Correlation of transarterial transport of various dextrans with their physicochemical properties

Local vascular drug delivery provides elevated concentrations of drug in th e target tissue while minimizing systemic side effects. To better character ize local pharmacokinetics we examined the arterial transport of locally ap plied dextran and dextran derivatives in vivo. Using a two-compartment phar macokinetic model to correct the measured transmural flux of these compound s for systemic redistribution and elimination as delivered from a photopoly merizable hydrogel surrounding rat carotid arteries, we found that the diff usivities and the transendothelial permeabilities were strongly dependent o n molecular weight and charge. For neutral dextrans, the effective diffusiv e resistance in the media increased with molecular weight approximately 4.1 -fold between the molecular weights of 10 and 282 kDa. Similarly, endotheli al resistance increased 28-fold over the same molecular weight range. The e ffective medial diffusive resistance was unaffected by cationic charge as s uch molecules moved identically to neutral compounds, but increased approxi mately 40% when dextrans were negatively charged. Transendothelial resistan ce was 20-fold lower for the cationic dextrans, and Ii-fold higher for the anionic dextrans, when both were compared to neutral counterparts. These re sults suggest that, while low molecular weight drugs will rapidly traverse the arterial wall with the endothelium posing a minimal barrier, the revers e is true for high molecular weight agents. With these data, the deposition and distribution of locally released vasotherapeutic compounds might be pr edicted based upon chemical properties, such as molecular weight and charge . (C) 2000 Elsevier Science Ltd. All rights reserved.