Drug Targeting Organ-Specific Strategies

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326 12 Use of Human Tissue Slices in Drug Targeting Research Figure 12.9. (a) TNFα production by rat liver slices (n = 9) after stimulation with 100 µg ml –1 LPS for 24 h in either the presence or absence of dexamethasone (D). Vehicle consists of PBS. *p < 0.05 versus vehicle + LPS. (b) TNFα production by rat liver slices (n = 9) after LPS stimulation for 24 h with or without Dexa 10-HSA (DH). Vehicle contains PBS and an equimolar amount of HSA. *p < 0.05 versus vehicle + LPS.
TNFα ng/ml 1.5 1 0.5 0 * Human (n=4) Rat (n=4) 12.8 Tissue Slices from Other Organs Precision-cut tissue slices have also been prepared from other organs apart from the liver. Kidney slices are prepared by the same method as liver slices [73]. Kidney slices from different species, including man are used in the study of the toxicology and metabolism of drugs [65,66,73,105–108], organic anion and cation transport [109,110], release of prostaglandin and noradrenalin [36,111], and also in the study of organ preservation [70,112]. Since region-selective slices (cortex or medulla slices) can be prepared from the kidney, toxicity and metabolism in different regions of the kidney can therefore be studied [36,108,113]. Lungs cannot be sliced directly but need to be filled with 1.5% (w/v) low melting agarose solution containing 0.9% (w/v) NaCl at 37°C and allowed to gel on ice [73]. Lung slices have been used for drug transport and toxicity studies [114–118]. Up until now slices from other organs have not been used in the (transport) study of drug targeting devices, but like liver slices, these in vitro preparations have the potential and advantages to be useful in the study of transport, cellular processing and efficacy of drug targeting devices. In addition, slices of tumours could be used to study drug targeting in cancer research. 12.9 Summary and Future Possibilities 12.9 Summary and Future Possibilities 327 Figure 12.10. Production of TNFα by human and rat liver slices in culture medium after 24 h stimulation with or without 100 µg ml –1 LPS. White bar: control; black bar: 100 µg ml –1 LPS present. Data are the mean of four experiments ± SEM. *p < 0.05 versus control. Drug targeting preparations are designed to be used in man, however most research with these preparations is carried out in animals. Due to known species differences, the study of these preparations in man in an early stage of development is therefore of paramount importance. In vitro studies exploiting human tissue can be used to ensure that these drug targeting devices reach the desired target cells and once there, are effective. When cells in the liver are the main target, in vitro research should be undertaken using preparations of both healthy and diseased human liver. As was discussed earlier in this chapter, liver slices seem like the ideal in vitro preparation for this purpose.The original architecture of the liver is still intact in the slice, which enables normal intercellular communication and cell-selective distribution of drugs. Slices can also be used to study drug interactions and the mechanisms and *
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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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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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Drug Targeting Organ-Specific Strategies

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