Drug Delivery in Oncology E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 3057

Veröffentlichungsjahr: 2013

Beschreibung

In this first authoritative overview on modern cancer chemotherapy 121 international specialists have contributed their experience and recent data for what is likely to become the gold standard in the field. The authors summarize knowledge gained over the past decade, from basic concepts to successful applications in the clinic, covering active and passive targeting strategies as well as tissue-specific approaches. All current and future targeted delivery systems are discussed, from ligand-based to antibody-based polymer-based systems, right up to micro- and nanoparticulate systems. A special section covers the delivery of nucleic acid therapeutics, such as siRNA, miRNA and antisense nucleotides. In each case, a description of the basic technique is followed by a discussion of the latest preclinical and clinical developments in the field. By virtue of its clear and didactic structure, rich illustrative material and summary chapters, this handbook and ready reference enables the efficient transfer of knowledge between different disciplines, from basic research to the clinician and vice versa. It is equally well suited for professionals, researchers and students in medical oncology and cancer biology, and is also excellent for teaching medical students the foundations of 21st century cancer chemotherapy.

Leseprobe

Table of Contents

Related Titles

Title Page

Copyright

Foreword

Preface

List of Contributors

Drug Delivery in Oncology – Challenges and Perspectives

Part I: Principles of Tumor Targeting

Chapter 1: Limits of Conventional Cancer Chemotherapy

1.1 Introduction: The Era of Cancer Chemotherapy

1.2 Dilemma and Challenge of Treating Malignant Diseases

1.3 Adverse Effects

1.4 Supportive Care

1.5 New Approaches Complementing Current Cancer Chemotherapy

1.6 Conclusions and Perspectives

References

Chapter 2: Pathophysiological and Vascular Characteristics of Solid Tumors in Relation to Drug Delivery

2.1 Introduction

2.2 Basic Principles of Blood Vessel Formation in Solid Tumors

2.3 Tumor Lymphangiogenesis

2.4 Tumor Vascularity and Blood Flow

2.5 Arteriovenous Shunt Perfusion in Tumors

2.6 Volume and Characteristics of the Tumor Interstitial Space

2.7 Interstitial Fluid Pressure in Tumors

2.8 Role of the Disorganized, Compromised Microcirculation as an Obstacle in Drug Delivery

2.9 Interstitial Barriers to Drug Delivery

2.10 Pathophysiological Tumor Microenvironment as an Obstacle in Tumor Therapy

2.11 Conclusions

Acknowledgments

References

Chapter 3: Enhanced Permeability and Retention Effect in Relation to Tumor Targeting

3.1 Background and Status Quo

3.2 What is the EPR Effect: Mechanism, Uniqueness, and Factors Involved

3.3 Heterogeneity of the EPR Effect: A Problem in Drug Delivery

3.4 Overcoming the Heterogeneity of the EPR Effect for Drug Delivery and How to Enhance the EPR Effect

3.5 PEG Dilemma: Stealth Effect and Anti-PEG IgM Antibody

3.6 Concluding Remarks

Acknowledgments

References

Chapter 4: Pharmacokinetics of Immunoglobulin G and Serum Albumin: Impact of the Neonatal Fc Receptor on Drug Design

4.1 Introduction

4.2 Discovery of FcRn

4.3 FcRn Structure

4.4 FcRn–Ligand Interactions

4.5 FcRn as a Multiplayer with Therapeutic Utilities

4.6 Engineering IgG for Altered FcRn Binding and Pharmacokinetics

4.7 Targeting FcRn by SA

4.8 Considering Cross-Species Binding

4.9 Concluding Remarks

Acknowledgment

References

Chapter 5: Development of Cancer-Targeting Ligands and Ligand–Drug Conjugates

5.1 Introduction

5.2 Overview of Cancer-Targeting Ligand–Drug Conjugates

5.3 Cancer-Targeting Ligands

5.4 Linkers

5.5 Examples of Cancer-Targeting Ligand–Drug Conjugates

5.6 Conclusions and Perspectives

Acknowledgments

References

Chapter 6: Antibody-Directed Enzyme Prodrug Therapy (ADEPT) – Basic Principles and its Practice So Far

6.1 Introduction

6.2 Principles and the Components of ADEPT

6.3 Third Essential

6.4 ADEPT Studies Elsewhere

6.5 Reagents for First Clinical Trials in London (1990–1995)

6.6 Technology Advances

6.7 ADEPT Future

References

Part II: Tumor Imaging

Chapter 7: Imaging Techniques in Drug Development and Clinical Practice

7.1 Introduction

7.2 Cancer Biology

7.3 Cancer Biomarkers

7.4 Imaging Techniques

7.5 Examples of Imaging Assessment of Tumor Response

7.6 Challenges of Imaging in Drug Development and Validation

7.7 Conclusions and Future Perspectives

References

Chapter 8: Magnetic Nanoparticles in Magnetic Resonance Imaging and Drug Delivery

8.1 Introduction

8.2 Passive Targeting of Nanoparticles

8.3 Active SPIO Nanoparticle Targeting

8.4 Nanoparticles in Targeted Therapy

8.5 Conclusions

References

Chapter 9: Preclinical and Clinical Tumor Imaging with SPECT/CT and PET/CT

9.1 Introduction

9.2 Technical Aspects of Functional and Molecular Imaging with SPECT and PET

9.3 Preclinical and Clinical Developments

9.4 Clinical Applications of SPECT/CT and PET

9.5 Conclusions and Perspectives

References

Part III: Macromolecular Drug Delivery Systems

Chapter 10: Empowered Antibodies for Cancer Therapy

10.1 Introduction and Rationale for Approach

10.2 Examples of Empowered Antibody Technologies

10.3 Clinical Developments

10.4 Alternative Scaffolds

10.5 Conclusions and Perspectives

References

Chapter 11: Mapping Accessible Vascular Targets to Penetrate Organs and Solid Tumors

