Correlation of transarterial transport of various dextrans with their physicochemical properties.
Local vascular drug delivery provides elevated concentrations of drug in the target tissue while minimizing systemic side effects. To better characterize local pharmacokinetics we examined the arterial transport of locally applied dextran and dextran derivatives in vivo. Using a two-compartment pharmacokinetic model to correct the measured transmural flux of these compounds for systemic redistribution and elimination as delivered from a photopolymerizable hydrogel surrounding rat carotid arteries, we found that the diffusivities and the transendothelial permeabilities were strongly dependent on molecular weight and charge. For neutral dextrans, the effective diffusive resistance in the media increased with molecular weight approximately 4.1-fold between the molecular weights of 10 and 282 kDa. Similarly, endothelial resistance increased 28-fold over the same molecular weight range. The effective medial diffusive resistance was unaffected by cationic charge as such molecules moved identically to neutral compounds, but increased approximately 40% when dextrans were negatively charged. Transendothelial resistance was 20-fold lower for the cationic dextrans, and 11-fold higher for the anionic dextrans, when both were compared to neutral counterparts. These results suggest that, while low molecular weight drugs will rapidly traverse the arterial wall with the endothelium posing a minimal barrier, the reverse is true for high molecular weight agents. With these data, the deposition and distribution of locally released vasotherapeutic compounds might be predicted based upon chemical properties, such as molecular weight and charge.
Elmalak
O
O
Harvard University-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Lovich
M A
MA
Edelman
E
E
D000818:Animals; D001672:Biocompatible Materials; D002339:Carotid Arteries / Q000502:physiology*; D016264:Dextran Sulfate / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D003911:Dextrans / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D004337:Drug Carriers; D004730:Endothelium, Vascular / Q000502:physiology; D007457:Iodine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D008433:Mathematics; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D008970:Molecular Weight; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D001672:Biocompatible Materials; D003911:Dextrans; D004337:Drug Carriers; D007457:Iodine Radioisotopes; D016264:Dextran Sulfate