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Mechanisms of S-nitrosothiols intestinal permeability and NO store formation within vascular wall to improve NO oral delivery systems

Abstract : S-nitrosothiols (RSNOs) such as S-nitrosoglutathione (GSNO) are promising nitric oxide (NO) donors for cardiovascular diseases treatment. However, they are poorly stable drug candidates. In previous studies, GSNO-loaded nanoparticles (GSNO-NP) were embedded into an alginate/chitosan matrix. Resulting nanocomposite particles showed high encapsulation and sustained release of GSNO, and led to the formation of a NO store in the wall of aorta after a single oral administration to rats. However, these nanocomposite particles have several limitations such as time-consuming preparation, lack of both stability and reproducibility. This thesis work aimed at: 1) Elucidate the mechanism of free RSNOs intestinal absorption; 2) Evaluate ability of free RSNOs to form a vascular NO store; 3) Optimize the GSNO formulation. In this study, we showed that the intestinal permeability (in vitro model of intestinal barrier) of GSNO, S-nitroso-N-acetylcysteine (NACNO) and S-nitroso-N-acetylpenicillamine (SNAP) was a passive diffusion, following the transcellular pathway (and also the paracellular way for SNAP) and belonging to the medium permeability class. After crossing the intestinal barrier, RSNOs will reach the vasculature. In order to compare the ability of free RSNOs to form a vascular store of NO either in endothelium-intact or endothelium-removed aortae, we quantified the store, verified its bioavailability for vasorelaxation and evaluated its impact on phenylephrine (PHE)-induced vasoconstriction. Incubation with RSNOs increased the basal NO store three to five times. This store is still bioavailable to induce vasorelaxation and efficient to induce vascular hyporeactivity to PHE (NACNO> GSNO = SNAP) only in endothelium-removed aortae. As intestinal permeability of RSNOs was in the medium class, the integration of GSNO into an appropriate delivery system is essential. Limitations of previously developed nanocomposites particles were impossible to bypass so the production process of GSNO-NP was modified (liquid or solid GSNO in the internal phase of the emulsion) to produce microparticles. Both kinds of microparticles exhibited a slower release of GSNO than GSNO-NP. Nano-and micro-particles were stable after lyophilization and presented an enhancement of GSNO intestinal permeability (up to high permeability class for microparticles). Thus, oral administration of GSNO/RSNO loaded nano/micro particles seems to be a promising avenue for the treatment of cardiovascular diseases.
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Submitted on : Wednesday, December 4, 2019 - 5:35:07 PM
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Yi Zhou. Mechanisms of S-nitrosothiols intestinal permeability and NO store formation within vascular wall to improve NO oral delivery systems. Pharmaceutical sciences. Université de Lorraine, 2019. English. ⟨NNT : 2019LORR0101⟩. ⟨tel-02394442⟩



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