11.1 Introduction

11.2 Current Approaches to Therapy

11.3 Defining New Target Spaces

11.4 Difficulties in Studying Endothelial Cells

11.5 Methods to Identify Tissue-Specific Targets

11.6 MS-Based Approaches to Map the Vascular Endothelial Cell Proteome

11.7 Means to Validation

11.8 In Vivo Tissue Targeting: The Lungs as Proof of Principle

11.9 Targeting Lung Tumors

11.10 Future Directions

References

Chapter 12: Considerations of Linker Technologies

12.1 Introduction

12.2 Linkage Site and Cross-Linking Chemistry

12.3 Linkers for Cytotoxic ADCs

12.4 Linkers for Radioactive Immunoconjugates

12.5 Conclusions

References

Chapter 13: Antibody–Maytansinoid Conjugates: From the Bench to the Clinic

13.1 Introduction

13.2 Conjugation Strategies

13.3 Selecting the Optimal Linker

13.4 Clinical Candidates

13.5 Activation of AMCs by Targeted Cancer Cells

13.6 In Vivo Tumor Delivery Studies

13.7 Conclusions

References

Chapter 14: Calicheamicin Antibody–Drug Conjugates and Beyond

14.1 Introduction

14.2 Discovery of Calicheamicin and Mechanism of Action

14.3 Calicheamicin ADCs

14.4 Clinical Development of Calicheamicin Conjugates: CMC-544

14.5 Conclusions and Future Directions

References

Chapter 15: Antibodies for the Delivery of Radionuclides

15.1 Introduction

15.2 Rationale for Using Antibodies for Radionuclide Delivery

15.3 Clinical Development

15.4 Conclusions and Perspectives

Acknowledgments

References

Chapter 16: Bispecific Antibodies and Immune Therapy Targeting

16.1 Introduction

16.2 Treatment Options in Cancer in the Pre-Antibody Era

16.3 Antibodies as Therapeutic Agents

16.4 Next Generation of Therapeutic Antibodies

16.5 Rationale for Immunotherapy with BsAbs

16.6 BsAb Formats

16.7 BsAbs in the Clinic

16.8 Conclusions and Future Prospects

References

Chapter 17: Design of Polymer–Drug Conjugates

17.1 Introduction

17.2 Polymer Carriers

17.3 Binding Drugs to Polymer Carriers

17.4 Attachment of Targeting Moieties

17.5 Novel Designs of Polymer Therapeutics

17.6 Conclusions and Perspectives

Acknowledgments

References

Chapter 18: Dendritic Polymers in Oncology: Facts, Features, and Applications

18.1 Introduction

18.2 Chemistry and Architecture

18.3 Dendritic Architectures and Oncology: Background and Application

18.4 Intracellular Trafficking, Cytotoxicity, and Pharmacokinetics of a Dendritic Architecture are Tunable

18.5 Other Medical Applications of Dendritic Polymers

18.6 Novel Therapeutic Approaches with Dendrimers

18.7 Conclusions

Acknowledgments

References

Chapter 19: Site-Specific Prodrug Activation and the Concept of Self-Immolation

19.1 Introduction

19.2 Rationale and Chemical Aspects of the Concept of Self-Immolation

19.3 Elimination-Based Trigger Groups for Tumor-Specific Activation

19.4 Branched Elimination Linkers–Chemical Adaptors or Building Blocks for More Complex Self-Immolative Architectures

19.5 Clinical Impact

19.6 Conclusion and Perspectives

References

Chapter 20: Ligand-Assisted Vascular Targeting of Polymer Therapeutics

20.1 Overview of Tumor Angiogenesis

20.2 Potential Angiogenic Markers

20.3 Drug Delivery Strategy: Targeted Polymer Therapeutics

20.4 Novel Targeted Polymeric Drug Delivery Systems Directed to Tumor Endothelial Cells

20.5 Opportunity for Dual Targeting of Angiogenesis-Related Markers

20.6 Tumor Angiogenesis-Targeted Polymeric Drug Delivery Systems: Summary and Lessons Learnt

References

Chapter 21: Drug Conjugates with Poly(Ethylene Glycol)

21.1 Introduction

21.2 Rationale for PEGylation and PEG-Drug Conjugates

21.3 Permanent PEGylation

21.4 Releasable PEGylation

21.5 Summary of Clinical Status

21.6 Conclusions and Perspectives

Acknowledgments

References

Chapter 22: Thermo-Responsive Polymers

22.1 Introduction

22.2 Hyperthermia in Cancer Treatment

22.3 Synergistic Advantages of Combining Thermo-Responsive Polymers and Hyperthermia

22.4 Selected Thermo-Responsive Polymer Classes

22.5 Elastin-Like Biopolymers

22.6 Conclusions and Perspectives

Acknowledgments

References

Chapter 23: Polysaccharide-Based Drug Conjugates for Tumor Targeting

23.1 Introduction

23.2 Chemistry of Polysaccharide–Drug Conjugation

23.3 Polysaccharide-Drug Conjugates

23.4 Cyclodextrin–Drug Conjugates

23.5 Conclusions and Perspectives

References

Chapter 24: Serum Proteins as Drug Carriers of Anticancer Agents

24.1 Introduction

24.2 Rationale for Exploiting Albumin, Transferrin, and LDL as Carriers for Drug Delivery to Solid Tumors

24.3 Examples of Drug Delivery Systems with Serum Proteins

24.4 Clinical Development

24.5 Conclusions and Perspectives

References

Chapter 25: Future Trends, Challenges, and Opportunities with Polymer-Based Combination Therapy in Cancer

25.1 Introduction

25.2 Concept of Polymer–Drug Conjugates for Combination Therapy

25.3 Challenges and Opportunities Associated with the Use of Polymer-Based Combination Therapy

25.4 Representative Examples of Polymer–Drug Conjugates for Combination Therapy

25.5 Conclusions and Perspectives

Acknowledgments

References

Chapter 26: Clinical Experience with Drug–Polymer Conjugates

26.1 Introduction

26.2 Rationale for Developing Drug–Polymer Conjugates

26.3 Clinical Development

26.4 Conclusions and Perspectives

References

Part IV: Nano- and Microparticulate Drug Delivery Systems

Chapter 27: Overview on Nanocarriers as Delivery Systems

27.1 Introduction

27.2 Overview on Liposome-Based Systems

27.3 Overview on Polymer Micelle-Based Systems

27.4 Other Nanoparticulate Drug Delivery Systems

27.5 MSV Drug Delivery Systems

27.6 Conclusions and Perspectives

References

Chapter 28: Development of PEGylated Liposomes

28.1 Introduction and Rationale

28.2 Structure, Formation, and Characteristics of Liposomes

28.3 Pharmacokinetics of Stealth Liposomes

28.4 Clinical Development

28.5 Newer Applications of PEGylated Liposomes

28.6 Conclusions and Perspective

References

Chapter 29: Immunoliposomes

29.1 Introduction: Drug Targeting and Liposomes as Drug Carriers

29.2 Tumor-Targeted Liposomes in Cancer Chemotherapy

29.3 Preparation and Administration of Antibody-Targeted Liposomal Drugs

29.4 Conclusions

References

Chapter 30: Responsive Liposomes (for Solid Tumor Therapy)

30.1 Introduction

30.2 Rationale: Uniformity in Delivery and Actual Delivery

30.3 Examples

30.4 Conclusions and Perspectives

Acknowledgments

References

Chapter 31: Nanoscale Delivery Systems for Combination Chemotherapy

31.1 Introduction

31.2 Rationale for Fixed Ratio Anticancer Combination Therapy

31.3 Application of Drug Delivery Systems to Develop Fixed-Ratio Drug Combination Formulations

31.4 Liposome-Based CombiPlex® Formulations

31.5 Clinical Studies of CombiPlex Formulations

31.6 CombiPlex Formulations of Hydrophobic Agents

31.7 Conclusions

References

Chapter 32: Micellar Structures as Drug Delivery Systems

32.1 Introduction

32.2 Rationale and Recent Advances in Micellar Structures as Drug Delivery Systems

32.3 Conclusions and Perspectives

References

Chapter 33: Tailor-Made Hydrogels for Tumor Delivery

33.1 Introduction

33.2 Rationale for Hydrogel-Based Cancer Therapy

33.3 Examples

33.4 Conclusions and Perspectives

References

Chapter 34: pH-Triggered Micelles for Tumor Delivery

34.1 Introduction

34.2 Tumor Extracellular Acidity

34.3 General Approaches to Construct pH-Sensitive Polymeric Micelles for Tumor Delivery

34.4 Recent Development in pH-Sensitive Micelles for Tumor-Targeted Drug Delivery

34.5 Conclusions and Perspective

References

Chapter 35: Albumin–Drug Nanoparticles

35.1 Introduction

35.2 Rationale for Using Albumin Nanoparticles for Drug Delivery

35.3 Examples of Albumin-Based Nanoparticles

35.4 Conclusions and Perspectives

Acknowledgments

References

Chapter 36: Carbon Nanotubes

36.1 Introduction

36.2 Arming of CNTs

36.3 Toxicity of CNTs

36.4 Conclusions

References

Part V: Ligand-Based Drug Delivery Systems

Chapter 37: Cell-Penetrating Peptides in Cancer Targeting

37.1 Introduction

37.2 Applications of CPPs

37.3 Tumor Targeting of CPPs

37.4 Advantages and Considerations of CPPs as Delivery Vectors

37.5 Conclusions

Acknowledgments

References

Chapter 38: Targeting to Peptide Receptors

38.1 Introduction

38.2 Rationale for the Concept of Delivery to Peptide Receptors

38.3 Example 1: Cytotoxic Analogs of LHRH1

38.4 Example 2: Targeted Cytotoxic Somatostatin Analogs

38.5 Example 3: Cytotoxic Analogs of Bombesin/Gastrin-Releasing Peptide

38.6 Example 4: Antagonists of GHRH

38.7 Conclusions and Perspectives

Acknowledgments

References

Chapter 39: Aptamer Conjugates: Emerging Delivery Platforms for Targeted Cancer Therapy

