Drug Targeting Organ-Specific Strategies

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Although there is no cellular barrier preventing diffusion from the ventricular surface into brain tissue (there are no tight junctions between the ependymal cells lining the ventricular surface), the low speed of diffusion severely restricts tissue uptake of even small molecular weight drugs and practically prevents the penetration of large molecules such as peptides and proteins into deep tissue layers. Possible enzymatic inactivation and binding or sequestration by brain cells along the diffusion path may even lower the actual drug concentrations in brain interstitial spaces to levels lower than predicted from the molecular size and diffusion coefficients [61]. Figure 2.7a shows an example of a large molecule, the 26-kDa nerve growth factor (NGF), that could not penetrate into rat brain deeper than 1–2 mm from the infused ventricle. This might be expected, as even small drugs show very steep concentration gradients over a distance of only 2–3 mm from the ventricular surface (Figure 2.7b). Exceptions are found in areas to which retrograde transport occurs, e.g. into the neurons of the basal cholinergic nuclei in the case of NGF (Figure 2.7a). After i.c.v. injection, the rate of elimination from the CNS compartment is dominated by cerebrospinal fluid dynamics. The CSF, which is secreted by the choroid plexus epithelium across the apical membrane, circulates along the surface and convexities of the brain in a rostral to caudal direction. It is reabsorbed by bulk flow into the peripheral bloodstream at the arachnoid villi within both cranial and spinal arachnoid spaces [62]. Of note is that the turnover rate of total CSF volume is species dependent and varies between approximately 1 h in rats and 5 h in humans. In adult human brain, the total CSF volume amounts to 100–140 ml and the production rate is 21 ml h –1 [63]. Accordingly, the entire cerebrospinal volume is exchanged regularly 4–5 times per day. This rapid drainage of CSF into peripheral blood leads to relatively high drug concentrations in the peripheral circulation. For instance, the concentration of methotrexate in peripheral blood reaches 1% of the ventricular CSF concentration following intrathecal administration of the drug [64]. In Rhesus monkeys, parenchymal concentrations of methotrexate of 1% of the intraventricular concentration have been measured at a distance of 2 mm from the ependymal surface [65]. Therefore, the concentration of methotrexate in the blood is actually higher than at tissue regions beyond 2 mm from the ependymal surface following intrathecal application. 2.4.2.2 Intraparenchymal Route 2.4 Drug Delivery Strategies 37 Restricted diffusion also limits tissue distribution after intraparenchymal drug administration, as shown in Figure 2.7c and d. Distribution has been measured in the rat brain after implantation of polymer discs containing NGF [66]. Drug concentrations decreased to less than 10% of the values measured on the disc surface within a distance of 2–3 mm, even after prolonged periods of several days. Therefore, applying this approach in the larger human brain would require the stereotaxic placement of multiple intraparenchymal depots, as has been evaluated in rat brain [67], on a repetitive schedule. The same pharmacokinetic limitation is true in principle for the implantation of encapsulated genetically engineered cells, which synthesize and release neurotrophic factors [68].
38 2 Brain-Specific Drug Targeting Strategies (e) (c) (a) 1.0 2day NGF concentration, ng/ml C tissue 2hr 6 hr A B C CSF 10, 12 hr Relative Concentration 0 0 0.5 1.0 1.5 2.0 Distance, cm (f) Distance from polymer, mm (d) cm from ventr. surface (b)
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Drug Targeting Organ-Specific Strat
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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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Page 27 and 28: Dexa dexamethasone DIVEMA divinyl e
Page 29 and 30: LRP lung resistance related protein
Page 31 and 32: ROS reactive oxygen species RSV res
Page 33 and 34: Index a ADEPT 217, 224, 268, 291 ad
Page 35 and 36: e E. coli expression system 292 eff
Page 37 and 38: polymers, soluble 4, 218 - dendrime
Page 39 and 40: 2 1 Drug Targeting: Basic Concepts
Page 61 and 62: 24 2 Brain-Specific Drug Targeting
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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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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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