Drug Targeting Organ-Specific Strategies

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218 8 Strategies for Specific Drug Targeting to Tumour Cells Table 8.4. ADEPT strategies developed for cancer therapy. Enzyme Pro-drug Active drug Carboxypeptidase G2 Benzoic acid Benzoic acid Mustard glutamates mustards Carboxypeptidase A Methotrexate-alanine Methotrexate Alkaline phosphatase Etoposide phosphate Etoposide Mitomycin phosphate Mitomycin Doxorubicin phosphate Doxorubicin Phenolmustard phosphate Phenolmustard Mitomycin phosphate Mitomycin Beta-glucuronidase Phenolmustard-glucuronide Phenolmustard Epirubicin-glucuronide Epirubicin Doxorubicin-glucuronide Doxorubicin Penicillin amidase Palytoxin-4hydroxyphenylacetamide Palytoxin Doxorubicin-phenoxyacetamide Doxorubicin Melphalan-phenoxyacetamide Melphalan Beta-lactamase Cephalosporin vinca alkaloid Desacetylvinblastine hydrazide Cephalosporin mustard Phenylenediamine mustard Cephalosporin mitomycin C Mitomycin C Cephalosporin doxorubicin Doxorubicin Carboxylesterase Paclitaxel carbonate Paclitaxel Carbonyloxycamptothecin Camptothecin Cytosine deaminase 5-Fluorocytosine Fluorouracil Plasmin Doxorubicin tripartate Doxorubicin Daunorubicin tripartate Daunorubicin One of the limitations of pro-drug monotherapy may be the risk of diffusion of the active drug away from the tumour site. 8.5.4 (Synthetic) (co)Polymers Polymers or synthetic copolymers are believed to accumulate in solid tumours due to enhanced vascular permeability of tumour blood vessels combined with a lack of lymphatic drainage in the tumour tissue [89,90]. Polymer-based targeting strategies can be divided into two main categories, i.e. polymer–protein conjugates (so far the most widely studied) and polymer–drug conjugates, particularly those containing conventional anti-tumour agents. Polymer–drug conjugation can be used to alter the biodistribution, elimination rate and rate of metabolism of covalently bound drugs. In the case of protein adducts, polymer conjugation can prolong the protein plasma elimination half-life, reduce proteolytic degradation and may have the added benefit of reducing immunogenicity. Polyethylene glycol (PEG) is the most widely used polymer for protein conjugation (Figure 8.4).
Monomethoxy-polyethylene glycol CH 3 –(OCH 2 CH 2 )–O–C–CH 2 –CH 2 –C O 8.5 Strategies to Deliver Drugs to Targets within the Tumour (Cells) 219 succinic acid O Linker Soluble polymer conjugates have also been proposed as macromolecular pro-drugs for controlled release and targeting of various low molecular weight, (non-protein) chemicals [91,92]. In this case, polymer conjugation not only serves to alter drug biodistribution by restricting cellular capture to the lysosomotropic route, but the polymer–drug linkage can also be designed to allow site-specific enzymatic or hydrolytic cleavage. Thus, both the rate and the site of drug delivery can in principle be controlled. Enhanced permeability of the microvasculature at certain sites, particularly within solid tumours, can be exploited to facilitate site-specific accumulation of polymer–drug conjugates [93]. Other (co)polymers of interest besides PEG are SMANCS (styrene-co-maleic anhydride neocarzinostatin; zinostatin stimalar) and HPMA (N-(2-hydroxypropyl) methylacrylamide). Targeting moieties such as sugars (galactose, mannose), proteins and antibodies have been incorporated into the conjugates to promote receptor-mediated recognition.Thus, cell- or organ-specific localization of therapy may be achieved [98]. It should be noted however, that various cell types in the liver and spleen are important target cells for sugar-derivatized proteins (see Chapter 4) and that hepatic clearance will always compete with extrahepatic distribution. Polymer conjugates are most useful in the context of immuno-conjugates. Other protein constructs such as fusion proteins can assist their future development. Soluble polymer con- PEG Protein NH-L-asparaginase Figure 8.4. Schematic diagram showing the structure of a typical polyethylene glycol (PEG) conjugate and the chemical structure of PEG-asparaginase.
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Drug Targeting Organ-Specific Strat
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Preface Drug Targeting Organ-Specif
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Foreword Drug Targeting Organ-Speci
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X List of Contributors Henderik W.
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XII List of Contributors Grietje Mo
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Contents Drug Targeting Organ-Speci
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Contents XVII 3 Pulmonary Drug Deli
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Contents XIX 5.2.1.6 Identification
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Contents XXI 7.5 In Vitro Technique
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Contents XXIII 9.4 Tumour Vasculatu
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Contents XXV 12.8. Tissue Slices fr
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Dexa dexamethasone DIVEMA divinyl e
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LRP lung resistance related protein
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ROS reactive oxygen species RSV res
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Index a ADEPT 217, 224, 268, 291 ad
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e E. coli expression system 292 eff
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polymers, soluble 4, 218 - dendrime
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2 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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Page 243 and 244: larly cytotoxic immune effector cel
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Page 265 and 266: References 231 [126] Czuczman MS, G
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270 10 Phage Display Technology for
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272 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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Drug Targeting Organ-Specific Strategies

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