Inducing angiogenesis with the controlled release of nitric oxide from biodegradable and biocompatible copolymeric nanoparticles

Abstract

Purpose: Nitric oxide (NO) can be clinically applied at low concentrations to regulate angiogenesis. However, studies using small molecule NO donors (N-diazeniumdiolate, S-nitrosothiol, etc) have yet to meet clinical requirements due to the short half-life and initial burst-release profile of NO donors. In this study, we report the feasibility of methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) as NO-releasing polymers (NO-NPs) for inducing angiogenesis. Materials and methods: The mPEG–PLGA copolymers were synthesized by typical ring-opening polymerization of lactide, glycolide and mPEG as macroinitiators. Double emulsion methods were used to prepare mPEG–PLGA NPs incorporating hydrophilic NONOate (dieth-ylenetriamine NONOate). Results: This liposomal NP encapsulates hydrophilic diethylenetriamine NONOate (70%±4%) more effectively than other previously reported materials. The application of NO-NPs at different ratios resulted in varying NO-release profiles with no significant cytotoxicity in various cell types: normal cells (fibroblasts, human umbilical vein endothelial cells and epithelial cells) and cancer cells (C6, A549 and MCF-7). The angiogenic potential of NO-NPs was confirmed in vitro by tube formation and ex vivo through an aorta ring assay. Tubular formation increased 189.8% in NO-NP–treated groups compared with that in the control group. Rat aorta exhibited robust sprouting angiogenesis in response to NO-NPs, indicating that NO was produced by polymeric NPs in a sustained manner. Conclusion: These findings provide initial results for an angiogenesis-related drug development platform by a straightforward method with biocompatible polymers.