39.1 Introduction

39.2 Isolating Aptamers for Targeted Delivery

39.3 Applications of Aptamer Conjugates for Targeted Cancer Therapy

39.4 Considerations of Aptamer Characteristics for Applications

39.5 Conclusions and Perspectives

Acknowledgments

References

Chapter 40: Design and Synthesis of Drug Conjugates of Vitaminsand Growth Factors

40.1 Introduction

40.2 Chemical Aspects of FA–Drug Conjugate Design

40.3 Chemical Aspects of Vitamin B12–Drug Conjugate Design

40.4 Chemical Aspects of Biotin–Drug Conjugate Design

40.5 Other Vitamin–Drug Conjugates

40.6 Concluding Remarks on Vitamin Targeting

40.7 Growth Factor Conjugates for Tumor Targeting

Acknowledgments

References

Chapter 41: Drug Conjugates with Polyunsaturated Fatty Acids

41.1 Introduction

41.2 Rationale for the Potential Benefits of PUFA Conjugation to Chemotherapeutic Drugs

41.3 Drug Conjugates with PUFAs

41.4 Case Study in PUFA Conjugation: TXP (DHA–Paclitaxel)

41.5 PUFA Conjugates of Second-Generation Taxoids

41.6 Conclusions and Perspectives

Acknowledgments

References

Part VI: Special Topics

Chapter 42: RNA Drug Delivery Approaches

42.1 Introduction

42.2 RNA Molecules with Potential for Cancer Treatment

42.3 Chemical Modification Strategies

42.4 Challenges in RNA Delivery

42.5 Potential Adverse Effects of RNA Therapy

42.6 RNA Delivery

42.7 Targeting Ligands

42.8 Therapeutic Application for Treatment of Cancer

42.9 Conclusions

Acknowledgments

References

Chapter 43: Local Gene Delivery for Therapy of Solid Tumors

43.1 Introduction

43.2 Gene Therapeutic Strategies for Cancer Treatment

43.3 Vectors for Cancer Gene Therapy

43.4 Local Application of Gene Therapy

43.5 Conclusions

References

Chapter 44: Viral Vectors for RNA Interference Applications in Cancer Research and Therapy

44.1 Introduction

44.2 Plasmid Expression of Short Hairpin RNAs

44.3 Conditional RNAi Systems

44.4 Viral Vectors for shRNA Delivery

44.5 Outlook

Acknowledgments

References

Chapter 45: Design of Targeted Protein Toxins

45.1 Introduction

45.2 Rationale for the Respective Drug Delivery Concept

45.3 Examples

45.4 Conclusions and Perspectives

Acknowledgments

References

Chapter 46: Drug Targeting to the Central Nervous System

46.1 Introduction

46.2 Anatomy of the BBB

46.3 Alterations of the BBB in Brain Tumors

46.4 Relevance of the BBB for Drug Delivery

46.5 Intranasal Delivery to Bypass the BBB

46.6 Conclusion and Perspectives

References

Chapter 47: Liver Tumor Targeting

47.1 Introduction

47.2 Rationale for Drug Delivery Concepts for Treating Liver Cancer

47.3 Preclinical Development of Hepatotropic Drug Delivery Systems

47.4 Clinical Development

47.5 Conclusions and Perspectives

References

Chapter 48: Photodynamic Therapy: Photosensitizer Targeting and Delivery

48.1 Introduction

48.2 Photochemistry and Photophysics

48.3 Photosensitizers

48.4 Subcellular Localization

48.5 Targeting in PDT

48.6 Preclinical Developments

48.7 Clinical Developments

48.8 Conclusions and Perspectives

Acknowledgments

References

Chapter 49: Tumor-Targeting Strategies with Anticancer Platinum Complexes

49.1 Introduction

49.2 Mode of Action of Platinum-Based Anticancer Drugs and Rationale for the Respective Drug Delivery Concept

49.3 Examples

49.4 Clinical Development

49.5 Conclusions and Perspectives

Acknowledgments

References

Index

End User License Agreement

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The Editors

Dr. Felix Kratz}

Head of the Division of

Macromolecular Prodrugs

Tumor Biology Center

Breisacherstrasse 117

D-79106 Freiburg

Germany

Dr. Peter Senter

Vice President Chemistry

Seattle Genetics, Inc.

218, Drive S.E. Bothell

Seattle, WA 98021

USA

Dr. Henning Steinhagen

Vice President

Head of Global Drug Discovery

Grünenthal GmbH

Zieglerstr. 6

52078 Aachen

Germany

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2012 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form — by photoprinting, microfilm, or any other means — nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

ISBN: 978-3-527-32823-9

oBook ISBN: 978-3-527-63405-7

Foreword

It is highly likely that the reason our therapies so often fail our patients with cancer is that either (i) those therapies actually never get to their intended targets or (ii) those therapies are “intercepted” by similar targets on normal cells. If we want to understand why many of our therapies fail our patients, and what we can do to possibly remedy those failures, this book Drug Delivery in Oncology can help all of us achieve that understanding – and with this book it will be a state-of-the-art understanding.

Drs. Kratz, Senter, and Steinhagen have assembled a respectable breadth of both seasoned and precocious investigators to put together this very special treatise (49 chapters in all). The chapters are well written with basic science, preclinical, and clinical perspectives.

The book begins with a history and the limitations of conventional chemotherapy. Expert discussions of the vascular physiology of tumors that affect drug delivery (and how to defeat those issues) then follow. There are excellent discussions of the neonatal Fc receptor, development of cancer targeted ligands, and antibody-directed enzyme prodrug therapy (ADEPT).

A very special part of this book is the emphasis on tumor imaging. Again, the authors are major experts in this field, which undoubtedly will continue to mature to enable us to document whether or not our therapeutics actually make it to their intended target(s) – and if not, why not.

There are impressive chapters on macromolecular drug delivery systems, including biospecific antibodies, antibody–drug conjugates, and antibody–radionuclide conjugates. Up-to-date discussions of polymer-based drug delivery systems including PEGylation, thermoresponsive polysaccharide-based and even low-density lipoprotein–drug complexes are also presented.

Those with an interest in learning about nano- and microparticulate drug delivery systems can study liposomes to immunoliposomes, to hydrogels, micelles, albumin–drug nanoparticles, and even carbon nanotubes, which are all covered in this book.

Other special delivery systems covered include peptides–drug conjugates, vitamin–drug conjugates, and growth factor–drug conjugates, conjugates of drugs with fatty acids, RNA and RNA interference delivery, and specific targeted organ drug delivery.

As investigators who want to more effectively treat and indeed cure cancer we have many worries. The first of these is that many of our therapeutics just do not make it into the targets in the tumors. This book gives the reader a comprehensive insight into multiple ways to address this problem. A second major worry is that we are losing our pharmacologists who can solve those drug delivery issues. The editors and the authors of this incredible treatise give us comfort that these pharmacologists are alive and well, and thinking as to how they can contribute to getting control of this awful disease.

Daniel D. Von Hoff, MD, FACP

Physician in Chief and Distinguished Professor,

Translational Genomics Research Institute (TGen)

Professor of Medicine, Mayo Clinic

Chief Scientific Officer, Scottsdale Healthcare and US Oncology

Preface

Modern oncology research is highly multidisciplinary, involving scientists from a wide array of specialties focused on both basic and applied areas of research. While significant therapeutic advancements have been made, there remains a great need for further progress in treating almost all of the most prevalent forms of cancer. Unlike many other diseases, cancer is commonly characterized by barriers to penetration, heterogeneity, genetic instability, and drug resistance. Coupled with the fact that successful treatment requires elimination of malignant cells that are very closely related to normal cells within the body, cancer therapy remains one of the greatest challenges in modern medicine.

Early on, chemotherapeutic drugs were renowned for their systemic toxicities, since they poorly distinguished tumor cells from normal cells. It became apparent to scientists within the field that further advancements in cancer medicine would require new-generation drugs that ideally targeted critical pathways, unique markers, and distinguishing physiological traits that were selectively found within the malignant cells and solid tumor masses. Several new areas of research evolved from this realization, including macromolecular-based therapies that exploit impaired lymphatic drainage often associated with solid tumors, antiangiogenesis research to cut the blood supply off from growing tumors, antibody-based strategies that allow for selective targeting to tumor-associated antigens, and new drug classes that attack uniquely critical pathways that promote and sustain tumor growth. A large proportion of both recently approved and clinically advanced anticancer drugs fall within these categories.

