Formulation and delivery mode affect disposition and activity of tyrphostin-loaded nanoparticles in the rat carotid model

Poor drug residence in the arterial wall hinders clinical implementation of local drug delivery strategies for the treatment of restenosis. A rat caro tid model of vascular injury and intraluminal delivery of tyrphostin-contai ning polylactic acid (PLA) nanoparticles (NPs) were used to determine the r elationship between residence properties and biological activity of differe nt formulations and administration modes. The effects of delivery modes (de nudation and delivery time) and formulation variables (adsorbed vs encapsul ated drug, and NP size) on arterial drug/NP retention were examined. Antire stenotic effects of large (160 nm) and small (90 nm) tyrphostin-containing NPs, surface-absorbed tyrphostin, and systemic treatment were compared. Flu orescent NPs were used to study the spatial distribution of the carrier in the arterial wall. The decrease in arterial tyrphostin level over time fitt ed a biexponential model. Delivery time and pressure, endothelium integrity , particle size, and drug-polymer association affected local pharmacokineti cs and the antirestenotic results after 14 days. The PLA-based tyrphostin N P formulation ensured a prolonged drug residence at the angioplasty site af ter single intraluminal application. Several readily adjustable formulation and procedural factors considerably modified arterial ingress of the drug- loaded NPs and governed their subsequent redistribution, tissue binding, el imination, and ensuing antirestenotic effect.