From systemic shotgun to site-specific nanoparticle-targeted delivery: a new paradigm for drug delivery.

Since the introduction of percutaneous techniques for the relief of symptomatic obstructive atherosclerotic coronary artery disease in the late 1970s, the major Achilles heel was restenosis. After nearly 3 decades of study, the cellular and molecular biology of this complex response to injury is now far better understood and includes the role of thrombosis, cellular proliferation, inflammation, matrix production, and elastic recoil.1,2 Some 15 years ago there was enthusiastic interest in the concept of “site specific” or “direct delivery” of antiproliferative or anticoagulant therapies.3–6 Edelman et al reported on the inhibition of SMC proliferation after vascular injury by surgical placement of heparinimpregnated polymer matrix in the periadventitial tissue of rat carotid arteries.3 At that time a catheter-based porous balloon catheter became available for “site specific” delivery7 but failed to be effective in limiting restenosis in an atherosclerotic rabbit femoral artery injury model.4 Although labeled heparin could be demonstrated to be present in the injured vessel wall, retention time of the drug and potential additional injury created by a jet effect of the porous balloon catheter were cited as potential explanations for the lack of efficacy. Subsequently, the concept of local delivery remained dormant and a multitude of clinical trials using systemically administered pharmacological agents to reduce or prevent restenosis demonstrated no benefit.8