Beyond the generation of such drug classes, it has also been recognized that approved cancer drugs could be made more effective and less toxic through delivery and transport technologies that maximize tumor exposure while sparing normal tissues from chemotherapeutic damage. By doing so, existing or highly potent cytotoxic drugs may display improved therapeutic indices. This has attracted considerable attention and has spawned the area of macromolecular-based delivery strategies.

There are few places where those actively engaged in drug delivery or who may wish to enter the field can find the major advancements consolidated in one place. This prompted us to organize the series of books entitled Drug Delivery in Oncology comprised of 49 chapters written by 121 internationally recognized leaders in the field. The work within the book series overviews many of the major breakthroughs in cancer medicine made in the last 10–15 years and features many of the chemotherapeutics of the future. Included among them are recombinant antibodies, antibody fragments, and antibody fusion proteins as well as tumor-seeking ligands for selective drug delivery and tumor imaging, and passive targeting strategies using macromolecules and nano- and microparticulate systems.

One of the special distinguishing features of this series is that the chapters are written for novices and experts alike. Each chapter is written in a style that allows interested readers to not only to find out about the most recent advancements within the field being discussed, but to actually see the data in numerous illustrations, photos, graphs, and tables that accompany each chapter.

None of this would have been possible without the devoted efforts of the contributing authors, all of whom shared the common goal of creating a new series of books that would provide an important cornerstone in the modern chemotherapeutic treatment of cancer. We are all very thankful for their efforts.

We also wish to thank the publishing team at Wiley-VCH in Weinheim, Germany. In particular, we want to give our wholehearted thanks and kind acknowledgments to Frank Weinreich, Gudrun Walter, Bernadette Gmeiner, Claudia Nubeck, Hans-Jochen Schmitt, and Ina Wiedemann, who were always helpful and supportive during the 2 years it took to put all this together. It is our hope that this series will provide readers with inspired ideas and new directions for research in drug delivery in oncology.

July 2011

Felix Kratz

Peter Senter

Henning Steinhagen

List of Contributors

Khalid Abu Ajaj received his BSc from Yarmouk University (Jordan, 1991), his MSc from the University of Jordan (Jordan, 1995), and his PhD in Chemistry from the University of Leipzig (Germany, 2002). He then carried out a Postdoctoral Fellowship in the research groups of Professor Dr. A. Zychlinsky (Max Planck Institute for Infection Biology, Berlin) and Professor Dr. M. Bienert (Institute of Molecular Pharmacology, Berlin), developing bacterial lipopeptides to investigate the mechanisms of activation of Toll-like receptors. He joined the Macromolecular Prodrug Research Group of Dr. Felix Kratz at the Tumor Biology Center in Freiburg in 2006. His research in the group is focused on developing dual-acting prodrugs for circumventing multidrug resistance.

Stephen C. Alley received his PhD in Organic Chemistry from the University of Washington and completed a Postdoctoral Fellowship in Chemistry at Pennsylvania State University. He joined the Research Biology Department at Pathogenesis Corp. and then came to Seattle Genetics in 2003. His research has surrounded conjugation technologies and determination of the mechanisms by which antibody– drug conjugates work.

Jan Terje Andersen graduated in Molecular Immunology at the Department of Molecular Biosciences, University of Oslo, Norway in 2008. He has a postdoctoral position at the Department of Molecular Biosciences, University of Oslo, and the Center for Immune Regulation at the Institute for Immunology, Norway. His research areas are molecular biology and immunology, with a current focus on receptor interactions and receptor targeting. Specifically, the interactions of antibodies of the IgG class with the Fcγ receptors as well as the interactions of IgG and albumin with the neonatal Fc receptor. He has authored approximately 15 scientific publications, including book chapters and patent applications.

Christopher Bachran studied Biochemistry at the Freie Universität Berlin, Germany. He joined the laboratory of Hendrik Fuchs at the Charité– Universitätsmedizin Berlin as a PhD student to study targeted protein toxins for targeted tumor therapy in 2002 and obtained his PhD from the Freie Universität Berlin in 2006. He stayed in Hendrik Fuchs' group as postdoc to investigate the efficacy of saporin-based targeted toxins in mouse models and to analyze the impact of saponins for drastically improved drug delivery in tumor mouse models. During this time he co-organized with Hendrik Fuchs the 2nd and 4th Fabisch-Symposium for Cancer Research and Molecular Cell Biology on the topic of targeted tumor therapies in 2006 and 2009. In 2009, he joined the laboratory of Stephen Leppla at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, in order to develop sophisticated anthrax toxin-based targeted tumor therapy approaches.

You Han Bae received his PhD degree in Pharmaceutics from the University of Utah in 1988, and has held a Full Professorship at the Department of Pharmaceutics and Pharmaceutical Chemistry of University of Utah since 2002. His research interests include self-assembled superintelligent nanoparticulates for multidrug-resistant tumors, acidic solid tumor targeting, protein drug stabilization and controlled release, polymeric vector design for genetic materials, and polymeric systems for rechargeable cell delivery. He has authored over 210 peer-reviewed scientific publications, book chapters, and US patents.

Kenneth D. Bagshawe is Emeritus Professor of Medical Oncology at Imperial College London. After service in the Royal Navy, he studied medicine at St. Mary's Hospital Medical School in London. He was a Research Fellow at Johns Hopkins Hospital Baltimore. He reported first use of combination chemotherapy resulting in cure of metastatic cancer. He established the first radioimmunoassay for human chorionic gonadotropin. He set up a national-scale registration scheme for patients with hydatidiform mole in 1973. He was Chairman of the Scientific Committee of the Cancer Research Campaign. He proposed ADEPT in 1987 and 1990 and carried out the first clinical trial of ADEPT. He is a Fellow of the Royal Society.

Ambros Beer studied Medicine at the Ludwig-Maximilians-Universiät in Munich, Germany. After his final exam in 1999, he performed his training in Radiology at the Department of Radiology at the Klinikum rechts der Isar of the Technical University in Munich (Professor Dr. E.J. Rummeny). Afterwards he performed his training in Nuclear Medicine at the Department of Nuclear Medicine at the Klinikum rechts der Isar of the Technical University in Munich (Professor Dr. M. Schwaiger). Currently he is working as Attending and Assistant professor at the Department of Nuclear Medicine at the Klinikum rechts der Isar of the Technical University in Munich. His main research interest is translational molecular imaging, with a focus on assessment of angiogenesis using targeted tracers, like αvβ3-specific tracers. Moreover, he is interested in multimodality molecular imaging, combining, for example, magnetic resonance imaging and positron emission tomography.

Elvin Blanco received his BS in Biomedical Engineering from Case Western Reserve University in Cleveland, OH. He received his PhD in Biomedical Engineering under the mentorship of Dr. Jinming Gao at the University of Texas Southwestern Medical Center at Dallas in 2008. In 2009, he began his postdoctoral training under the mentorship of Dr. Mauro Ferrari at the University of Texas Health Science Center at Houston. He is currently a Research Associate at the Methodist Hospital Research Institute in Houston under the mentorship of Dr. Mauro Ferrari.

Andreas K. Buck graduated in Medicine at the University of Ulm, Germany in 1996. From 1997 to 2003 he worked as a Resident and from 2003 to 2006 as a Senior Physician at the Department of Nuclear Medicine at the University of Ulm. From 2006 to 2010 he worked as Associate Professor at the Department of Nuclear Medicine at the Technical University in Munich, Germany. Since 2011 he has been Director of the Department of Nuclear Medicine at the University of Wuerzburg, Germany. His research is focused on hemato- oncology and cancer treatment with radiopharmaceuticals.

Horacio Cabral received his PhD under the supervision of Professor K. Kataoka in Materials Engineering from the University of Tokyo in 2007. He worked as an Assistant Professor at the Division of Clinical Biotechnology, Graduate School of Medicine, University of Tokyo until 2009. From 2010, he has been a Lecturer at the Bioengineering Department, University of Tokyo. His main research interests relate to smart nanodevices for the diagnosis and therapy of cancer.

