Sequential Targeted Delivery of Liposomes to Ischemic Tissues by Controlling Blood Vessel Permeability.

Delivery systems for therapeutic angiogenesis that deliver angiogenic factors to ischemic tissues have recently been fabricated. However, these systems are designed for surgical implantation or multiple local injections which can cause pain and potential physical burden in patients. Here, we propose a minimally invasive sequential nanoparticle-mediated delivery strategy for ischemic tissue using a murine hindlimb ischemic model. Intravenously injected liposomes that encapsulate VEGF, an angiogenic factor, first target the ischemic sites via the enhanced permeability and retention (EPR) effect in early stages of ischemia. VEGF released from the targeted liposomes maintains the blood vessel permeability for a longer period of time compared to the delivery of empty liposomes. This first nanoparticle-mediated delivery of VEGF to the ischemic site enables extending the temporal window of leaky blood vessel up to 7 days so that the second liposomes could be targeted to the ischemic sites via EPR effect. This strategy will provide opportunities for the targeted delivery of other vessel maturation agents loaded in nanoparticles to ischemic tissue.