Drug Targeting Organ-Specific Strategies

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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
Foreword 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) 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
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Page 5: Preface Drug Targeting Organ-Specif
Page 9 and 10: X List of Contributors Henderik W.
Page 11 and 12: XII List of Contributors Grietje Mo
Page 13 and 14: Contents Drug Targeting Organ-Speci
Page 15 and 16: Contents XVII 3 Pulmonary Drug Deli
Page 17 and 18: Contents XIX 5.2.1.6 Identification
Page 19 and 20: Contents XXI 7.5 In Vitro Technique
Page 21 and 22: Contents XXIII 9.4 Tumour Vasculatu
Page 23 and 24: Contents XXV 12.8. Tissue Slices fr
Page 27 and 28: Dexa dexamethasone DIVEMA divinyl e
Page 29 and 30: LRP lung resistance related protein
Page 31 and 32: ROS reactive oxygen species RSV res
Page 33 and 34: Index a ADEPT 217, 224, 268, 291 ad
Page 35 and 36: e E. coli expression system 292 eff
Page 37 and 38: polymers, soluble 4, 218 - dendrime
Page 39 and 40: 2 1 Drug Targeting: Basic Concepts
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20 1 Drug Targeting: Basic Concepts
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22 1 Drug Targeting: Basic Concepts
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24 2 Brain-Specific Drug Targeting
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54 3 Pulmonary Drug Delivery: Deliv
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4 Cell Specific Delivery of Anti-In
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The sinusoids are lined by the disc
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4.2.2.2 Phagocytosis and Transcytos
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ther inflammatory cells or accessor
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4.3 Hepatic Inflammation and Fibros
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process is not yet available. Sever
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this carrier to the KCs.When the ma
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e taken up rapidly by mannose recep
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y the transcriptional regulatory pr
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4.8 Testing Liver Targeting Prepara
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4.8 Testing Liver Targeting Prepara
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4.9 Targeting of Anti-inflammatory
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4.9 Targeting of Anti-inflammatory
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with monoclonal and bispecific anti
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References 117 [50] Coleman DL, Eur
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References 119 [133] Cronstein BN,
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5 Delivery of Drugs and Antisense O
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5.1 Introduction 123 convoluted tub
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treatment of the targeted cell and
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CL uptake (ml/min/g) centration pro
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5.2.1.4 Specific Binding of Alkylgl
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5.2 Renal Delivery Using Pro-Drugs
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5.2 Renal Delivery Using Pro-Drugs
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5.3 Renal Delivery Using Macromolec
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5.4 Renal Delivary of Antisense Oli
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5.4 Renal Delivery of Antisense Oli
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5.4.8 Benefits and Limitations of A
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via reabsorption from the luminal s
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References 153 [66] Franssen EJF, M
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References 155 [145] Van Zwieten PA
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158 6 A Practical Approach in the D
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172 7 Vascular Endothelium in Infla
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8 Strategies for Specific Drug Targ
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8.2.2 Histogenesis The traditional
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may become obstructed and compresse
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8.5 Strategies to Deliver Drugs to
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8.5 Strategies to Deliver Drugs to
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larly cytotoxic immune effector cel
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contributes to limited tumour penet
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ples onto anti-EGP-2 scFv. Biologic
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In the case of drug-monoclonal anti
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cells, the presence of co-stimulato
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Monomethoxy-polyethylene glycol CH
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e efficiently loaded into the lipos
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8.6 Clinical Studies 223 Table 8.5.
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8.6.3 (Synthetic) (co)Polymers Solu
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8.8 Conclusions and Future Perspect
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References 229 [43] Chaouchi NA, Va
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References 231 [126] Czuczman MS, G
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234 9 Tumour Vasculature Targeting
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256 10 Phage Display Technology for
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11 Development of Proteinaceous Dru
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carrier is an homogenous product. I
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11.3 The Homing Device 11.3 The Hom
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malian cell lines that have acquire
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jugates for the delivery of other a
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11.5 The Linkage Between Drug and C
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actions are directed towards these
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11.5 The Linkage Between Drug and C
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homing potential if the antigen rec
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ly used promoters include T7 RNA po
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the baculovirus expression vector,
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11.8 Recombinant DNA Constructs 297
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11.8 Recombinant DNA Constructs 299
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toxic activity. Anthrax and tetanus
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11.9 Recombinant Domains as Buildin
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References 305 [16] Milstein C, Wal
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References 307 [99] Verma R, Boleti
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12 Use of Human Tissue Slices in Dr
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are also extensively used in a vari
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Meanwhile many incubation systems h
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12.3 Incubation and Culture of Live
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to investigate the effect of differ
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The mechanisms of uptake and excret
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12.6 The Use of Liver Slices in Dru
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12.7 Efficacy Testing of the Drug T
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NO x µM 80 60 40 20 * * 12.7 Effic
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TNFα ng/ml 1.5 1 0.5 0 * Human (n=
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References 329 [33] Ikejima K, Enom
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References 331 [109] Dutt A, Priebe
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334 13 Pharmacokinetic/Pharmacodyna
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372 14 Drug Targeting Strategy: Scr
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374 14 Drug Targeting Strategy: Scr
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