Increased Intramural Retention After Local Delivery of Molecules with Increased Binding Properties: Implications for Regional Delivery of Pharmacologic Agents.

Abstract

BACKGROUND: Catheter-based local vascular delivery results in concentrated qualtities of pharmaceutical agents or genes into focal areas of the arterial wall. However, intramural retention is short and has reduced the potential efficacy of this approach. It was postulated that agents that possess increased intramural binding would show increased intramural retention. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were models of agents with increased cellular and extracellular matrix binding properties. METHODS AND RESULTS: The delivery efficiency and intramural retention of 2 mL of saline containing I(125) labeled PDGF (n = 35 arteries) and bFGF (n = 24) were compared with albumin (n = 21) after local delivery into porcine coronary arteries. Animals were sacrificed at three or more prespecified timepoints: immediately after delivery, 1 day, or 3 days after delivery and if necessary at 5 or 7 days to document prolonged retention. Autoradiograms of the arterial sections were evaluated for the extent of delivery. Delivery efficiency, defined as the amount leaving the catheter and retrieved from the arterial wall, was 0.60% +/- 0.42% for albumin, 1.98% +/- 0.88% for PDGF (P =.001), and 0.31% +/- 0.11% for bFGF. The calculated intramural half-life of albumin was 7.4 hours, 56.2 hours for PDGF, and 14.9 hours for bFGF (P =.0001 for PDGF). Infusate covering >50% of the medial area was observed in 85% of arteries immediately after delivery. Although myocardial delivery was similar for albumin, PDGF, and bFGF, myocardial retention was significantlylonger for bFGF (P <.001). CONCLUSIONS: Molecules that exhibit preferential intramural binding show a longer intramural residence duration than solutes without such binding properties. In addition, delivery and subsequent prolonged retention in the myocardium can be obtained by local delivery via the arterial lumen of solutions with preferential binding properties.