Cell-Penetrating Delivery of Nitric Oxide by Biocompatible Dinitrosyl Iron Complex and Its Dermato-Physiological Implications

After the discovery of endogenous dinitrosyl iron complexes (DNICs) as a potential biological equivalent of nitric oxide (NO), bioinorganic engineering of [Fe(NO)(2)] unit has emerged to develop biomimetic DNICs [(NO)(2)Fe(L)(2)] as a chemical biology tool for controlled delivery of NO. For example, water-soluble DNIC [Fe-2(mu-SCH2CH2OH)(2)(NO)(4)] (DNIC-1) was explored for oral delivery of NO to the brain and for the activation of hippocampal neurogenesis. However, the kinetics and mechanism for cellular uptake and intracellular release of NO, as well as the biocompatibility of synthetic DNICs, remain elusive. Prompted by the potential application of NO to dermato-physiological regulations, in this study, cellular uptake and intracellular delivery of DNIC [Fe-2(mu-SCH2CH2COOH)(2)(NO)(4)] (DNIC-2) and its regulatory effect/biocompatibility toward epidermal cells were investigated. Upon the treatment of DNIC-2 to human fibroblast cells, cellular uptake of DNIC-2 followed by transformation into protein-bound DNICs occur to trigger the intracellular release of NO with a half-life of 1.8 +/- 0.2 h. As opposed to the burst release of extracellular NO from diethylamine NONOate (DEANO), the cell-penetrating nature of DNIC-2 rationalizes its overwhelming efficacy for intracellular delivery of NO. Moreover, NO-delivery DNIC-2 can regulate cell proliferation, accelerate wound healing, and enhance the deposition of collagen in human fibroblast cells. Based on the in vitro and in vivo biocompatibility evaluation, biocompatible DNIC-2 holds the potential to be a novel active ingredient for skincare products.

Automated summary

The study investigated the cellular uptake, intracellular release, and regulatory effects of a compound DNIC-2 on epidermal cells. The results showed that DNIC-2 can be taken up by human fibroblast cells, transformed into protein-bound forms, and release NO intracellularly, leading to enhanced cellular proliferation, accelerated wound healing, and increased collagen deposition. The biocompatible DNIC-2 holds potential to be a novel active ingredient for skincare products based on in vitro and in vivo biocompatibility evaluation.