Hydrogen Sulfide-Responsive Bicontinuous Nanospheres

Block copolymers (BCPs) that can self-assemble into particles and be triggered by disease-specific molecules such as hydrogen sulfide (H₂S) have the potential to impact on drug delivery, decreasing off-target toxicities while increasing drug efficacy. However, the incorporation of H₂S-responsive aryl azides into BCPs for self-assembly has been limited by heat, light, and radical sensitivities. In this study, a robust activator regenerated by the electron-transfer atom-transfer radical polymerization reaction was used to synthesize aryl-azide-containing BCPs under ambient conditions. Conditions controlling self-assembly of the BCPs into 150-200 nm particles and the physicochemical properties of the particles were investigated. The use of nanoprecipitation with tetrahydrofuran to promote self-assembly of the BCPs resulted in vesicle structures, while dimethylformamide or dimethylsulfoxide resulted in polymeric bicontinuous nanospheres (BCNs). Triggering of the BCPs and particles (vesicles or BCNs) via exposure to H₂S revealed that unsubstituted aryl azides were readily reduced (by HS^-), resulting in particle disruption or cross-linking. The relative polar nature of the particle bilayers containing unsubstituted aryl azides and the open structure of the BCNs did however limit encapsulation of small hydrophilic and hydrophobic payloads. Incorporation of a benzylamide substituent onto the aryl azide group increased the hydrophobicity of the particles and encapsulation of hydrophilic cargo but reduced sensitivity to H₂S, likely due to the reduced penetration of HS^- into the bilayer.