Tuning the intentional corona of cerium oxide nanoparticles to promote angiogenesis via fibroblast growth factor 2 signalling

Abstract

Inadequate angiogenesis is a hallmark of conditions including cardiovascular diseases, stroke and chronic diabetic wounds, which exhibit tissue ischaemia ensuring that therapeutic strategies to promote angiogenesis are of great interest. However, many angiogenic treatments involve the delivery of growth factors which have limited clinical success due to poor stability, high manufacturing cost and poor efficacy. Cerium oxide nanoparticles (nanoceria) can either promote or inhibit angiogenesis depending on their surface corona chemistry. Here, nanoceria were functionalized with an intentional heparin corona, a polysaccharide which binds and signals growth factors, of different chain lengths and surface grafting density to establish their effect on angiogenesis. These nanoparticles promoted angiogenesis in vivo with the surface grafting density positively correlated with angiogenesis over the widest concentration range; however, chain length did not play a role. The heparin-nanoceria supported fibroblast growth factor 2 (FGF2) signalling in vitro and promoted FGF2-mediated angiogenesis in vivo. The nanoparticles were internalized by endothelial cells in vitro where they trafficked to the lysosomes and reduced cell viability suggesting that the angiogenic activity of heparin-nanoceria is mediated in the extracellular environment. Together, this study adds to our knowledge of the angiogenic effects of heparin-nanoceria towards finding new angiogenic treatments.