NANOPARTICULATEDRUG DELIVERYSYSTEMS

NANOPARTICULATEDRUG DELIVERYSYSTEMS

Strategies, Technologies,and Applications

Edited by

YOON YEO

College of Pharmacy

Weldon School of Biomedical Engineering

Purdue University

West Lafayette, Indiana

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Library of Congress Cataloging-in-Publication Data:

Nanoparticulate drug delivery systems; strategies, technologies, and applications / edited by Yoon Yeo

Includes bibliographic references and index.

ISBN 978-1-118-14887-7 (cloth)

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

CONTENTS

Preface vii

Contributors ix

1 Tumor-Targeted Nanoparticles: State-of-the-Art and RemainingChallenges 1Gaurav Bajaj and Yoon Yeo

2 Applications of Ligand-Engineered Nanomedicines 21Gayong Shim, Joo Yeon Park, Lee Dong Roh, Yu-Kyoung Oh, and Sangbin Lee

3 Lipid Nanoparticles for the Delivery of Nucleic Acids 51Yuhua Wang and Leaf Huang

4 Photosensitive Liposomes as Potential Targeted Therapeutic Agents 81David H. Thompson, Pochi Shum, Oleg V. Gerasimov, and Marquita Qualls

5 Multifunctional Dendritic Nanocarriers: The Architecture

and Applications in Targeted Drug Delivery 101Ryan M. Pearson, Jin Woo Bae, and Seungpyo Hong

6 Chitosan-Based Nanoparticles for Biomedical Applications 129Heebeom Koo, Kuiwon Choi, Ick Chan Kwon, and Kwangmeyung Kim

7 Polymer–Drug Nanoconjugates 151Rong Tong, Li Tang, Nathan P. Gabrielson, Qian Yin, and Jianjun Cheng

8 Nanocrystals Production, Characterization, and Application

for Cancer Therapy 183Christin P. Hollis and Tonglei Li

v

9 Clearance of Nanoparticles During Circulation 209Seung-Young Lee and Ji-Xin Cheng

10 Drug Delivery Strategies for Combating Multiple Drug Resistance 241Joseph W. Nichols and You Han Bae

11 Intracellular Trafficking of Nanoparticles: Implications

for Therapeutic Efficacy of the Encapsulated Drug 261Lin Niu and Jayanth Panyam

12 Toxicological Assessment of Nanomedicine 281Hayley Nehoff, Sebastien Taurin, and Khaled Greish

Index 307

vi CONTENTS

PREFACE

Enthusiasm for nanomedicine has grown exponentially over the years with an

expectation that nanomedicine will enable the delivery of drugs or imaging agents

to tissues and organs that they would otherwise not reach effectively. Early nano-

medicine indeed addressed several critical problems inherent to some drugs, such as

poor solubility and toxic side effects. Liposomal doxorubicin, micelle formulations

of paclitaxel, and protein-bound paclitaxel are now used in clinical practice. At the

same time, new approaches have continuously emerged with the view to develop ever

more sophisticated, multifunctional nanoparticulate systems for more effective

diagnosis and safe therapy of diseases.

On the other hand, this field has faced several challenges in translating novel ideas

into clinical benefits. For example, the “active targeting” strategy, originally

expected to increase tumor accumulation of nanoparticles by orders of magnitude,

has fallen short of the expectations. Polymeric micelles or nanoparticles, designed to

circulate in the blood for a prolonged period of time, are unstable in the presence of

amphiphilic biological components, losing their ability to reach target tissues in

intact form. Consequently, despite the increasing complexity, newer nanoparticle

systems bring about only modest therapeutic benefits, failing to gain significant

attention from commercial, clinical, and/or regulatory sectors. In order to further

advance the field of nanomedicine and to develop clinically effective products, it is

necessary to make a practical assessment of the potential and challenges of modern

nanomedicines.

This book brings together a collection of recent nanomedicine technologies and

discusses their promises and the remaining challenges. It does not intend to duplicate

the existing compilations of established nanoparticle systems, nor does it attempt to

broaden the topic to systems that are less relevant to drug delivery. Therefore, instead

vii

of covering established nanoparticulate systems that have been described in a

number of recent books and review articles, we focus on the rationales and

preclinical evaluation of relatively new nanoparticulate drug carriers.

