betancourt, Amber Doiron, and Lisa Brannon-Peppas

Chapter 13 Long-Circulating Polymeric Nanoparticles for Drug and

Gene Delivery to Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Sushma Kommareddy, Dinesh B. Shenoy, and Mansoor M. Amiji

Chapter 14 Biodegradable PLGA/PLA Nanoparticles for Anti-cancer

Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Sanjeeb K. Sahoo and Vinod Labhasetwar

Chapter 15 Poly(Alkyl Cyanoacrylate) Nanoparticles for Delivery

of Anti-Cancer Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
R. S. R. Murthy and L. Harivardhan Reddy

Chapter 16 Aptamers and Cancer Nanotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Omid C. Farokhzad, Sangyong Jon, and Robert Langer

Section 4
Polymeric Micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

Chapter 17 Polymeric Micelles for Formulation of Anti-Cancer Drugs. . . . . . . . . . . . . . . 317

Helen Lee, Patrick Lim Soo, Jubo Liu, Mark Butler, and Christine Allen

Chapter 18 PEO-Modified Poly(L-Amino Acid) Micelles for

Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Xiao-Bing Xiong, Hamidreza Montazeri Aliabadi, and Afsaneh Lavasanifar

Chapter 19 Hydrotropic Polymer Micelles for Cancer Therapeutics . . . . . . . . . . . . . . . . . 385

Sang Cheon Lee, Kang Moo Huh, Tooru Ooya, and Kinam Park

Chapter 20 Tumor-Targeted Delivery of Sparingly-Soluble Anti-Cancer

Drugs with Polymeric Lipid-Core Immunomicelles . . . . . . . . . . . . . . . . . . . . 409
Vladimir P. Torchilin

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Chapter 21 Combined Cancer Therapy by Micellar-Encapsulated
Drugs and Ultrasound. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
Natalya Rapoport

Chapter 22 Polymeric Micelles Targeting Tumor pH. . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

Eun Seong Lee and You Han Bae

Chapter 23 cRGD-Encoded, MRI-Visible Polymeric Micelles

for Tumor-Targeted Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Jinming Gao, Norased Nasongkla, and Chalermchai Khemtong

Chapter 24 Targeted Antisense Oligonucleotide Micellar

Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Ji Hoon Jeong, Sun Hwa Kim, and Tae Gwan Park

Section 5
Dendritic Nanocarriers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487

Chapter 25 Dendrimers as Drug and Gene Delivery Systems . . . . . . . . . . . . . . . . . . . . . . 489

Tae-il Kim and Jong-Sang Park

Chapter 26 Dendritic Nanostructures for Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . 509

Ashootosh V. Ambade, Elamprakash N. Savariar, and S. (Thai) Thayumanavan

Chapter 27 PEGylated Dendritic Nanoparticulate Carriers of

Anti-Cancer Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
D. Bhadra, S. Bhadra, and N. K. Jain

Chapter 28 Dendrimer Nanocomposites for Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . 551

Lajos P. Balogh and Mohamed K. Khan

Section 6
Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593

Chapter 29 Applications of Liposomal Drug Delivery Systems

to Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Alberto A. Gabizon

Chapter 30 Positively-Charged Liposomes for Targeting

Tumor Vasculature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
Robert B. Campbell

Chapter 31 Cell Penetrating Peptide (CPP)–Modified Liposomal

Nanocarriers for Intracellular Drug and Gene Delivery . . . . . . . . . . . . . . . . . 629
Vladimir P. Torchilin

q 2006 by Taylor & Francis Group, LLC

Chapter 32 RGD-Modified Liposomes for Tumor Targeting . . . . . . . . . . . . . . . . . . . . . . 643
P. K. Dubey, S. Mahor, and S. P. Vyas

Chapter 33 Folate Receptor-Targeted Liposomes for

Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
Xiaobin B. Zhao, Natarajan Muthusamy, John C. Byrd, and Robert J. Lee

Chapter 34 Nanoscale Drug Delivery Vehicles for Solid Tumors:

A New Paradigm for Localized Drug Delivery
Using Temperature Sensitive Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
David Needham and Ana Ponce

Section 7
Other Lipid Nanostructures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721

Chapter 35 Nanoemulsion Formulations for Tumor-Targeted Delivery . . . . . . . . . . . . . . . 723

Sandip B. Tiwari and Mansoor M. Amiji

Chapter 36 Solid Lipid Nanoparticles for Antitumor Drug Delivery . . . . . . . . . . . . . . . . . 741

Ho Lun Wong, Yongqiang Li, Reina Bendayan, Mike Andrew Rauth, and Xiao Yu Wu

Chapter 37 Lipoprotein Nanoparticles as Delivery Vehicles

for Anti-Cancer Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
Andras G. Lacko, Maya Nair, and Walter J. McConathy

Chapter 38 DQAsomes as Mitochondria-Targeted Nanocarriers

for Anti-Cancer Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
Shing-Ming Cheng, Sarathi V. Boddapati, Gerard G. M. D’Souza, and Volkmar Weissig

q 2006 by Taylor & Francis Group, LLC