Drug Targeting Organ-Specific Strategies

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

Drug Targeting

Organ-Specific Strategies

Edited by Grietje Molema and Dirk K. F. Meijer

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

Methods and Principles

in Medicinal Chemistry

Edited by

R. Mannhold

H. Kubinyi

H. Timmerman

Editorial Board

G.Folkers, H.-D. Höltje, J. Vacca,

H.van de Waterbeemd, T. Wieland

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

Drug Targeting

Organ-Specific Strategies

Edited by

Grietje Molema and Dirk K. F. Meijer

Weinheim · New York · Chichester · Brisbane · Singapore · Toronto

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

Series Editors:
Prof. Dr. Raimund Mannhold	Prof. Dr. Hugo Kubinyi	Prof. Dr. Hendrik Timmerman
Biomedical Research Center	BASF AG Ludwigshafen	Faculty of Chemistry
Molecular Drug Research Group	c/o Donnersbergstrasse 9	Dept. of Pharmacochemistry
Heinrich-Heine-Universität	D-67256 Weisenheim am Sand	Free University of Amsterdam
Universitätsstraße 1	Germany	De Boelelaan 1083
D-40225 Düsseldorf		NL-1081 HV Amsterdam
Germany		The Netherlands
Volume Editors:
Dr. Grietje Molema	Prof. Dr. Dirk K. F. Meijer
University Centre for Pharmacy	University Centre for Pharmacy
Department of Pharmacokinetics	Department of Pharmacokinetics
and Drug Delivery	and Drug Delivery
Antonius Deusinglaan 1	Antonius Deusinglaan 1
NL-9713 AV Groningen	NL-9713 AV Groningen
The Netherlands	The Netherlands

This book was carefully produced. Nevertheless, authors, editors and publisher do not warrant the information contained therein 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.

Die Deutsche Bibliothek – CIP Cataloguing-in-Publication-Data

A catalogue record for this publication is available from Die Deutsche Bibliothek

ISBN 3-527-29989-0

© WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany), 2001

Printed on acid-free paper.

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.

Composition: Datascan GmbH, D-64295 Darmstadt

Printing: betz-druck GmbH, D-63291 Darmstadt

Bookbinding: Wilhelm Osswald & Co., D-67433 Neustadt (Weinstraße)

Printed in the Federal Republik of Germany.

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

Preface

It is our prime intention to cover the topics of this series as comprehensively as possible. Thus, we are very pleased to introduce this volume focussing on organ specific strategies of drug targeting.

About hundred years ago Paul Ehrlich put forward his theory of “the magic bullet” as an approach to tame disease. Scientists have ever since worked on the principle of drug targeting based on this idea of specifically delivering drugs to diseased cells. Especially nowadays that by high-throughput screening and molecular modelling techniques highly potent drugs are being developed that interfere with general (signal transduction) processes in cells in the body, the need for their application by a drug targeting approach has almost become inevitable.

Progress in the field of drug targeting has been slow till thirty years ago. With the advent of the monoclonal antibody technology in the mid seventies of the last century as well as the development of liposomal devices as carriers did the drug targeting field expand and did the clinical application become a feasible aim.

Monoclonal antibodies, liposomes, polymers, proteins, and many other entities have ever since seen the light as carrier molecules. And, as with most technological developments, they have all encountered a vast array of difficulties, ranging from problems in the synthesis of the carriers and drug conjugates to unfavorable pharmacokinetics and toxicity. Furthermore, lack of knowledge on the anatomical and physiological barriers in the body hampered application. However, many problems have been solved, not in the least due to the advent of recombinant DNA technology to construct better defined carriers that can be produced in large amounts, and advanced pharmaceutical formulation technology. Similarly, the rapid developments in molecular biology, cell biology and immunology led to a better understanding of the processes taking place in vivo upon administration of carriers and conjugates. Important conclusion is that drug targeting has become a multidisciplinary research area.

What has been achieved until now? In the year 2001, several liposome and antibody based strategies have been or will soon be approved for clinical application, some for the treatment of cancer, some for the treatment of bacterial infections, some for chronic inflammatory diseases. Furthermore many monoclonal antibodies without a drug or pharmacologically active molecule attached are in the clinic. Their intrinsic targeting and effector function is obviously sufficient for the pharmacological effect.

Only a few polymer or protein based drug targeting strategies have reached the clinic and an important question in the coming years will be whether these strategies eventually will reach it. All will depend on their effectiveness and improved toxicity profiles as compared to free drug only and the ease of their production at large scale.

The present volume is in several respects unique. It provides a map of the body from the viewpoint of drug targeting/drug delivery. Potentials and limitations of targeting strategies

VI Preface

are discussed in the light of organ related diseases for each organ separately. Furthermore, novel technologies are described that may be useful in the future to allow an even better product to be developed that can be clinically exploited at a more rapid pace.

The series editors are grateful to the contributors to this volume, in particular Grietje Molema and Dirk K. F. Meijer, as well as Wiley-VCH publishers, for the fruitful collaboration and the straightforward realization of this project.