Marcelo Calderón received his PhD in Organic Chemistry in 2007 from the National University of Córdoba, Argentina, under the supervision of Professor Miriam Strumia. In the following years, he joined the Research Group of Professor Rainer Haag at the Free University of Berlin as a Postdoctoral Fellow. He is currently working as an Associate Researcher at the same University, with a research interest in the development of nanotransporters based on dendritic polyglycerol for intelligent delivery of drugs, gene, and imaging probes.

John C. Chang MD, PhD graduated from the University of Illinois at Urbana-Champaign with an MD and an Electrical Engineering PhD degree in 2004. During his graduate training, he has authored and coauthored five refereed articles focused on neural engineering. During his radiology residency at Stanford University, he pursued research in nanoparticle application in optical and magnetic resonance imaging with ultimate application in understanding cancer biology and novel therapy. He currently serves as a Clinical Instructor in Radiology at Stanford University.

Coralie Deladriere studied Chemistry at the University Paris Sud (France) and obtained her Master's degree in Analytical Chemistry in 2006. She then joined the Polymer Therapeutics Laboratory headed by Dr. Vicent at the Centro de Investigación Príncipe Felipe, Valencia (Spain) as a PhD Student. Her PhD work is focused on the development of polymer– drug conjugates as a platform for combination therapy in the treatment of hormone-dependent breast cancer.

Neil Desai is currently Senior Vice President of Global Research and Development at Abraxis BioScience in Los Angeles, CA, where he is responsible for the development of the company's growing product pipeline and the development of the company's intellectual property portfolio. He is an inventor of ABI's nanotechnology and nanoparticle-albumin bound (nab™) drug delivery platform, and was primarily responsible for the development of its nanotechnology drug nab-paclitaxel and the discovery of the novel targeted biological pathway utilized by nab-drugs. Prior to joining ABI, he was Senior Director of Biopolymer Research at VivoRx Inc., where he developed novel encapsulation systems for living cells and was part of the team that performed the world's first successful encapsulated islet cell transplant in a diabetic patient. With more than 20 years of experience in the research and development of novel drug delivery systems and biocompatible polymers, he holds over 100 issued patents and peer-reviewed publications, has made over 150 presentations at scientific meetings, and has organized and chaired symposia in the areas of biocompatible polymers and nanotechnology-based delivery systems. He is a reviewer for several scientific journals, and an active participant in the US Food and Drug Administration (FDA) Nanotechnology Task Force and FDA-Alliance for Nanohealth initiatives. He holds a MS and PhD in Chemical Engineering from the University of Texas at Austin, USA, and a BS in Chemical Engineering from the University Institute of Chemical Technology in Mumbai, India.

Laurent Ducry studied Chemistry at the University of Lausanne (Switzerland) and did his Diploma thesis with Professor T. Gallagher at the University of Bristol (UK). He obtained his PhD from the ETH Zürich (Switzerland) with Professor F. Diederich in 1998. During his graduate studies, he worked for 6 months with Dr. G. Olson at Hoffmann-La Roche in Nutley (New Jersey). He then held a Swiss National Science Foundation Postdoctoral Fellowship at the University of Pennsylvania in Philadelphia with Professor A.B. Smith III and Professor R. Hirschmann. He began his industrial carrier in process R&D at Lonza in Visp (Switzerland) in 2000 and became Project Leader the following year. His activities focused on the development and scale-up of chemical processes, as well as the production of pharmaceutical intermediates and active pharmaceutical ingredients under current Good Manufacturing Practices. In the second half of 2006 he trained the Lonza R&D team in Nansha (China) and was promoted to Senior Research Associate in 2007. Since 2008, he has been leading the antibody– drug conjugates R&D group of Lonza.

Anat Eldar-Boock is currently undertaking her PhD studies at Tel Aviv University under the supervision of Dr Ronit Satchi-Fainaro. Her thesis goal is to synthesize and characterize antiangiogenic and anticancer polymer therapeutics bearing paclitaxel and RGD peptidomimetics for the treatment of breast cancer. She graduated her MS studies from Tel Aviv University at the Department of Developmental Biology investigating the involvement of sphingolipid metabolism in aging and apoptosis of rat oocytes.

Bakheet Elsadek graduated in Pharmaceutical Sciences from Al-Azhar University, Egypt in 2001. He was then awarded the Master's degree in Biochemistry from the Faculty of Pharmacy, Assiut University, Egypt. In 2010 he received his PhD from the Faculty of Pharmacy, Assiut University, supervised by Dr. Felix Kratz, Head of the Division of Macromolecular Prodrugs, Clinical Research, Tumor Biology Center, Freiburg, Germany and Professor Dr. Tahia Saleem, Professor of Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University. His PhD thesis was funded through the Egyptian Scientific Channel System and focused on the development of prodrugs for treating prostate cancer. His current research areas are angiogenesis, drug targeting, and drug delivery systems in oncology and prodrugs.

Hans Erickson received his PhD in Biochemistry from the University of California, San Diego. After a Postdoctoral Fellowship at the University of Utah, he joined ImmunoGen, Inc., where his efforts have focused on understanding the mechanisms associated with the efficacy and toxicity of antibody– drug conjugates.

Freddie Escorcia is a MD PhD candidate at the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional Program. He has a BS in Chemistry and Bioengineering from the University of Illinois. His research interests are in understanding the mechanisms of action and therapeutic applications for targeting of tumor vasculature and tumor angiogenesis.

Omid C. Farokhzad received his MD and MA from Boston University School of Medicine. He completed his postdoctoral clinical and research training at Brigham and Women's Hospital/Harvard Medical School (HMS) and MIT in the laboratory of Professor Robert Langer. He is an Associate Professor at HMS, and directs the Laboratory of Nanomedicine and Biomaterials at Brigham and Women's Hospital. He pioneered the development of aptamer– nanoparticle conjugates for cancer therapy. His laboratory is currently focused on the high-throughput screening of targeting ligands and the development of multifunctional targeted nanoparticle platforms for medical applications.

Henry Fechner studied Veterinary Medicine at the Humboldt University of Berlin and received his DVM in 1995 at the Free University of Berlin in the Institute of Virology. He then worked as an assistant in the Institute of Veterinary Pathology in the Free University of Berlin and as a postdoc in the “Lipidlabor” of the Charité Berlin from 1996 to 1998. From 1998 to 2010 he was postdoc and group leader in the Department of Cardiology and Pneumology of the Charité Berlin. In 2010 he received a senior group leader position at the University of Berlin in the Institute of Biotechnology. His research interests focus on the development of gene therapeutic strategies for the treatment of cardiovascular and tumor diseases.

Mauro Ferrari obtained his Dottore in Mathematics from Università di Padova in Italy and received his PhD in Mechanical Engineering from the University of California at Berkeley. From 2003 to 2005, he served as an Expert on Nanotechnology at the National Cancer Institute (NCI), providing leadership into the formulation, refinement, and approval of the NCI's Alliance for Nanotechnology in Cancer. Currently, he is the President, CEO, and Director of the Methodist Research Institute, Ernest Cockrell Jr. Endowed Chair, and President of the Alliance for NanoHealth in Houston, TX.

Efrén J. Flores MD received his medical degree at the University of Puerto Rico School of Medicine in 2005 and completed his Residency in Diagnostic Radiology at Massachusetts General Hospital in 2010. His relationship with Dr. Mukesh Harisinghani as a mentor has allowed him to developed a new interest in the future impact of magnetic nanoparticles in cancer treatment.

Gert Fricker graduated in Chemistry from the University of Freiburg, Germany in 1986. He then did postdoctoral research at the Department of Clinical Pharmacology, University Hospital Zurich, Switzerland. From 1988 to 1995, he worked as a Research Scientist at Sandoz, Basle, Switzerland. In 1995, he was appointed Professor of Pharmaceutical Technology and Biopharmacy at the University of Heidelberg, Germany. Since 2002 he has been Director of the Institute of Pharmacy and Molecular Biotechnology at the University of Heidelberg and the Steinbeis Technology Transfer Center Biopharmacy and Analytics. His research interests include drug delivery, membrane transport proteins, and the blood– brain barrier.

