Drug Targeting Organ-Specific Strategies

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314 12 Use of Human Tissue Slices in <strong>Drug</strong> <strong>Targeting</strong> Research Figure 12.2. The five incubation systems for liver slices, divided into two groups: incubation systems continuously submerged in culture medium and dynamic organ culture-related incubation systems, where the liver slices are intermittently exposed to the medium and to the air.
12.3 Incubation and Culture of Liver Slices 315 Based on these various findings under a variety of conditions a thorough comparison of five incubation systems (Figure 12.2) was made by us in a collaborative study of four laboratories [52]. The five systems that were evaluated included: the shaken flask (a 25-ml Erlenmeyer flask in a shaking water bath [40]), the stirred well (24-well culture plate equipped with stainless steel grids and magnetic stirrers [38,64]), the rocker platform (a DOC system using six-well culture plates with Netwell inserts, rocked on a platform [41]), the roller system (dynamic organ culture rolled on an insert in a glass vial [35]) and the six-well shaker (sixwell culture plates in a shaking water bath). In the rocker platform 40% O 2/5% CO 2/55% N 2 was used whereas in the other four systems 95% O 2/5% CO 2 was used to oxygenate the tissue.The liver slices were incubated in these incubation systems for 0.5, 1.5 and 24.5 h and subsequently subjected to viability and metabolic function tests. The viability of the incubated liver slices was evaluated by potassium content, MTT assay, energy charge, histomorphology and lactate dehydrogenase (LDH) leakage.Their metabolic functions were studied by determination of the metabolism of lidocaine (Figure 12.3), testosterone and antipyrine. Up to 1.5 h of incubation, all five incubation systems gave similar results with respect to viability and metabolic function of the slices. However, after 24 h, the shaken flask, the rocker platform and the six-well shaker incubation systems, appeared to be superior to the stirred well and the roller incubator. It is notable that the cytochrome P450-dependent metabolism of testosterone and lidocaine was retained at the same levels as found after 0.5 and 1.5 h of incubation in the shaken flask, rocker platform and six-well incubation systems. This suggests that the de-differentiation seen after 24 h in pure hepatocyte culture does not occur in slices for at least 24 h. nmol MEGX/mg wet weight liver slice 20 15 10 5 0 * 0.5 1.5 24.5 Incubation time (hours) ** ** Shaken flask Stirred well Rocker platform Roller system 6 Well shaker Figure 12.3. Metabolism of lidocaine to MEGX (in nmol MEGX mg –1 wet weight liver slice) in liver slices after different incubation times (h). *p < 0.05 versus shaken flask, rocker platform, roller system and six-well shaker. **p < 0.05 versus shaken flask, rocker platform and six-well shaker. Data are the mean of three separate experiments ± SEM.
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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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Page 311 and 312: 11.3 The Homing Device 11.3 The Hom
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Page 329 and 330: 11.8 Recombinant DNA Constructs 297
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366 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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