Drug Targeting Organ-Specific Strategies

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214 8 Strategies for Specific Drug Targeting to Tumour Cells Conventional cytotoxic drugs such as doxorubicin, idarubicin, bleomycin, methotrexate, cytosine arabinoside, chlorambucil, cisplatin, vinca alkaloids, and mitomycin C have all been conjugated to tumour-binding MAbs [65–69] (Figure 8.1e). Drug conjugates can be prepared by covalently coupling drugs directly to a MAb or indirectly through an intermediate spacer molecule such as dextran, human serum albumin, poly-glutamic acid, carboxymethyl dextran, or amino-dextran. An indirect linkage facilitates the attachment of more drug molecules to one MAb molecule, in theory resulting in an increased delivery of drug molecules to the tumour (see Chapter 11 on drug–carrier conjugate synthesis strategies). The members of the enediyne family of antibiotics are highly potent drugs that are good candidates for attachment to MAbs [70]. Calicheamicin conjugates of e.g. the MAb CT-M-01, exerted strong cell specific activity against s.c. breast-tumour xenografts in athymic mice [71]. Similar impressive anti-tumour activity was shown with a calicheamicin conjugate of antiganglioside-GD2 MAb used to treat experimental liver metastases in immunocompetent mice [72]. Table 8.2. MAb-drug conjugates that have been developed for cancer therapy. Class of anti-neoplastic drug Drug Disease Antimetabolites Methotrexate Lung cancer, Colon cancer, Teratocarcinoma, T cell lymphoma 5-Fluorouracil B leukaemia Cytosine arabinoside B leukaemia Aminopterin Murine thymoma 5-Fluoro-2’-deoxyuridine Colon carcinoma Alkylating agents Chlorambucil Murine thymoma, Murine lymphoma, Melanoma Melphalan Colon Cancer, Murine thymoma Mitomycin C Lung cancer, Various disseminated refractory malignancies, Gastric cancer Cisplatinum Ovarian carcinoma Trenimon Hepatoma Anthracyclines Doxorubicin/adriamycin Melanoma, Ovarian carcinoma, T-cell lymphoma, Colon carcinoma, B-cell lymphoma, Various disseminated refractory malignancies, Breast cancer, Lung cancer, Pancreatic cancer, Liver cancer, Neuroblastoma Daunomycin Soft-tissue sarcomas, Mammalian carcinoma, Hepatoma Antimitotic agents Vinca alkaloids Lung adenocarcinoma Miscellaneous agents Bleomycin Leukaemia Idarubicin Murine thymoma Maytansine Colon cancer Calicheamicins Human breast carcinoma xenografts
In the case of drug–monoclonal antibody conjugates, the entire conjugate may be internalized after which the drug can be released intracellularly.The drug may also be cleaved extracellularly and subsequently taken up into tumour cells by diffusion or active transport. Success with drug–MAb conjugates has been limited thus far because of poor uptake of the MAb–conjugates especially in solid tumours. Drug delivery is also limited by the number of drug molecules that can be efficiently carried by each antibody molecule. Furthermore chemical conjugation is usually a complex procedure that can damage both the MAb and the drug and MAb–conjugates require intra- or extracellularly active biochemicals and/or enzymes to cleave the active drug from the antibody. Table 8.2 gives an overview of the various antibody–drug conjugates that have been developed for cancer therapy to date. 8.5.1.6 Radioimmunoconjugates 8.5 Strategies to Deliver Drugs to Targets within the Tumour (Cells) 215 Another way of using MAbs as therapeutic agents is to couple them to radionuclides (Figure 8.1e and Table 8.3). Radioimmunoconjugates offer many advantages in the treatment of cancer. Cell killing does not rely on the host’s immune system and occurs by the ionizing effects of emitted radioactive particles [73]. These radioactive cytotoxic particles are effective over a distance of several cell diameters, allowing eradication of antigen-negative cells by the radioimmunoconjugate bound to the adjacent antigen-positive tumour cells. This is useful considering the heterogeneity of antigen expression in some tumours. Finally, the amount of radioactive MAb delivered to a tumour can be measured non-invasively by imaging [67].The most important factors for therapeutic efficacy of radioimmunoconjugates are good penetration, favourable pharmacokinetics, and a prolonged time of retention in the tumour [74]. Table 8.3. Isotopes used for radioimmunotherapy in cancer Radioisotope Beta-emitters lodine-131 Yttrium-90 Rhenium-188 Rhenium-186 Copper-67 Alpha-emitters Bismuth-212 Astatine-211 Electron capture Iodine-125 8.5.2 Bispecific Monoclonal Antibodies Another approach to selectively inducing tumour cell killing is by the use of bispecific monoclonal antibodies (BsMAb). They combine the specificity of two separate antibodies within one molecule and cross-link an effector killer cell or a toxic molecule with the target cell to be destroyed [75]. There are three major approaches for creating BsMAbs. They can be obtained by chemical cross-linking of two MAbs, by fusing two hybridomas [76], or by genetic
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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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160 6 A Practical Approach in the D
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266 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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