Jillian H. Frieder earned her Bachelor in Physiology from the University of Arizona in 2010. In July 2010 she joined Professor Omid Farokhzad's group at Brigham and Women's Hospital. Her current work involves aptamer– nanoparticle targeting for in vivo applications.

Hendrik Fuchs studied Biochemistry at the Freie Universität Berlin, Germany, and finished his PhD work on the human transferrin receptor in 1996 in the laboratory of Reinhard Geßner. After a short postdoc at the Rudolf Virchow University Hospital in Berlin, he became a group leader in 1997 at the Department for Clinical Chemistry and Pathobiochemistry, headed by Rudolf Tauber, at the Benjamin Franklin University Hospital in the same city. Since that time his research focus is on the investigation of systemic and cellular iron metabolism and on the development of protein-based targeted antitumor drugs. After his habilitation in 2002 he continued his research as a German Privatdozent and was appointed as Professor at the Department of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry at the Charitè– Universitätsmedizin Berlin in 2010. He organized together with Christopher Bachran the 2nd and 4th Fabisch-Symposium for Cancer Research and Molecular Cell Biology on the topic of targeted tumor therapies in 2006 and 2009.

Mathea Sophia Galanski graduated in 1994 and obtained her PhD degree in 1996, both from the University of Heidelberg. In 1996, she moved to the University of Vienna together with Bernhard Keppler and was promoted to the rank of Associate Professor in 2007. She is Deputy Head of the Institute of Inorganic Chemistry and working on the development of anticancer platinum complexes.

Sanjiv Sam Gambhir MD, PhD is Professor of Radiology, Bioengineering, and Materials Science and Engineering at Stanford University. He is Director of the Molecular Imaging Program at Stanford and Head of Nuclear Medicine. He has published over 375 articles in the field of molecular Imaging, edited three books, has over 30 patents granted or filed, and is a member of the Institute of Medicine of the US National Academies.

Florian Gärtner studied Medicine at the Technical University in Munich, Germany and received his Approbation in 2005. During his Doctorate thesis he worked on tumor targeting with radiolabeled compounds. Currently, he is working as a Resident in the Department of Nuclear Medicine at the Technical University in Munich. His current research subjects are neuroendocrine tumors, peptide receptor radionuclide therapy, and tumor hypoxia.

Hans-Peter Gerber received an MS in Biochemistry and a PhD in Molecular Biology from the University of Zurich, Switzerland. He joined Genentech in 1995 as a Visiting Scientist, where he spent 11 years in research studying the mechanisms involved in regulating blood vessel formation and developing therapeutic antibodies interfering with tumor angiogenesis. He was a member of several teams reviewing preclinical and clinical data from trials conducted with ® (bevacizumab), a therapeutic antibody blocking the angiogenic factor VEGF-A. In March 2006, he joined Seattle Genetics as Head of the Translational Biology Department, where he contributed to the development of therapeutic antibodies and antibody– drug conjugates (ADCs) including SGN-35, SGN-40, SGN-75, and SGN-19A targeting hematopoietic malignancies and solid tumors. In April 2009, he joined Wyeth Discovery Research Oncology in Pearl River, NY. After the acquisition by Pfizer in late 2009, he now leads the Vascular Biology/BioConjugate Development group at the Center of Integrative Biology and Biotherapeutics, where he is building a program to develop novel ADCs to target tumor and stromal cells.

Biana Godin studied Pharmaceutical Sciences at the Hebrew University of Jerusalem (Israel) under the supervision of Professor Touitou. She conducted her research toward the PhD degree designing novel lipid nanovesicular carriers for treatment of challenging infectious diseases. After her graduation, she joined the group of Professor Ferrari at the University of Texas Health Science Center at Houston, focusing on the delivery of drugs and imaging agents from injectable porous silicon multistage nanovectors. She is currently an Assistant Member at the Methodist Hospital Research Institute in Houston, TX.

Lee M. Greenberger received his PhD from Emory University (Atlanta, GA) in 1984. He did Postdoctoral training at Albert Einstein College of Medicine (with Dr. Susan Horwitz) where he studied ABC transporters associated with resistance to cancer therapy. Since 1991 he has worked at various pharmaceutical companies identifying novel cancer therapeutics, including antimicrotubule agents, antiestrogens, erbB inhibitors, and transport inhibitors. As Vice President of Research at Enzon Pharmaceuticals since 2006, he oversees the preclinical development of RNA antagonists and novel drug conjugates to treat cancer.

Rainer Haag obtained his PhD with A. de Meijere at the University of Göttingen in 1995. After postdoctoral work with S.V. Ley, University of Cambridge (UK), and G.M. Whitesides, Harvard University, Cambridge (USA), he completed his habilitation at the University of Freiburg in 2002. He then became Associate Professor at the University of Dortmund, and in 2004 was appointed Full Professor of organic and macromolecular chemistry at the Freie Universität at Berlin. His main research interests are in the mimicry of biological systems by functional dendritic polymers. Polyglycerol-based materials feature heavily in the diverse range of projects within the Haag group, with particular focus on applications in nanomedicine, such as drug, dye, and gene delivery, as well as regenerative medicine, such as nonfouling surfaces and matrix materials.

Gabor Halmos PharmD, PhD graduated in Pharmacy in 1986, and then received his pharmaceutical, biomedical, and biochemical training as well as his PharmD and PhD degrees from the University of Szeged and University of Debrecen (Hungary). In 1991 he was invited by Dr. Andrew V. Schally to work at the Endocrine, Polypeptide and Cancer Institute at the Veterans Affairs Medical Center and Tulane University, Department of Medicine, New Orleans, LA. He was the Head of the Receptor Section of the Institute (1991– 2005), and his research work was focused on peptide hormone receptors and the development of new drugs targeting various human cancers. In 2005, he became Professor and Chair, Department of Biopharmacy at the University of Debrecen, Medical and Health Science Center (Hungary), retaining his research ties with Dr. Schally. In 2006, he also became a Visiting Professor at the University of Miami, Miller School of Medicine, Miami, FL, where he conducts cancer research for 2– 4 months a year. His research areas are the expression and pathophysiological function of peptide hormone receptors and development of peptide hormone analogs for targeted cancer therapy. He has nearly 200 publications.

Michael R. Hamblin is a Principal Investigator at the Wellman Center for Photomedicine at Massachusetts General Hospital and an Associate Professor of Dermatology at Harvard Medical School. He was trained as a synthetic organic chemist and received his PhD from Trent University in the UK. His research interests lie in the areas of photodynamic therapy (PDT) for infections, cancer, and heart disease. In particular, he has worked on covalent photosensitizer conjugates, induction of antitumor immunity by PDT, PDT for vulnerable atherosclerotic plaque, and antimicrobial photoinactivation in vitro and in vivo. He is also interested in basic mechanistic studies in low-level laser (light) therapy, and its application to wound healing, traumatic brain injury, and hair regrowth. He has published over 120 peer-reviewed articles, over 150 conference proceedings, book chapters, and international abstracts, and holds eight patents.

Troy O. Harasym is Director (Biological Evaluation) at Celator Pharmaceuticals. He received his BS and PhD degrees from the Department of Biochemistry at the University of British Columbia. He has 15 years experience in the biotechnology industry, and has held previous positions at The Canadian Liposome Company assessing liposomal drug carriers and Inex Pharmaceuticals developing liposomal antisense therapeutics. He joined Celator Pharmaceuticals in December 2000 as Director of Pharmacodynamics where he focused on developing external research collaborations and preclinical guidance in xenograft evaluations. He has since held key Director positions at Celator, including the Director of Drug Screening, where he developed Celator's automated process for the identification of synergistic drug ratios and, currently, as the Director of Biological Evaluation where he leads the team in pharmacokinetics/pharmacodynamics and efficacy evaluations.

