Thermosensitive Injectable Composite Hydrogels Enhancing The Photothermal Therapy And Interventional Embolization Therapy For Tumors

Photothermal therapy（PTT）and transcatheter arterial embolization（TAE）therapy,as two minimally invasive therapies,have the advantages of low side effects,high specificity and significant efficacy.However,further improvements and applications of these therapies are hindered by some problems.For example,the PTT is unable to activate effective anti-tumor immune responses,lacking hydrophilic carbon base NIR-Ⅱphotothermal materials.Besides,PTT is liable to cause bacterial infection of wound.Additionally,there is the contradiction between"firm embolization"and"hypoxic response"in TAE therapy for tumor.Among a large number of materials for treating tumor,injectable thermosensitive hydrogels are competitive due to the good histocompatibility,easy to be modified and have a temperature responsive sol-gel phase transition to achieve lasting therapeutic effects in tumor tissues or vessels.Based on these,this thesis has developed a variety of temperature-sensitive injectable composite hydrogels to overcome the above problems in PTT and TAE therapy for tumor to improve the therapeutic effects.The main contents and results of this dissertation are as follows:（1）A photothermal reagent Mn O₂ nanoparticles（NPs）loaded poly（N-isopropylacrylamide-co-dopamine methacrylamide）（PND）nanogel（Mn O₂@PND）was developed to solve the problem that the antigens in photothermal immunotherapy are easy to be cleared and quickly to induce insufficient immune activation,based on the strong protein adhesion ability of catechol groups in mussel-inspired material,.The aqueous dispersion of the Mn O₂@PND nanogels(100 mg m L^-1)underwent a sol-gel phase transition at～30℃.Moreover,this injectable hydrogel effectively killed tumor cells by its photothermal property,as well as induced the immunogenic cell death of tumor cells,and captured tumor antigens to recruit dendritic cells（DCs）and stimulate DCs to become mature.After intra-tumoral injection,under the irradiation of 808 nm laser,the Mn O₂@PND injectable hydrogel effectively removed the unilateral tumor,inhibited the growth of distal tumor and rechallenged tumor of the mice,and stimulated a systemic anti-tumor immune response.（2）The edge-hydroxylated graphene（EHG）,with good water dispersibility and complete plane conjugate structure,was used as a NIR-II photothermal materials to prepare the injectable EHG@PND composite hydrogel.This hydrogel performed a good photothermal effect under the irradiation of 1064 nm laser,which effectively killed tumor cells in vitro and in vivo.Moreover,the PTT based on the injectable EHG@PND hydrogel significantly inhibited the growth of the distal tumor,and promoted an effectively activated systemic anti-tumor immune response.（3）Based on the good photothermal property and antibacterial effects of the"iodine-starch"complex structure,poly（N-isopropylacrylamide）-g-starch nanogels containing"iodine-starch"composite structure（PNSI）was prepared.The injectable hydrogel derived from PNSI nanogels aqueous dispersion could kill tumor cells in vitro due to its good photothermal effect,and inhibit the growth of bacterial by releasing iodine.In animal experiment,this PNSI hydrogel not only ablated tumor of the mice,but also inhibited the bacterial infection,and promoted wound healing.（4）Based on the strong adhesive ability of mussel-inspired PND hydrogel and Fenton-like effect of Mn²⁺on H₂O₂,the adhesive thermosensitive injectable PND hydrogel containing Mn²⁺（PNDM）was prepared,which could firmly occlude the tumor vessels and inhibit hypoxic response.The PNDM injectable hydrogel was easy to be injected at room temperature,and rapidly transformed to hydrogel in situ at physiological temperature to achieve firm and durable occlusion of vessels.In addition,this PNDM injectable hydrogel decreased the intracellular ROS,and down-regulated the expression of hypoxic responses related proteins include HIF-1αand VEGF by consuming extracellular H₂O₂.Thus,the pathway of tumor hypoxic responses was suppressed,and the therapeutic effect of TAE were promoted.