Photo-responsive Injectable Hydrogel For Starvation Therapy Of Triple Negative Breast Cancer

Triple-negative breast cancer(TNBC)has been recognized as the most malignant type of breast cancer.Although there are various treatment modes such as surgery,chemotherapy,radiotherapy and targeted therapy,the effect is still not ideal.Postoperative recurrence(including the regeneration of the primary tumor)and distant metastasis caused by residual tumor cells are still problems for clinicians.It is well known that tumor growth and metastasis are based on tumor blood vessels.The abundant blood vessels of tumor tissue not only provide nutrients for its growth,invasion and metastasis,but also provide a way for the transportation and metastasis of tumor cells.In recent years,the emerging starvation therapy has found a more effective treatment method for tumor therapy,preventing recurrence and metastasis,which is mainly realized by inhibiting tumor angiogenesis,blocking the supply of nutrients with tumor blood vessels and inhibiting the supply of metabolic nutrients.However,existing studies have shown that after blocking tumor cells' nutrient access or metabolic pathways,tumor cells maintain growth through other "surrogate" stress pathways and even metastasize to distant organs.Therefore,it is difficult to achieve an ideal therapeutic effect if the starvation treatment strategy only blocks a single nutrient supply pathway.Seeking a starvation treatment method that can simultaneously inhibit multiple metabolic pathways and combining with other treatment methods is an effective strategy to improve the efficacy of starvation treatment and prevent TNBC recurrence and metastasis.In this thesis,a photoresponsive injectable hydrogel was constructed by using dopamine crosslinked collagen/silk fibroin composite.In the constructed system,dopamine could self-assemble to form polydopamine,which was a reagent in photothermal therapy.At the same time,polydopamine could also react with amino groups on the protein to accelerate the formation of hydrogel.The short chain nucleic acid loaded the thrombin into the hydrogel in a complementary and paired manner.On the one hand,the heat released by the hydrogel after near-infrared light irradiation can open the hydrogen bond between double-stranded nucleic acids,realize the precise and controlled release of thrombin,promote the formation of thrombus in the blood vessels around the tumor,and cut off the supply of nutrients.On the other hand,it can inhibit the activity of tumor cells,making them unable to secrete the chemical signals that promote angiogenesis,thus inhibiting the formation of tumor blood vessels.Therefore,from the perspective of inhibiting angiogenesis and destroying its existence,the hydrogel composite system can completely block the nutritional pathway of tumor growth or metastasis from both sides.In vivo and in vitro studies showed that the hydrogel composite system could rapidly heat up to 52.9 °C after NIR illumination.Transwell experiment confirmed that photothermal therapy could effectively inhibit the invasion of tumor cells.ELISA assay,matrigel tube formation assay and immunohistochemical assay of mouse tumor tissue proved that the tumor cells were killed by the hydrogel with NIR light,less VEGF was secreted to result in fewer blood vessels formation.At the same time,through the use of BCA protein quantification kit and thrombin fluorescence substrate to determine the activity of thrombin and the H&E staining of tissues surrounding tumors,it was confirmed that thrombin can be rapidly released to block the blood vessels around the tumor.This two-pronged approach effectively inhibits TNBC recurrence and metastasis,providing a new approach and method for the starvation therapy of triple negative breast cancer.