Syntheses And Biological Applications Of Carbon Monoxide/Nitric Oxide Regulating Polymer Materials

Recent evidences have established the major roles for Carbon monoxide(CO)and Nitric oxide(NO)as gasotransmitters.They are essential for maintaining a balance between physiological and pathological functions in mammalian tissues.CO displays many physiological functions including anti-inflammatory,anti-apoptotic and accelerating wound healing.NO shares several common properties including cardioprotective and immune systems.They are beneficial at low concentrations but hazardous in higher amounts.A variety of CO-releasing molecules(CORMs)have been developed,which are primarily categorized into metal carbonyls and nonmetallic CORMs.Metal carbonyls have been the most extensively investigated CORMs,while recent studies discovered that they are unstable in PBS buffer and cell culture media.Notably,nonmetallic CORMs are receiving increasing attention.Most of CORMs are sensitive to ultraviolet(UV)irradiation,so it would be necessary to activate photoCORMs under long-wavelength illumination with decreased phototoxicity.Overproduction of NO has been associated with several diseases,and a reasonable treatment is to scavenge excess NO,for which a few NO scavenger molecules have been developed.In this paper,we focus on preparation of NO scavenger polymer material and photoresponsive CO-releasing polymers.The biological applications of these materials include accelerating wound healing,treatment of rheumatoid arthritis and antibacterial been clarified.The specific content can be divided into the following three parts:(1)Metal-free carbon monoxide-releasing micelles undergoing tandem photochemical reactions were developed for cutaneous wound healing.The development of carbon monoxide(CO)-releasing polymers(CORPs)can increase the stability,optimize pharmacokinetic behavior,and reduce the side effects of small molecule precursors.We fabricated metal-free CO releasing polymers based on photoresponsive 3-hydroxyflavone(3-HF)derivatives in a direct polymerization strategy.Such CO releasing amphiphiles self-assemble into micelles,having excellent water-dispersity.Photo-triggered tandem photochemical reactions confer successive fluorescence transitions from blue-to-red-to-colorless,enabling self-reporting CO release in vitro and in vivo.More importantly,the localized CO delivery of CORPs by taking advantage of the spatiotemporal control of light stimulus outperformed conventional metal carbonyls such as CORMs in terms of anti-inflammation and cutaneous wound healing.This work opens a novel avenue toward metal-free CORPs for potential biomedical applications.(2)Fabricated breathing micelles for combinatorial treatment of rheumatoid arthritis.Breathing process involves inhalation and exhalation of different gases in animals.The gas exchange of the breathing process plays a critical role in maintaining the physiological functions of living organisms.Although artificial breathing materials exhibiting volume expansion and contraction upon alternate exposuring to different gases have been well explored,those being able to realize the gas exchange remain elusive.Herein,we report breathing micelles(BM)capable of inhaling nitric oxide(NO)and exhaling carbon monoxide(CO),both of which are endogenous gaseous signaling molecules.We demonstrate that BM can simultaneously scavenge overproduced NO and attenuate proinflammatory cytokines in lipopolysaccharide(LPS)-challenged macrophage cells.In vivo studies revealed that BM outperformed conventional nonsteroidal anti-inflammatory drugs such as dexamethasone(Dexa)in treatment of rheumatoid arthritis(RA)in adjuvant-induced arthritis(AIA)rats,likely due to the combinatorial effect of NO depletion,CO-mediated deactivation of inducible NO synthase(iNOS)and activation of heme oxygenase-1(HO-1).This work provides new insights into artificial BM for potential biomedical applications.(3)Red light-triggered carbon monoxide releasing system was developed for selective eradication of Methicillin-resistant Staphylococcus aureus(MRSA)infection.The use of metal carbonyls CO-releasing molecules enables the elucidation of the pleiotropic functions of CO.Although metal carbonyls show a broadspectrum antimicrobial activity,it remains unclear whether the bactericidal property originates from the transition metals or the released CO.Here,we develop nonmetallic COreleasing micelles via a photooxygenation mechanism of 3-hydroxyflavone derivatives,enabling CO release under 650 nm irradiation.Unlike metal carbonyls that nonspecifically internalize into both Gram-positive and Gram-negative bacteria,the nonmetallic micelles are selectively taken up by S.aureus instead of E.coli cells,exerting a selective bactericidal effect.Further,we demonstrate that the CO-releasing micelles can cure MRSA infected wounds,simultaneously eradicating MRSA pathogens and accelerating wound healing.