The chapters of this book are organized with two goals in mind. The first chapter

presents a general overview of targeted nanomedicine. Chapters 2–8 discuss nano-

particulate drug delivery systems that have gained increasing recognition in the

recent literature. Chapters 9–12 discuss new opportunities and barriers in the biology

relevant to drug delivery based on nanomedicine. Each chapter reviews a state of the

art of the topic with extensive references and concludes with an open assessment of

the remaining challenges. I hope that this arrangement helps readers to formulate

innovative nanomedicine systems and to design evaluation strategies without reliv-

ing the existing experiences, be they positive or negative.

As the editor of this book, I am most appreciative of the insightful and comprehen-

sive contributions of the chapter authors. Special thanks go to all the authors, who

immediately agreed to contribute their time and effort, and have endured reminders

and editing requests. I would also like to thank the staff members of the publisher,

Wiley-Blackwell, especially Jonathan T. Rose, for their patience and support. It is my

hope that this book will serve as a starting point for stimulating discussions and new

experimentations toward the development of better nanomedicines that can translate

in the near future into clinical benefits for patients.

YOON YEO

viii PREFACE

CONTRIBUTORS

Jin Woo Bae, Department of Biopharmaceutical Sciences, College of Pharmacy,

University of Illinois, Chicago, IL, USA

You Han Bae, Department of Pharmaceutics, University of Utah, Salt Lake City,

UT, USA

Gaurav Bajaj, Division of Clinical Pharmacology and Therapeutics, The Children’s

Hospital of Philadelphia, Philadelphia, PA, USA

Jianjun Cheng, Department of Materials Science and Engineering, University of

Illinois at Urbana�Champaign, Urbana, IL, USA

Ji-Xin Cheng, Weldon School of Biomedical Engineering, Purdue University,

West Lafayette, IN, USA

Kuiwon Choi, Center for Theragnosis, Biomedical Research Institute, Korea

Institute of Science and Technology, Seongbuk-gu, Seoul, Republic of Korea

Nathan P. Gabrielson, Department of Materials Science and Engineering,

University of Illinois at Urbana�Champaign, Urbana, IL, USA

Oleg V. Gerasimov, Department of Chemistry, Purdue University, West Lafayette,

IN, USA

Khaled Greish, Department of Pharmacology and Toxicology, Otago School of

Medical Sciences, University of Otago, Dunedin, New Zealand; Department of

Oncology, Faculty of Medicine, Suez Canal University, Egypt

Christin P. Hollis, College of Pharmacy, University of Kentucky, Lexington, KY,

USA

ix

Seungpyo Hong, Department of Biopharmaceutical Sciences, College of Phar-

macy, University of Illinois, Chicago, IL, USA

Leaf Huang, Division of Molecular Pharmaceutics and Center for Nano-

technology in Drug Delivery, Eshelman School of Pharmacy, University of

North Carolina at Chapel Hill, Chapel Hill, NC, USA

Kwangmeyung Kim, Center for Theragnosis, Biomedical Research Institute,

Korea Institute of Science and Technology, Seongbuk-gu, Seoul, Republic of

Korea

Heebeom Koo, Center for Theragnosis, Biomedical Research Institute, Korea

Institute of Science and Technology, Seongbuk-gu, Seoul, Republic of Korea

Ick Chan Kwon, Center for Theragnosis, Biomedical Research Institute, Korea

Institute of Science and Technology, Seongbuk-gu, Seoul, Republic of Korea

Sangbin Lee, School of Life Sciences and Biotechnology, Korea University,

Seoul, South Korea

Seung-Young Lee, Weldon School of Biomedical Engineering, Purdue University,

West Lafayette, IN, USA

Tonglei Li, Department of Industrial and Physical Pharmacy, Purdue University,

West Lafayette, IN, USA

Hayley Nehoff, Department of Pharmacology and Toxicology, Otago School of

Medical Sciences, University of Otago, Dunedin, New Zealand

Joseph W. Nichols, Department of Bioengineering, University of Utah, Salt Lake

City, UT, USA

Lin Niu, Department of Pharmaceutics, College of Pharmacy, University of

Minnesota, Minneapolis, MN, USA

Yu-Kyoung Oh, College of Pharmacy, Seoul National University, Daehak-dong,

Seoul, South Korea

Jayanth Panyam, Department of Pharmaceutics, College of Pharmacy, University

of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of

