Nitric oxide-releasing photocrosslinked chitosan cryogels.

The highly porous morphology of chitosan cryogels, with submicrometric-sized pore cell walls, provides a large surface area which leads to fast water absorption and elevated swelling degrees. These characteristics are crucial for the applications of nitric oxide (NO) releasing biomaterials, in which the release of NO is triggered by the hydration of the material. In the present study, we report the development of chitosan cryogels (CS) with a porous structure of interconnected cells, with wall thicknesses in the range of 340-881 nm, capable of releasing NO triggered by the rapid hydration process. This property was obtained using an innovative strategy based on the functionalization of CS with two previously synthesized S-nitrosothiols: S-nitrosothioglycolic acid (TGA(SNO)) and S-nitrosomercaptosuccinic acid (MSA(SNO)). For this purpose, CS was previously methacrylated with glycidyl methacrylate and subsequently submitted to photocrosslinking and freeze-drying processes. The photocrosslinked hydrogels thus obtained were then functionalized with TGA(SNO) and MSA(SNO) in reactions mediated by carbodiimide. After functionalization, the hydrogels were frozen and freeze-dried to obtain porous S-nitrosated chitosan cryogels with high swelling capacities. Through chemiluminescence measurements, we demonstrated that CS-TGA(SNO) and CS-MSA(SNO) cryogels spontaneously release NO upon water absorption at rates of 3.34 × 10-2 nmol mg-1 min-1 and 1.27 × 10-1 nmol mg-1 min-1, respectively, opening new perspectives for the use of CS as a platform for localized NO delivery in biomedical applications.

S-Nitrosothiols as Platforms for Topical Nitric Oxide Delivery.

Nitric oxide (NO) is a small radical species involved in several fundamental physiological processes, including the control of vascular tone, the immune response and neuronal signalling. Endothelial dysfunction with the decreased NO bioavailability is the underlying cause of several diseases and has led to the development of a wide range of systemic NO donor compounds to lower the blood pressure and control hypertensive crises. However, several potential therapeutic actions of NO, not related to the cardiovascular system, demand exclusively local actions. Primary S-nitrosothiols (RSNOs) are endogenously found NO carriers and donors and have emerged as platforms for the localized delivery of NO in topical applications. Formulations for this purpose have evolved from low molecular weight RSNOs incorporated in polymeric films, hydrogels and viscous vehicles, to polymeric RSNOs where the SNO moiety is covalently bound to the polymer backbone. The biological actions displayed by these formulations include the increase in dermal vasodilation, the acceleration of wound healing, the killing of infectious microorganisms and an analgesic action against inflammatory pain. This MiniReview focuses on the state of the art of experimental topical formulations for NO delivery based on S-nitrosothiols and their potential therapeutic applications.

Thermal and photochemical nitric oxide release from S-nitrosothiols incorporated in Pluronic F127 gel: potential uses for local and controlled nitric oxide release.

The local delivery of nitric oxide (nitrogen monoxide, NO) by thermal or photochemical means to target cells or organs has a great potential in several biomedical applications, especially if the NO donors are incorporated into non-toxic viscous matrices. In this work, we have shown that the NO donors S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC) can be incorporated into F127 hydrogels, from where NO can be released thermally or photochemically (with lambda(irr)>480nm). High sensitivity differential scanning calorimetry (HSDSC) and a new spectrophotometric method, were used to characterize the micellization and the reversal thermal gelation processes of the F127 hydrogels containing NO donors, and to modulate the gelation temperatures to the range 29-32 degrees C. Spectral monitoring of the S-NO bond cleavage showed that the initial rates of thermal and photochemical NO release (ranging from 2 to 45 micromoll(-1)min(-1)) are decreased in the hydrogel matrices, relative to those obtained in aqueous solutions. This stabilization effect was assigned to a cage recombination mechanism and offers an additional advantage for the storage and handling of S-nitrosothiols. These results indicate that F127 hydrogels might be used for the thermal and photochemical delivery of NO from S-nitrosothiols to target areas in biomedical applications.