Drug Targeting Organ-Specific Strategies

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128 5 Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell (a) (b) Figure 5.4. Schematic diagram for (a) the integration plot analysis and (b) renal processing of alkylglycoside. ation from the basal site of the kidney (Figure 5.4b). Based on this equation, the targeting efficiency from the basal site can be estimated as CL uptake,kidney.A similar analysis for p-aminohippurate and inulin enabled us to estimate the renal plasma flow rate (Q r) and GFR, respectively. The CL uptake,app for Glc-O-C8-AVP was close to Q r (~2.4 ml min –1 g –1 ) and much higher than f pGFR (~0.13 ml min –1 g –1 ), suggesting that renal accumulation of Glc-O-C8- AVP occurs mainly from the blood (f pGFR
5.2.1.4 Specific Binding of Alkylglycoside-derivatized AVP in Kidney Plasma Membranes Possible explanations for a blood flow-limited uptake in kidney include the existence of specific uptake mechanisms, such as receptor-mediated endocytosis and carrier-mediated transport. Since the former mechanism is initiated by binding of the ligand to the cell-surface receptor, the specific binding of alkylglycoside compounds to isolated tubular plasma membranes was examined [23,24]. Scatchard analysis revealed specific binding of Glc-, Man- and 2dGlc-O-C8-AVP exhibiting kidney-specific distribution in vivo (Figure 5.3b), with a dissociation constant (Kd) of 10–60 nM.This did not occur with Gal- and Man(α)-O-C8-AVP. Saturation of the CL uptake of Glc-O-C8-AVP in the kidney in vivo occurred at a similar concentration (40–80 nM) of unbound ligand in the renal capillary space [23]. These results suggest that specific binding site(s) are involved in the renal distribution of alkylglycoside conjugates of AVP. 5.2.1.5 Structure–Kinetic Relationship Studies 5.2 Renal Delivery Using Pro-Drugs 129 To develop alkylglycoside moieties as drug delivery vectors, a systematic analysis was performed to identify the structural requirements for both vectors and drugs. This allowed us to understand the spectrum and limitations of compounds that can be delivered by this system. A binding study using isolated tubular membranes enabled the investigation of such struc- Figure 5.5. Inhibition of specific binding of Glc-O-C8-AVP to rat kidney membrane fraction. Adapted from reference [24].
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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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Page 125 and 126: 4 Cell Specific Delivery of Anti-In
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Page 129 and 130: 4.2.2.2 Phagocytosis and Transcytos
Page 131 and 132: ther inflammatory cells or accessor
Page 133 and 134: 4.3 Hepatic Inflammation and Fibros
Page 135 and 136: process is not yet available. Sever
Page 137 and 138: this carrier to the KCs.When the ma
Page 139 and 140: e taken up rapidly by mannose recep
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Page 143 and 144: 4.8 Testing Liver Targeting Prepara
Page 145 and 146: 4.8 Testing Liver Targeting Prepara
Page 147 and 148: 4.9 Targeting of Anti-inflammatory
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Page 151 and 152: with monoclonal and bispecific anti
Page 153 and 154: References 117 [50] Coleman DL, Eur
Page 155 and 156: References 119 [133] Cronstein BN,
Page 157 and 158: 5 Delivery of Drugs and Antisense O
Page 159 and 160: 5.1 Introduction 123 convoluted tub
Page 161 and 162: treatment of the targeted cell and
Page 163: CL uptake (ml/min/g) centration pro
Page 167 and 168: 5.2 Renal Delivery Using Pro-Drugs
Page 169 and 170: 5.2 Renal Delivery Using Pro-Drugs
Page 171 and 172: 5.3 Renal Delivery Using Macromolec
Page 181 and 182: 5.4 Renal Delivary of Antisense Oli
Page 183 and 184: 5.4 Renal Delivery of Antisense Oli
Page 185 and 186: 5.4.8 Benefits and Limitations of A
Page 187 and 188: via reabsorption from the luminal s
Page 189 and 190: References 153 [66] Franssen EJF, M
Page 191 and 192: References 155 [145] Van Zwieten PA
Page 193 and 194: 158 6 A Practical Approach in the D
Page 207 and 208: 172 7 Vascular Endothelium in Infla
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180 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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