Minnesota, Minneapolis, MN, USA

Joo Yeon Park, College of Pharmacy, Seoul National University, Daehak-dong,

Seoul, South Korea

Ryan M. Pearson, Department of Biopharmaceutical Sciences, College of

Pharmacy, University of Illinois, Chicago, IL, USA

Marquita Qualls, Department of Chemistry, Purdue University, West Lafayette,

IN, USA

Lee Dong Roh, College of Pharmacy, Seoul National University, Daehak-dong,

Seoul, South Korea

x CONTRIBUTORS

Gayong Shim, College of Pharmacy, Seoul National University, Daehak-dong,

Seoul, South Korea

Pochi Shum, Department of Chemistry, Purdue University, West Lafayette, IN,

USA

Li Tang, Department of Materials Science and Engineering, University of Illinois

at Urbana�Champaign, Urbana, IL, USA

Sebastien Taurin, Department of Pharmacology and Toxicology, Otago School of

Medical Sciences, University of Otago, Dunedin, New Zealand

David H. Thompson, Department of Chemistry, Purdue University, West Lafay-

ette, IN, USA

Rong Tong, Department of Chemical Engineering, Massachusetts Institute of

Technology, Cambridge, MA, USA Laboratory for Biomaterials and Drug

Delivery, Department of Anesthesiology, Division of Critical Care Medicine,

Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA

Yuhua Wang, Division of Molecular Pharmaceutics and Center for Nano-

technology in Drug Delivery, Eshelman School of Pharmacy, University of

North Carolina at Chapel Hill, Chapel Hill, NC, USA

Yoon Yeo, Department of Industrial and Physical Pharmacy, Purdue University,

West Lafayette, IN, USA

Qian Yin, Department of Materials Science and Engineering, University of Illinois

at Urbana�Champaign, Urbana, IL, USA

CONTRIBUTORS xi

EDITOR

Yoon Yeo, Ph.D., is an Assistant Professor of Industrial and Physical Pharmacy at

the College of Pharmacy, with a joint appointment as Assistant Professor at the

Weldon School of Biomedical Engineering, at Purdue University. She earned her B.S.

in Pharmacy andM.S. in Microbial Chemistry at Seoul National University in Korea,

and her Ph.D. in Pharmaceutics at Purdue University in the United States. She

completed postdoctoral training in Chemical Engineering at Massachusetts Institute

of Technology and returned to Purdue as a faculty member. Her research focuses on

nanoparticle surface engineering for drug delivery to solid tumors, inhalable drug/

gene delivery for cystic fibrosis therapy, and functional biomaterials based on

carbohydrates. Dr. Yeo has published 52 peer-reviewed papers and 7 book chapters,

and received the NSF CAREER Award (2011) and New Investigator Awards from

the American Association of Pharmaceutical Scientists (2009) and American

Association of Colleges of Pharmacy (2008).

1TUMOR-TARGETEDNANOPARTICLES: STATE-OF-THE-ART AND REMAINING CHALLENGES

GAURAV BAJAJ

Division of Clinical Pharmacology and Therapeutics, The Children’s Hospital of

Philadelphia, Philadelphia, PA, USA

YOON YEO

Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette,

IN, USA

1.1 INTRODUCTION

Bringing a drug only to target tissues without spilling any molecule in unwanted

places would be an ideal goal for any pharmacological therapies [1]. Owing to the

dose-limiting side effects of chemotherapy, a number of drug delivery strategies have

been developed in the context of cancer, where “targeted” therapy is most antici-

pated. Most tumor-targeted drug delivery systems are based on the fact that cancer

cells express various molecular markers that are distinguished from those of normal

cells. In particular, nanomedicines have received enormous attention in the past

decades as a potential tool to increase the selectivity of chemotherapy and diagnosis,

due to the small size conducive to circulation and the large surface area to volume

ratio that facilitates surface functionalization. Several nanomedicine products have

been launched in the market or in the clinical development stage as summarized in

Table 1.1. Newer approaches are actively developed to increase target selectivity,

although the number of targeted nanomedicines that reached the later phase of

1

Nanoparticulate Drug Delivery Systems: Strategies, Technologies, and Applications, First Edition.Edited by Yoon Yeo.� 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.