Mukesh Harisinghani MD completed his Diagnostic Radiology Residency at the Massachusetts General Hospital and Harvard Medical School in 2000. He then pursued an Abdominal Imaging and Intervention Fellowship at the Massachusetts General Hospital till 2001 and has been on Faculty in the same Division since then. He is an Associate Professor of Radiology at the Harvard Medical School and Director of Abdominal Magnetic Resonance Imaging at the Massachusetts General Hospital. He also leads the Translational Imaging Group, Clinical Discovery Program, at the Center for Molecular Imaging and Research. Since his radiology residency, he has been involved with clinical bench to bedside applications of magnetic nanoparticles, carrying out clinical trials using nanoparticle-enhanced magnetic resonance imaging for staging genitourinary malignancies.

I. Craig Henderson is currently an Adjunct Professor of Medicine at UCSF and serves as a consultant to various biotechnology companies. In 1992, he founded the Bay Area Breast Cancer Translational Research Program and served as the principle investigator on the SPORE grant that funded that program. One of the key projects in that program was the creation of immunoliposomes using PEGylated liposomes and monoclonal antibodies directed toward HER2/neu. (This project within the SPORE was initially led by Dr. Demtri Papahadjopoulos and later by Dr. John Park). In 1993, he joined the Board of SEQUUS Pharmaceuticals, and in 1995, he became CEO and Chairman of the company. At SEQUUS he played a leadership role in shepherding Doxil®/Caelyx® through the regulatory process and in developing strategies that eventually demonstrated its value in ovarian and breast cancers and multiple myeloma. As CEO of SEQUUS he had oversight on both preclinical and clinical studies of SPI-77, a PEGylated liposomal platinum. He initiated the program to encapsulate topoisomerase I inhibitors. From 1975 to 1992, he was on the staff of the Dana-Farber Cancer Institute, where he founded the Breast Evaluation Center, and was a member of the Harvard Medical School Faculty. From 1992 to 1995, he was Chief of Medical Oncology and Deputy Director of the Cancer Center at UCSF. More recently he has been CEO of Access Oncology and President of Keryx Biopharmaceuticals where he developed an oral AKT inhibitor, perifosine. He has designed and conducted numerous phases I– III trials, and he has published nearly 300 books and papers.

Ken Herrmann studied Medicine at the Universities of Berlin and Lausanne. In 2004 he graduated and started working under the supervision of Professor M. Schwaiger in Munich. After finishing his medical thesis in the Research Group of Cellular Neurosciences at Max Delbrück Centrum Berlin he joined Dr. Buck's team investigating molecular imaging of proliferation in a variety of different tumors, including lymphomas, sarcomas, gastric, and pancreatic cancer. Currently, he is finishing the Postdoctoral Lecture qualification.

Katrin Hochdörffer studied Chemistry at the Technische Universität Kaiserslautern and received her Diploma at Boehringer Ingelheim Pharma (Ingelheim) in 2005. Under the supervision of Professor T. Schrader, she carried out her PhD thesis research on trimeric aminopyrazoles against the pathological aggregation of the Alzheimer peptide Aβ. After finishing her PhD thesis in 2009 she joined the research group of Dr. Felix Kratz at the Tumor Biology Center in Freiburg. She is currently working on the development of prodrugs for targeted cancer therapy.

Ivan D. Horak received his MD from the University of Medicine, Bratislava, Czechoslovakia. He is Board-Certified in Internal Medicine and Medical Oncology. From 1999 to 2002, he acted as Clinical Vice President of Oncology in Research & Development at Pharmacia Corp. From 2002 to 2005, he was Chief Scientific Officer at Immunomedics where he led the development of monoclonal antibody therapy for cancer and autoimmune diseases including radiolabeled antibody for patients with solid tumors and hematologic malignancies. He joined Enzon in September 2005 as Executive Vice President and Chief Scientific Officer, and currently he is President of Research and Development. He has published extensively in the field of oncology and has served on the editorial boards of several scientific journals. He also has lectured extensively at scientific symposia and conferences.

Leaf Huang PhD is the Fred N. Eshelman Distinguished Professor and Chair, Division of Molecular Pharmaceutics in the Eshelman School of Pharmacy, University of North Carolina at Chapel Hill. His research has been in the area of gene therapy and targeted drug delivery. He pioneered the liposome nonviral vector and produced the vector for the first nonviral clinical trial in 1992. His current work centers on further improvement of liposome vectors for gene transfer in tumor, liver, and lung. He also continues research in establishing a ligand targeted delivery system for siRNA and peptides for tumor growth inhibition, and for peptide vaccines in treating cervical cancer. He has authored or coauthored more than 300 peer-reviewed papers, and more than 120 reviews and book chapters. The h-index of his publications is 74. He is also the inventor or coinventor of 16 US and foreign patents. In 2004, he received the Alec D. Bangham MD FRS Achievement Award, which is the highest honor in the field of liposome research. He has also cofounded five biotech start-ups in the past.

Yingying Huang received her MD degree of Clinical Medicine from Xiangya Medical College of Central South University (China) in 2004. In 2007 she received a Masters degree in Dermatology from Sun Yat-Sen University (China) and in April 2008 she joined the research group of Dr. Michael R. Hamblin at the Wellman Center for Photomedicine, Massachusetts General Hospital. She is currently investigating the mechanism of quantitative structure– activity relationships of photosensitizers for photodynamic therapy purposes.

Simone Jeger obtained her MS degree in Pharmaceutical Sciences from the University of Basel, Switzerland, in 2005. In 2009, she received a PhD from the Swiss Federal Institute of Technology, Zurich for research in the area of novel conjugation methods to produce tumor-selective radioimmunoconjugates for diagnostics and therapy. In 2010, she started postdoctoral studies on antibody engineering and immunoconjugation technologies at Seattle Genetics.

John DiJoseph is a Principal Research Scientist of Oncology at Pfizer Research in Pearl River, NY. He received his postgraduate training at Rutgers University and joined Ayerst Research in 1981. He has received many awards for his contributions, including the 1998 MMP13/TACE Discovery Teamwork Award, the Discovery Achievement Award (humanized anti-CD20 SMIP), and the 2007 Discovery Achievement Award (Anti-5 T4 P2 Team). He has been instrumental in the development of CMC-544 (Inotuzumab ozogamicin). He has been an Invited Lecturer at oncology and hematology workshops and symposia. He holds four patents for his work, and has authored or co-authored numerous articles in national and international journals, including Blood, International Journal of Oncology, and Journal of Pharmacology and Therapeutics.

Kazunori Kataoka received his PhD from the University of Tokyo in 1979. He has been a Professor of Biomaterials at the Graduate School of Engineering, University of Tokyo, Japan since 1998. He has also been appointed in a joint position as a Professor of Clinical Biotechnology since 2004 at the Graduate School of Medicine, University of Tokyo. He is the author of more than 380 scientific papers in international journals and a recipient of many awards. His current major research interests include the development of new polymeric carrier systems, especially block copolymer micelles, for drug and gene targeting.

Bernhard K. Keppler received his Diploma and PhD in Chemistry from the University of Heidelberg in 1979 and 1981, respectively, and a PhD in Medicine from the German Cancer Research Center at Heidelberg in 1986 as well as the license to practice medicine (Approbation). He habilitated and gained the qualification of a University Lecturer in Inorganic Chemistry at the University of Heidelberg in 1990. In 1995, he joined the Institute of Inorganic Chemistry at the University of Vienna as a Full Professor. He is Head of the Institute of Inorganic Chemistry and Dean of the Faculty of Chemistry at the University of Vienna.

Kwangmeyung Kim graduated in Chemical Engineering from Sung Kyun Kwan University. He obtained his PhD under the supervision of Professor Youngro Byun at Gwangju Institute of Science and Technology in 2003. He then joined Dr. Ick Chan Kwon's group, and carried out postdoctoral research at the Korea Institute of Science and Technology (KIST) and developed cancer-specific optical imaging systems. Since 2004 he has been a Senior Research Scientist at KIST where he is now in charge of organizing and managing translational research from the laboratory to the clinic. His research interests are noninvasive and diagnostic imaging for various human diseases, molecular and cellular imaging for biological processes, and inorganic/organic nanoparticulate imaging probes. He has published over 80 peer-reviewed papers and four review articles.

