277 - Encapsulation of tDodSNO generates a nitric oxide releasing nanoparticle

Abstract

The development of drugs for the controlled delivery of therapeutic nitric oxide (NO) is an ongoing challenge. Current options include organonitrates and nitroprusside which have severe limitations to their use, with organonitrates inducing tolerance and nitroprusside releasing toxic cyanide ions. An alternative is the s-nitrosothiol drug class which breaks down to release NO; however, this NO release is normally too rapid to be therapeutically useful. The molecule tDodSNO has recently been developed as a stable s-nitrosothiol which is resistant to metabolic and thermal degradation. Its key property is that it can be selectively degraded by light, with photoactivation causing NO release. To render this s-nitrosothiol suitable for in vivo applications we report encapsulating tDodSNO within a nanoparticle consisting of a co-polymer of styrene and maleic acid (SMA). The resulting SMA-tDodSNO was fully water soluble, and the nanoparticle also further protected tDodSNO from degradation by glutathione, with a half-life increase of 24 hours. Encapsulation did not affect tDodSNO’s NO release profile, with similar NO levels (0-2 µM) recorded over a range of photoactivation levels for both tDodSNO and SMA-tDodSNO. Moving into cardiovascular activity assays, photoactivation of SMA-tDodSNO allowed controllable vasodilation of rat aortic rings, with vascular tone proportional to photoactivation. Additionally, in rat mesenteric beds, photoactivated SMA-tDodSNO induced selective hyperpermeability to macromolecules. In comparison to nitroprusside and the s-nitrosothiols GSNO and SNAP, without photoactivation SMA-tDodSNO induced vasodilation at a 40 fold higher EC50. However, upon photoactivation, SMA-tDodSNO was the only molecule to display enhanced NO release, with its EC50 decreasing to GSNO levels. This EC50 shift demonstrated that SMA-tDodSNO can be used to selectively induce NO dependent signalling by photoactivation. Future development of SMA-tDodSNO is therefore predicted to find applications for treating cardiovascular disease, as well as for enhancing the delivery of macromolecules, including antibodies and nanoconstructs, to target tissue.