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

Abstract

PurposeNitric 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 methodsThe 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).ResultsThis 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.ConclusionThese findings provide initial results for an angiogenesis-related drug development platform by a straightforward method with biocompatible polymers.

Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases

“…More importantly, they can be specifically functionalized to target particular pathways and sites on the BMECs. They are designed to have greater BBB permeability [2,6,9,11,17,19], stability [5,9], half-life [11,18,82,83] and shelf-life [5], high-site specific targeting [10,14,84], and a controlled load-release of drugs [18,19,21,84,85].…”

“…They are highly biocompatible and readily internalized by brain cells [17]. Nano-scaffolds made from cationic polysaccharides/polymers (10-1000 nm) have been used to adsorb the drug and facilitate its transport across the BBB by masking the drug's steric effect [20,21].…”

“…The brain stroke, which is caused by the constriction of brain blood vessels or hemorrhage requires immediate treatment as the therapeutic window is only 3-4.5 h. Restoring blood circulation and controlling vascular degeneration through angiogenesis are the major strategies for the above conditions. Various pro-angiogenic materials have been reported, some of which already are available as NMs such as Simvastatin [11], VEGF [18,87], nitric oxide (NO) donors [21], ZL006 [10], Cyclosporine A (CsA) [12], and microRNAs [14,17] (see Table 1).…”

“…In another study, angiogenesis was induced by releasing low concentrations of NO, from NO donors with short half-life, such as N-diazeniumdiolate and S-nitrosothiol. They were loaded onto nano-scaffolds made of methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (mPEG-PLGA) [21].…”

“…Recently, NMs have been investigated for their efficacy in treating brain angiogenesis conditions. These have included nano-capsules, such as solid lipid nanoparticles (SLNs) [4][5][6][7][8], liposomes [9][10][11][12][13][14][15][16], exosomes [17], and others [18], as well as nano-scaffolds made of chitosan [19], polymers [20,21], inorganic nanoparticles (NPs) [22][23][24], etc. (see Table 1).…”