Heparinized chitosan/poly(γ-glutamic acid) nanoparticles for multi-functional delivery of fibroblast growth factor and heparin.

To improve blood supply following ischemic injury, angiogenic factors such as fibroblast growth factor (bFGF) that stimulate new blood vessel formation have been used for therapeutic angiogenesis in ischemic tissues. In this study, heparin-functionalized chitosan (CS)/poly(γ-glutamic acid) (γ-PGA) nanoparticles (HP-CS/γ-PGA nanoparticles) were prepared for multi-functional delivery of basic fibroblast growth factor (bFGF) and heparin. The mean particle sizes and bFGF loading efficiency increased with the increase of functionalized heparin contents. The HP-CS/γ-PGA nanoparticles were pH-sensitive that could sustain bFGF release at pH 񥌈 6.7 (simulate the pH of ischemia tissue) and were rapidly disintegrated at pH 7.4 (simulate the pH of repaired tissue). Sustained release of bFGF from the nanoparticles enhanced the proliferation of human foreskin fibroblast cells (HFF) and angiogenic tube formation by human umbilical vein endothelial cells (HUVEC), suggesting the retaining of bFGF mitogenic activity. Heparin, a traditionally used anticoagulant, could release from the disintegrated nanoparticles to maintain the anti-factor Xa activity in blood plasma, after increasing the pH value from 6.6 to 7.4. The nanocarriers for multi-functional delivery of bFGF and heparin developed in this study may be a potential therapeutic method for enhancing ischemic tissue regeneration and preventing blood vessel rethrombosis.