Sungwon Kim received his PhD in Materials Science and Engineering from Gwangju Institute of Science and Technology (Korea) in 2004. After postdoctoral research on drug delivery and molecular imaging at Korea Institute of Science and Technology (Korea), he joined Professor Kinam Park's group at Purdue University (USA), and has worked on polymer micelles and microfabrication since 2006. His research interests are nanomedicine, medical imaging, and tissue engineering.

Sergej Kiprijanov graduated in Biochemistry and Molecular Biology from Novosibirsk State University (Novosibirsk, Russia) and received his PhD degree from the Institute of Genetics and Selection of Industrial Microorganisms (Moscow, Russia). He then carried out his postdoctoral research at the German Cancer Research Center (DKFZ) in Heidelberg (Germany), where he played a key role in the design and generation of the novel bispecific antibody formats useful for tumor therapy. During 2000– 2006, he was Head of Antibody Engineering and then Head of Research and Development at Affimed Therapeutics AG (Heidelberg, Germany) focusing on engineering bispecific antibodies for cancer indications. He then served as Chief Scientific Officer at Novoplant GmbH (Gatersleben, Germany), a German plant biotech company developing antibodies for oral applications. In 2008, he joined Affitech AS (Oslo, Norway) as Vice President of Discovery, Research, and Preclinical Development, dealing with the generation of fully human therapeutic antibodies. He has authored more than 70 research articles, reviews, and book chapters, and is named as an inventor on 20 patents and patent applications.

Paul J. Kleindl graduated from Marquette University in 1995 with a BS degree in Chemistry. Under the direction of Professor David R. Williams, he received a MS degree in Organic Chemistry in 1997 from Indiana University-Bloomington. Upon graduation, he was employed first at Great Lakes Chemical Co. and then Custom Synthesis Services (Madison, WI), as a Synthetic Organic Chemist. His work included the synthesis of flame retardants, polymer additives, stable-isotope mass standards, and the scale-up of processes to produce material for preclinical evaluation. In 2003, he joined Endocyte and is currently employed in the Discovery Chemistry Department as a Synthetic Scientist working on the synthesis of folate conjugates for the treatment of inflammation and cancer.

Jindřich Kopeček received his PhD in Macromolecular Chemistry and DSc in Chemistry from the Czechoslovak Academy of Sciences. He is currently Distinguished Professor of Pharmaceutical Chemistry and Distinguished Professor of Bioengineering at the University of Utah. His research focuses on biorecognition of macromolecules, bioconjugate chemistry, targetable macromolecular therapeutics, and self-assembly of block and graft copolymers into hybrid hydrogels.

Pavla Kopečková received her PhD in Macromolecular Chemistry from the Institute of Macromolecular Chemistry, Czechoslovak Academy of Sciences in Prague. She is currently Research Professor of Pharmaceutics and Pharmaceutical Chemistry at the University of Utah. Her research centers on bioorganic polymer chemistry, biodegradability of polymers, and drug delivery systems.

Felix Kratz graduated in Chemistry from the University of Heidelberg in 1991. He then carried out postdoctoral research at the Bioinorganic Institute of the University of Florence and developed tumor-specific carrier systems with Ru(III) complexes. Since 1994, he has been Head of Macromolecular Prodrugs at the Tumor Biology Center in Freiburg, Germany, where he is now in charge of organizing and managing translational research from the laboratory to the clinic. His research areas are drug targeting, drug delivery systems in oncology, prodrugs, receptor targeting, bioconjugate chemistry, and nanocarriers.

Jens Kurreck studied Biochemistry and Philosophy at the Free University of Berlin, and received his Doctorate in 1998 at the University of Technology Berlin. After a stay at Arizona State University he went to the Free University of Berlin, where he completed his Habilitation in 2006. From 2007 to 2009 he was Professor for Nucleic Acid Technology at the University of Stuttgart and since 2009 he has been Professor for Applied Biochemistry at the University of Technology Berlin. His work involves the application of RNAi for medically relevant topics, in particular virology and pain research.

Kaido Kurrikoff is currently a Research Fellow at the Institute of Technology, University of Tartu, Estonia. He acquired his PhD degree (Neurosciences) at the University of Tartu in 2009. His main research areas have been molecular pain mechanisms and peptide-based drug delivery carriers. He has also worked as an Assistant Teacher in the Department of Medicine, University of Tartu. He is a coauthor of about 10 scientific publications.

Ick Chan Kwon is currently Head of Biomedical Research Center at the Korea Institute of Science and Technology (KIST). He received his BS and MS degrees from the Department of Textile Engineering at Seoul National University in 1982 and 1984, and his PhD in Pharmaceutics and Pharmaceutical Chemistry from the University of Utah under the guidance of Professor Sung Wan Kim in 1993. After postdoctoral training in the Center for Controlled Chemical Delivery at the University of Utah, he joined KIST in 1994. He is currently President of the Korean Society of Molecular Imaging (2008– 2010). He also serves as an Editor Asia of the Journal of Controlled Release (Elsevier), Asian Editor of the Journal of Biomedical Nanotechnology (American Scientific Publisher), and as a member of the Editorial Boards of Journal of Biomedical Engineering Research and Journal of Biomaterials Science, Polymer Edition. His main research interest is targeted drug delivery with polymeric nanoparticles and is now expanding to the development of smart nanoprobes for theranostic imaging. He is a project leader of “Real-time molecular imaging” supported by the Ministry of Science and Technology of Korea. He has published 140 peer-reviewed articles, 11 book chapters, and eight review articles.

Kit S. Lam obtained his PhD in Oncology from McArdle Laboratory for Cancer Research, University of Wisconsin, and his MD from Stanford University School of Medicine. He completed his Internal Medicine residency training and Medical Oncology Fellowship training at the University of Arizona. He is board certified in both Internal Medicine and Medical Oncology. He was the Division Chief of Hematology/Oncology at UC Davis for over 10 years until recently when he became s the Chair of the Department of Biochemistry and Molecular Medicine. He is both a practicing medical oncologist and a laboratory investigator. He invented the “one-bead/one-compound” combinatorial library method. He has published over 258 scientific publications and is an inventor on 14 patents. He received the Cathay Award in 1998 and the Combinatorial Science Award in 2007. His research encompasses the development and applications of combinatorial chemistry to basic research and drug development.

Ülo Langel is a Professor and Chairman at the Department of Neurochemistry, Stockholm University, Sweden. He graduated from Tartu University, Tartu, Estonia, as a Bioorganic Chemist in 1974; he has received his PhD degree twice: in 1980 from Tartu University (Bioorganic Chemistry) and in 1993 from Tartu University/Stockholm University (Biochemistry/Neurochemistry). His professional experience includes a career at Tartu University (from Junior Research Fellow to Associate Professor, Visiting Professor, and Adjunct Professor; 1974 till now); The Scripps Research Institute, La Jolla, CA, USA (Associate Professor and Adjunct Professor; 2000 till now); and Stockholm University (from Research Fellow to Associate Professor, Professor, and Chairman; 1987 till now). He is an Honorary Professor at Ljubljana University, Slovenia. He has been awarded a White Star Order, fourth class, by the Estonian Republic. He is a coauthor of more than 290 scientific articles and 15 approved patents or patent applications.

Barry D. Liboiron is Associate Director (Biophysical Characterization) at Celator Pharmaceuticals. He received his PhD from the University of British Columbia in 2002. Following a Postdoctoral Fellowship at Stanford University, he joined Celator Pharmaceuticals in 2006, as a Research Scientist in biophysics, and was promoted to his current position in 2008. Through the elucidation of key physicochemical properties of Celator's drug products and proprietary technologies, his work has furthered the development of the company's liposomal and nanoparticle drug platforms. His research interests include drug delivery, in vivo spectroscopy, and inorganic biochemistry. He is the author of 15 publications, including an invited review on the use of electron paramagnetic resonance as a tool to aid drug development for diabetes mellitus.

Ruiwu Liu