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

Authors Yang C, Hwang HH, Jeong S, Seo D, Jeong Y, Lee DY, Lee K

Received 25 May 2018

Accepted for publication 9 August 2018

Published 16 October 2018 Volume 2018:13 Pages 6517—6530

DOI https://doi.org/10.2147/IJN.S174989

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Farooq Shiekh

Peer reviewer comments 3

Editor who approved publication: Dr Thomas Webster


Chungmo Yang,1,* Hae Hyun Hwang,2,* Soohyun Jeong,1 Deokwon Seo,1 Yoon Jeong,1 Dong Yun Lee,2,3 Kangwon Lee1,4

1Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea; 2Department of Bioengineering, College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul 04763, Republic of Korea; 3Institute of Nano Science & Technology (INST), Hanyang University, Seoul 04763, Republic of Korea; 4Advanced Institutes of Convergence Technology, Gyeonggi-do 16229, Republic of Korea

*These authors contributed equally to this work

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 (diethylenetriamine 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.

Keywords: mPEG-PLGA nanoparticles, sprouting angiogenesis, low concentration of nitric oxide, liposomal nanoparticles, amphiphilic polymers

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