January 2001	Raimund Mannhold, Düsseldorf
	Hugo Kubinyi, Ludwigshafen
	Henk Timmerman, Amsterdam

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

Foreword

It was in the mid-1970s I think, just a few years after Brenda Ryman and I introduced liposomes as a drug delivery system, when a well meaning colleague af mine advised me not to put all my eggs in one basket.The eggs were liposomes and the basket my career.At the same time there were all sorts of prophecies and rumours from a variety of quarters about liposomal stability problems, expense, toxicity, difficulties with large scale manufacture, etc. Some went as far as to dismiss the system as a flash in the pan phenomenon. Indeed, the yellow brick road to the magic bullet is littered with systems that once made the headlines and then fell by the wayside. So, such comments on liposomes, and later on on antibodies, were not surprising. I believe that what made many of us persevere throughout the decades in developing drug carrier systems such as liposomes, and associated technologies was the realization that, for the foreseeable future at least, molecular modelling is not the answer to drug selectivity for most therapeutics. The vagaries of the biological milieu in vivo ensures that optimal drug action (seen in the test tube) is compromised by such factors as opsonins and proteolytic enzymes in the bloodstream, membrane barriers, loss through the kidneys, and premature interception of therapeutics by the reticuloendothelial system. In the case of liposomes, monoclonal antibodies and some polymers, carrier development was greatly facilitated by their structural versatility which enabled the design of advanced versions of unique sophistication.

The first generation of liposome-based systems approved for clinical use are believed to function on the basis of their passive uptake by the target tissues (e.g. the AmBisome and the virosome vaccine Hepaxal) or by avoiding certain tissues (e.g. heart, kidneys) that are prone to damage by the drug when given as such (e.g. Doxil, Daunoxome). The next challenge is to create or build on the systems that can be actively targeted to specific tissues or circulation cells for which systems such as liposomes have little or no affinity. They include a variety of molecules with genuine targeting properties, for instance (neo-) glycoproteins, monoclonal antibodies and fragments thereof, applied either as a means to deliver drugs attached to these biopolymers, or as homing devices when attached to the surface of other drug delivery systems, for instance liposomes and other particle-type carriers. Success to that end will greatly enlarge the spectrum of therapeutics that can be selectively delivered, and widen the range of applications.

In this respect, Grietje Molema, Dirk K. F. Meijer and a team of drug delivery experts have taken an important step with the present book. Unlike previous volumes, this one is not devoted exclusively to liposome or antibody technologies. Rather, the book deals with organspecific drug targeting strategies developed for the treatment of a wide spectrum of diseases and includes a collection of novel techniques applied to drug targeting research. Thus, the book provides a blueprint for both the experienced and the semi-experienced reader interested in drug targeting and related optimization strategies.

London, 2001

Gregory Gregoriadis

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

List of Contributors

Jan-Willem Arends

Maastricht University

Department of Pathology

PO Box 616

6200 MD Maastricht

the Netherlands

Sigridur A. Ásgeirsdóttir

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmacokinetics and Drug Delivery

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands

[e-mail]

Leonie Beljaars

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmacokinetics and Drug Delivery

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands [e-mail]

Ulrich Bickel

Texas Tech University HSC School of Pharmacy Pharmaceutical Sciences 1300 S Coulter

Amarillo, Texas 79106 USA [e-mail]

Anne H. de Boer

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmaceutical Technology and Biopharmacy

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands [e-mail]

Maaike Everts

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmacokinetics and Drug Delivery

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands [e-mail]

X	List of Contributors

Henderik W. Frijlink

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmaceutical Technology and Biopharmacy

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands [e-mail]

Arjan W. Griffioen

Maastricht University/ University Hospital Maastricht Department of Internal Medicine Tumor Angiogenesis Laboratory Peter Debyelaan 25

6202 AZ Maastricht the Netherlands

[e-mail]

Geny M. M. Groothuis

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmacokinetics and Drug Delivery

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands

[e-mail]

Marijke Haas

Groningen University Institute for Drug Exploration (GUIDE)

Department of Clinical Pharmacology Ant. Deusinglaan 1

9713 AV Groningen the Netherlands [e-mail]

R. Folgert G. Haverdings

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmacokinetics and Drug Delivery

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands

[e-mail]

Wijnand Helfrich

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pathology and Laboratory Medicine

Medical Biology Section Tumor Immunology Laboratory Hanzeplein 1

9713 GZ Groningen the Netherlands [e-mail]

Hennie R. Hoogenboom

Dyax bv

PO Box 5800

6202 AZ Maastricht the Netherlands

[e-mail]

Jörg Huwyler

F. Hoffmann-LaRoche Ltd. CNS Research

PRBN, Bldg. 68/323a CH-4070 Basel Switzerland [e-mail]

Young-Sook Kang

Physiology and Pathophysiology Laboratory College of Pharmacy

Sookmyung Women’s University Chungpa-dong 2 ga 53-12 Yongsan gu, 140-742

Seoul

Korea [e-mail]

Yukio Kato

University of Tokyo

Graduate School of Pharmaceutical Sciences

7-3-1 Hongo

Bunkyo-ku Tokyo 113-0033

[e-mail]

Robbert J. Kok

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmacokinetics and Drug Delivery

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands [e-mail]

Jos G. W. Kosterink

University Hospital Groningen Department of Hospital and Clinical Pharmacy

Hanzeplein 1

9713 GZ Groningen the Netherlands

[e-mail]

List of Contributors

XI

Lou F. M. H. de Leij

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pathology and Laboratory Medicine

Medical Biology Section Tumor Immunology Laboratory Hanzeplein 1

9713 GZ Groningen the Netherlands

[e-mail]

Claudia S. Leopold

University of Leipzig

Department of Pharmaceutical Technology Schönauer Str. 160

04207 Leipzig Germany

[e-mail]

Dirk K. F. Meijer

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmacokinetics and Drug Delivery

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands [e-mail]

Barbro N. Melgert

Groningen University Institute for Drug Exploration (GUIDE)

Department of Pharmacokinetics and Drug Delivery

Ant. Deusinglaan 1

9713 AV Groningen the Netherlands [e-mail]