Mechanisms of transmural heparin transport in the rat abdominal aorta after local vascular delivery.
Local vascular drug delivery systems provide elevated concentrations in target arterial tissues, while minimizing systemic side effects. Drug can now be released to isolated arterial segments from the endovascular or perivascular aspects of the blood vessel, yet the forces that determine drug distribution and deposition for these different modes of delivery have not been rigorously investigated. This study examines mechanisms of transmural transport of a model vasoactive drug, heparin, and compares estimates of the distribution after administration from either aspect of the artery. We showed that (1) heparin traversed the arterial wall rapidly; (2) diffusion far outweighed convection in the control of transmural heparin transport in the normal artery, but after endothelial injury, convective forces rose to one quarter the magnitude of diffusive forces; (3) the endothelium posed a minimal diffusive barrier to heparin; and (4) the diffusive barrier imposed by the adventitia depended on its thickness. These findings strongly suggest that vasoregulatory compounds can be administered to target tissue by either perivascular or endovascular means with equal efficacy, because the forces governing transport of heparin from either aspect of the blood vessel wall are not significantly different. Furthermore, the differences in arterial transport properties between heparin and other macromolecules suggest that distribution and the optimal aspect of delivery will depend just as much on the physicochemical properties of the drug as the state of the blood vessel wall.
Lovich
M A
MA
Division of Health Sciences and Technology, Harvard University-Massachusetts Institute of Technology, Cambridge 02139, USA.
Edelman
E R
ER
D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism*; D001692:Biological Transport; D004058:Diffusion; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage* / Q000378:metabolism*; D066298:In Vitro Techniques; D008954:Models, Biological; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D006493:Heparin