Construction Of Smart Hydrogel Carrier With Controllable Release Of NO And Its Biological Application

Nitric oxide(NO),as an important gas messenger molecule,is not only closely related to the occurrence,development and apoptosis of tumors,but also to wound healing.Nowadays,the application of NO in cancer treatment and wound healing has become one of the research hotspots in the field of biomedicine.Although NO has important application prospects in the above research fields,its application is greatly limited by its short half-life and easy diffusion.Therefore,it is of great significance to develop a donor system with good biocompatibility,good stability and controlled release of NO for cancer treatment and wound healing.Based on the above problems,an injectable Smart hydrogel which responds to the tumor microenvironment and wound inflammation was constructed to promote wound healing by synergistic treatment of tumors and bacteriostasis.In this paper,the hydrogel materials were prepared by chemical crosslinking of polyvinyl alcohol(PVA)aqueous solution and boric acid precursor(TSPBA)aqueous solution.Specifically,the following two works were carried out in this paper.(1)Tumor Microenvironment Responsive Hydrogel for Controlled NO Release and Combined Tumor TherapyIn this part of the work,a 10% PVA aqueous solution and a 10% TSPBA aqueous solution were first mixed into a gel,which were characterized by scanning electron microscopy and nuclear magnetic resonance spectroscopy.The chemotherapeutic drug and the endogenous NO donor L-arginine(L-Arg)were then loaded in the hydrogel,and the drug release and NO release were tested.Finally,the results of in vivo evaluation showed that the combination treatment method inhibited tumor growth and prolonged the survival period of mice.(2)Smart Hydrogel with Controllable NO Release for Bacteriostasis and Wound HealingIn this part of the work,the endogenous NO donor L-Arg was coated in the hydrogel.First,the absorption of exudate from the wound site by the hydrogel was investigated by Blood Clotting Index(BCI)experiment.The antibacterial properties of the hydrogel dressings were investigated by turbidity method and plate counting method respectively,and the combined treatment group showed excellent antibacterial properties.In order to explore the potential of the hydrogel dressing in vivo,MTT test,live/dead cell staining test and skin sensitivity test were carried out respectively.The experimental results show that the smart hydrogel dressing has high biosafety.In the mouse wound model experiment,the effect of the smart hydrogel on wound healing was evaluated by measuring growth factor expression,Hematoxylin-eosin staining(H&E),Masson staining,CD31 immunofluorescence staining and F4/80 immunofluorescence staining.To sum up,this study used ROS responsive smart hydrogel to encapsulate endogenous LArg donors,which improved the short half-life and easy diffusion of NO,and applied them in combination therapy of tumor and bacteriostasis to promote wound healing.Combined treatment not only significantly inhibited tumor growth in tumor bearing mice,but also accelerated the expression of transforming growth factor(TGF-?1),neovascularization and macrophages in wound sites in mice,which significantly promoted wound healing.In this study,a combination therapy strategy was proposed,which could inhibit tumor growth and promote wound healing through smart hydrogel encapsulated endogenous NO donor.It may provide a theoretical basis for clinical treatment.