Nitrate-functionalized patch confers cardioprotection and improves heart repair after myocardial infarction via local nitric oxide delivery

Dashuai Zhu,Meng Qian,Shuting Wu,Fei Wang,Qiang Zhao,Jingli Hou,Jie Shen,Shuo Liu,Lanping Wu,Yongzhe Che,Yumin Zhong,Deling Kong,Dawei Jin,Yanjun Pan,Meng Yin,Zhilu Yang,He Wang,Tian Hao

doi:10.1038/s41467-021-24804-3

Abstract

Nitric oxide (NO) is a short-lived signaling molecule that plays a pivotal role in cardiovascular system. Organic nitrates represent a class of NO-donating drugs for treating coronary artery diseases, acting through the vasodilation of systemic vasculature that often leads to adverse effects. Herein, we design a nitrate-functionalized patch, wherein the nitrate pharmacological functional groups are covalently bound to biodegradable polymers, thus transforming small-molecule drugs into therapeutic biomaterials. When implanted onto the myocardium, the patch releases NO locally through a stepwise biotransformation, and NO generation is remarkably enhanced in infarcted myocardium because of the ischemic microenvironment, which gives rise to mitochondrial-targeted cardioprotection as well as enhanced cardiac repair. The therapeutic efficacy is further confirmed in a clinically relevant porcine model of myocardial infarction. All these results support the translational potential of this functional patch for treating ischemic heart disease by therapeutic mechanisms different from conventional organic nitrate drugs.

Highlights

Nitric oxide (NO) is a short-lived signaling molecule that plays a pivotal role in cardiovascular system
The biodegradability and biocompatibility of the material guarantees that this patch can be directly implanted onto the heart, and the implanted patch demonstrated local NO delivery to infarcted myocardium that is controlled by the ischemic microenvironment, a vast improvement and advantage over glyceryl trinitrate (GTN) patches
PCL oligomers with both ends capped with nitrates (PCL-ONO2) were first synthesized by acylation of PCLdiol (Mn = 2000) with 4-bromobutanoyl chloride, followed by substitution of the terminal bromide with AgNO3 (Supplementary Fig. 1), and the structure of PCL-Br and PCL-ONO2 was verified by 1H NMR and 13C NMR spectra (Supplementary Figs. 2, 3)

Summary

Introduction

Nitric oxide (NO) is a short-lived signaling molecule that plays a pivotal role in cardiovascular system. The therapeutic efficacy is further confirmed in a clinically relevant porcine model of myocardial infarction. All these results support the translational potential of this functional patch for treating ischemic heart disease by therapeutic mechanisms different from conventional organic nitrate drugs. Dysfunction of the NO signaling pathway is always correlated with the increased morbidity of MI5 In this regard, exogenous supplementation with NO can prevent infarction formation[6,7,8] by relaxing vascular tone, inhibiting platelet aggregation[9,10], and modulating the inflammatory response[11], adding a cardioprotective effect[12]. We designed a NO cardiac patch based on an original and different concept, wherein the nitrate moiety was covalently bound to biodegradable poly(ε-caprolactone) (PCL), transforming small-molecule drugs into functional biomaterials. The therapeutics efficacy was further confirmed in a clinical-relevant porcine MI model, with the intent to establish the substantial clinical viability and improvement of the NO cardiac patches

Methods

Results

Conclusion