Injectable Hydrogels Applied In Chemo-Photothermal Therapy Of Cancer

Accurate intraoperative definition of tumor boundaries is a challenging problem in clinical application,patients with tumor lesions often suffer from recurrence and metastasis due to incomplete clearance of tumor cells.On the other hand,postoperative wound tissue is very fragile,often easy to accumulate a lot of tissue fluid,thus breeding bacteria,causing a more serious inflammatory reaction.In view of these defects such as high risk of cancer clinical surgery,easy bleeding,easy infection,easy recurrence,and difficult adhesion and embedding due to irregular surgical wounds,this paper proposes an innovative idea of using injectable high adhesion hydrogel for postoperative chemo-photothermal therapy to prevent tumor regeneration.Inspired by mussels,gallic acid with catecholoid structure and chitosan,a natural antibacterial hemostatic material with positive charge on the surface,were selected as raw materials in this paper.Chitosan crosslinked gallic acid?CSG?precursor was prepared through soluble modification of chitosan by gallic acid.DOX was loaded on CSG precursor and then bound with Fe³⁺,so as to obtain injectable CSG/Fe³⁺hydrogel with adhesion,antibacterial,hemostasis,anti-inflammatory,and anti-tumor properties.In addition,the abnormal tumor vasculature and increased interstitial fluid pressure in solid tumor tissues are the main obstacles to the entry of chemotherapy drugs into tumor.By injecting injectable hydrogels directly into the tumor site,the efficiency of chemotherapy can be improved while the systemic side effects can be reduced.Hydrogels formed by hydrophilic macromolecules through certain chemical or physical crosslinks are considered as effective carriers of such therapeutic drugs.However,molecular hydrogels still have weaknesses at present such as weak ability to control drug release,slow release of drugs at low concentrations,and susceptibility to drug resistance in tumors,which limit their clinical application.Aiming at the problems of complex synthesis,crosslinking agent introduction and controllability of molecular hydrogels,a homogeneous injectable hydrogels was prepared based on the charge reversal of nanoparticles induced by solution pH.This method is suitable for the treatment of malignant tumors in different locations,and the construction materials used are biocompatible and biodegradable materials,which has a good clinical application prospect.The main contents and results of this dissertation are described in two parts as below:1)CSG precursors were prepared by a simple amide reaction between chiotsan and gallic acid,which showed good biocompatibility,anti-tumor,anti-inflammation and anti-bacterial activity.Further,we synthesized CSG/Fe³⁺hydrogel,which has good cellular biocompatibility and self-healing performance.The hydrogel has a swelling rate of 200%in a phosphate buffer under pH of 6.Through the shear lap test of the tissue adhesive,the tissue adhesion strength of the wetting state reached 7.2 Kpa.The hemostatic property of rat liver was proved to be superior.CSG precursors were dissolved in DOX aqueous solution and then chelate with Fe³⁺to obtain an anti-tumor sustained-release implant with strong tissue adhesion and hemostasis function.We verified its ability to cure tumors by thermochemotherapy combined with chemotherapy in mouse 4T1 tumor model.2)Injectable and colloidal hydrogel composed of amphoteric gelatin nanoparticles?Gela NPs?and polydopamine nanoparticles?PDA NPs?was developed here to realize multi-stimuli?such as acidic pH,enzymes and near infrared light?responsive drug delivery properties and combined chemo-photothermal cancer treatment.Upon the decomposition of glucono delta-lactone,the system pH would decrease below the isoelectric point of Gela NPs and then the charge reversal of Gela NPs could induce the formation of uniform hydrogel.The optimized hydrogel with varied composition showed good viscoelasticity and self-healing performances,as well as excellent biocompatibility for implantation.When irradiation with near infrared light,the DOX-loaded colloidal hydrogel exhibited synergistic cell-killing effect,indicating their good potential for therapeutic applications.