Biodegradable citrate-based polyesters with S-nitrosothiol functional groups for nitric oxide release

Nitric oxide (NO) is a biologically-active free radical involved in numerous physiological processes such as regulation of vasodilation, promotion of cell proliferation and angiogenesis, and modulation of the inflammatory and immune responses. Furthermore, NO has demonstrated the ability to mitigate the foreign body response that often results in the failure of implanted biomedical devices. Although NO has promising therapeutic value, the short physiological half-life of exogenous NO complicates its effective delivery. For this reason, the development of NO-releasing materials that permit the localized delivery of NO is an advantageous method of utilizing this molecule for biomedical applications. Herein, we report the synthesis and characterization of biodegradable NO-releasing polyesters prepared from citric acid, maleic acid, and 1,8-octanediol. NO release was achieved by incorporation of S-nitrosothiol donor groups through conjugation of cysteamine and ethyl cysteinate to the polyesters, followed by S-nitrosation with tert-butyl nitrite. The extent of NO loading and the release properties under physiological conditions (pH 7.4 PBS, 37 °C) were determined by chemiluminesence-based NO detection. The average total NO content of poly(citric-co-maleic acid-co-1,8-octanediol)-cysteamine was determined to be 0.45 ± 0.07 mol NO g polymer, while the NO content for poly(citric-co-maleic acid-co-1,8-octanediol)-ethyl cysteinate was 0.16 ± 0.04 mol NO g polymer. Continuous NO release under physiological conditions was observed for at least 6 days for the cysteamine analog and 4 days for the ethyl cysteinate analog. Cell viability assays and morphological studies with human dermal fibroblasts indicated an absence of toxic leachates at a cytotoxic level, and suggested that these citrate-based polyesters may be suitable for future biomedical applications.