Abstract
Nitric oxide (NO) is an important biological signalling molecule that acts to vasodilate blood vessels and change the permeability of the blood vessel wall. Due to these cardiovascular actions, co-administering NO with a therapeutic could enhance drug uptake. However current NO donors are not suitable for targeted drug delivery as they systemically release NO. To overcome this limitation we report the development of a smart polymer, SMA-BmobaSNO, designed to release NO in response to a photostimulus. The polymer's NO releasing functionality is an S-nitrosothiol group that, at 10 mg ml(-1), is highly resistant to both thermal (t (1/2) 16 d) and metabolic (t (1/2) 32 h) decomposition, but rapidly brakes down under photoactivation (2700 W m(-2), halogen source) to release NO (t (1/2) 25 min). Photoresponsive NO release from SMA-BmobaSNO was confirmed in a cardiovascular preparation, where irradiation resulted in a 12-fold decrease in vasorelaxation EC50 (from 5.2 mu M to 420 nM). To demonstrate the polymer's utility for drug delivery we then used SMA-BmobaSNO to fabricate a nanoparticle containing the probe Nile Red (NR). The resulting SMA-BmobaSNO-NR nanoparticle exhibited spherical morphology (180 nm diameter) and sustained NR release (approximate to 20% over 5 d). Targeted delivery was characterised in an abdominal preparation, where photoactivation (450 W m(-2)) caused localized increases in vasodilation and blood vessel permeability, resulting in a 3-fold increase in NR uptake into photoactivated tissue. Nanoparticles fabricated from SMA-BmobaSNO therefore display highly photoresponsive NO release and can apply the Trojan Horse paradigm by using endogenous NO signalling pathways to smuggle a therapeutic cargo into target tissue.