Oxygen-Tolerant Photoredox Catalysis Triggers Nitric Oxide Release For Antibacterial Application

Nitric oxide(NO),a kind of significant signalling molecule,participates in many physiological and pathological processes,including nerve conduction,angiogenesis,immune regulation and vasodilation.It also showed tremendous therapeutic potential in the treatment of cardiovascular diseases,cancer,bacterial infection and inflammation.Light is a mildly external stimulus with non-invasive property and spatiotemporal precision which was extensively applied to triggering drug release,for instance,photoresponsive NO-releasing molecules(photoNORMs).However,photoNORMs mainly respond to ultraviolet light(UV),which is detrimental for biomedical applications due to unwanted phototoxicity and poor tissue penetration.Photoredox catalysis has been the subject of in-depth research in the last few decades and has made great progress in the synthesis of small molecules and polymers,as well as the production of pharmaceutical molecules,fine chemicals and other industrial products.Although photoredox catalysis has made great achievements in chemical synthesis,there is no precedent to trigger bioactive molecules releasing.On account of the complexity of the physiological environment,which contains a large number of bioactive molecules(e.g.oxygen),triplet excited photocatalyst would be readily quenched by oxygen.This thesis is dedicated to constructing nanomaterials which can release NO through photoredox catalysis in physiological environment and evaluating the antibacterial potential of the as-prepared nanomaterial through in vivo and in vitro experiments.Inspired by the advantage of photocatalysts that enables extending the activationirradiation wavelength of target molecules,oxygen-tolerant NO-releasing micelles triggered by photoredox catalysis were developed and showed huge therapeutic potentials in bacterial eradication and wound healing.Firstly,we synthesized UVabsorbing N,N’dinitroso-1,4-phenylenediamine-based photoNORMs(BNN-NO2 and BNN)and BNN-Me without NO-releasing moiety as a control molecule.BNN-NO2 and BNN can be activated by fac-Ir(ppy)3 photocatalyst in aerated aqueous solutions under visible light irradiation followed by NO release and quinondiimine(QDI)formation which can deplete reactive oxygen species(ROS)in situ.The self-promoed ROS depletion guaranteed photoredox catalysis operates throughout the NO-releasing process,requiring neither a prior deoxygenation process nor the addition of oxygen scavengers.We continue to copolymerize BNN-NO2/BNN monomers with hexamethylene diisocyanate,followed by end-capping with poly(ethylene glycol)methyl ether.PBNN-NO2 and PBNN amphiphilic copolymers were obtained to load fac-Ir(ppy)3 photocatalyst.The fabricated micelles(Ir@PBNN-NO2 and Ir@PBNN)successfully release NO triggered by photoredox catalysis in aerated solution.We also found Ir@PBNN-NO2 can efficiently kill Staphylococcus aureus(S.aureus),Escherichia coli(E.coli)and methicillin-resistant Staphylococcus aureus(MRSA)with the observation of cavities in microbial cell membranes and the loss of cytoplasm.Moreover,we further demonstrate that the photoredox catalysis-mediated NO release can be implemented under physiological conditions,enabling the efficient treatment of methicillin-resistant Staphylococcus aureus(MRSA) infections in vivo.