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

Abstract

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)2Fe(L)2] as a chemical biology tool for controlled delivery of NO. For example, water-soluble DNIC [Fe2(μ-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 [Fe2(μ-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.

Cationic dinitrosyl iron complexes with thiourea exhibit selective toxicity to brain tumor cells in vitro

“…DNICs in free or protein bound form were proposed as a “working form” of NO under physiological conditions. 6 Bioinorganic engineering of the [Fe(NO) 2 ] unit has emerged for the development of biomimetic DNICs as a chemical biology tool for controlled delivery of NO 7 and translation of NO-related functions into biomedical applications. 8,9 Biomimetic DNICs were explored for antiaging, anti-inflammatory, antiviral and antihypertensive therapy, modulation of wound healing, penile erection and angiogenesis in diabetes, treatment of mild cognitive impairment and neurodegenerative diseases.…”

Magnetic Responsive Release of Nitric Oxide from an MOF-Derived Fe3O4@PLGA Microsphere for the Treatment of Bacteria-Infected Cutaneous Wound

“…Based on the characterization of residual MagNORM collected from the skin surface of mice, burst release of NO under AMF builds the pores on the surface of MagNORM with Fe 3 O 4 retained in the incomplete PLGA microsphere (Figure S12). That is, after the burst release of nitric oxide from MagNORM under AMF triggering the effective bactericidal activity, subsequent degradation of AMF-treated MagNORM in the skin tissue, according to the reduced diameter as 11–20 μm (Figure c, MagNORM + AMF), results in the steady and local release of NO, which accelerates the vessel regeneration and collagen formation …”

“…As shown in Table S1, long-term release of NO from the PLGA microsphere loaded with S -nitrosothiols (or diazeniumdiolates) was reported as a convenient therapeutic approach for anti-bacterial treatment and prevention on wound infection. ,,,,, In this study, encapsulation of NO-delivery DNIC-TG and ferrimagnetic Fe 3 O 4 @C in the PLGA microsphere enables the AMF as an ON/OFF switch triggering the burst release of high concentration of NO from assembled MagNORM, which reflects on the prominent bactericidal activity against acute bacteria-infected cutaneous wound. In addition to the potential synergistic effect of magnetothermal and NO-induced bactericidal activity, slow and steady release of low concentration of NO from MagNORM in the absence of the AMF promotes vessel regeneration and collagen formation. ,,, …”

Strontium Peroxide-Loaded Composite Scaffolds Capable of Generating Oxygen and Modulating Behaviors of Osteoblasts and Osteoclasts

“…MC3T3-E1 cells were seeded in 48-well plates at a density of 2.5 × 10 4 cells per well and incubated for 24 h before treatment with five SrO 2 + MnO 2 @PLGA/gelatin scaffolds for 24 h. A Cell Counting Kit-8 assay (CCK-8; IMT Formosa New Materials, Kaohsiung, Taiwan) was used to quantify cell viability [ 37 ]. Wells that contained only culture medium were used as blank wells.…”