Abstract 434: A New Drug Delivery System Using Fibronectin-vegf Fusion Is More Effective And Harmless Than Vegf Alone For The Therapeutic Neovascularization
Background: Recent clinical trials for therapeutic angiogenesis reported limited efficacy. To overcome these limitations, we developed a fusion protein of fibronectin (Fn) and VEGF (Fn-VEGF), with high collagen affinity, binding to extracellular matrix of ischemic area. We hypothesized that controlled delivery of VEGF using this protein is useful for therapeutic angiogenesis.
Methods and Results: We examined biological effects of Fn-VEGF on human endothelial cells cultured on collagen coated dishes, and found that a single administration of Fn-VEGF caused sustained proliferation at least for a week. We then produced hindlimb ischemia in mice, and injected PBS, VEGF, Fn, or Fn-VEGF (10 μg/day) into ischemic muscles. Fn-VEGF retained in the injected area for 5 days, whereas VEGF alone rapidly disappeared from the injected area after 3 hours. Moreover, injection of Fn-VEGF enhanced recovery of blood perfusion of ischemic limb, the degrees of which is greater than those afforded by VEGF (Fn-VEGF 94.1 ±12.3 vs VEGF 72.3 ±9.2 %, p<0.01). Importantly, Fn-VEGF enhanced limb salvage rate better than VEGF, and high dose administration of VEGF worsened limb ischemia up to complete amputation, whereas high dose Fn-VEGF (40 μg/day) represented a proper effect (Figure⇓). Moreover, as well as VEGF, Fn-VEGF has also capacity making mononuclear cells to endothelial progenitor cells, and induced proper degree of angiogenesis from endothelial cells.
Conclusions: Injection of Fn-VEGF was more effective and harmless than VEGF, suggesting that controlled delivery of VEGF using this protein may be a clinically useful and feasible strategy for next-generation neovascularization.