Speaker
Description
NO is a free radical molecule synthesized by nitric oxide synthase (NOS) in the process of converting L-arginine to L-citrulline in cells. It has various physiological roles in the body, depending on the concentration of NO. Low concentrations of NO are involved in vasodilation and serve as cellular signal transduction. In contrast, at relatively high concentrations of NO, it is known to be involved in immune regulation and tissue destruction by reacting with reactive oxygen species. Preliminary results have revealed the potential of NO for BBB disruption, although its mechanism has not been clearly demonstrated. In addition, its practical application has been limited owing to the poor stability and uncontrollability of the release of NO. Therefore, a stimuli-responsive and on-demand NO-delivery system is a prerequisite for the transport of therapeutic agents through the BBB.
In this study, we report the design of a multifunctional system comprised of NO-releasing N,N′-di-sec-butyl-N,N′-dinitroso-1,4-phenylenediamine (BNN6) and piezoelectric barium titanate nanoparticle (BTNP) coated with polydopamine (pDA). The nanoparticles can generate both NO and direct current only in response to ultrasound. We investigated the ultrasound-responsive NO-releasing profile of the nanoparticle and its NO-mediated BBB opening, as well as the mechanism of BBB opening by NO. We verified the crucial role and the mechanism of NO-mediated temporary BBB opening, and show that the piezoelectric nanoparticles can alleviate the symptoms of Parkinson’s disease in the animals.
NO is also involved in the immune response in rheumatoid arthritis (RA). Therefore, selective depletion of overproduced NO with nanoscavengers is a promising approach for treating RA, preventing both oxidative/nitrosative stress and the upregulation of immune cells. However, its practical applications are limited owing to the minimum time interval between intra-articular injections and unwanted off-target NO depletion. Herein, we report the rational design of an injectable in situ polymeric aggregate-embodied hybrid NO-scavenging and sequential drug-releasing gel platform for the combinatorial treatment of RA by incorporating a “clickable” NO-cleavable cross-linker. This network is held together with polymeric aggregates to achieve a self-healing capability for visco-supplementation and on-demand dual drug-releasing properties, depending on the NO concentration. Moreover, consecutive NO-scavenging action reduces pro-inflammatory cytokine levels in LPS-stimulated macrophage cell lines in vitro. Finally, the intra-articularly injected M-NO gel with anti-inflammatory dexamethasone significantly alleviated the symptoms of RA, with negligible toxicity, in animal models.
References
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| Keywords | Nitric oxide donor/scavenger, multifunctional system |
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