Construction Of The Nanosystem Based On Tumor Microenvironment Response And The Therapeutic Application In Breast Cancer

Tumors are the result of different pathological factors.The complex tumor microenvironment(TME)promotes tumor progression and develops therapeutic resistance.Various modalities have been investigated for antitumor therapy,such as surgical resection,targeted drug delivery,specific chemotherapy and radiation therapy.However,cancer treatment still faces many difficulties due to the limitations of different treatment modalities and the heterogeneity of tumors.With the advancement of nanotechnology,nanomedical engineering-based therapeutic modalities have been skillfully applied to antitumor treatment to provide stronger therapeutic effects.In this dissertation,nano-formulations based on responsive TME were designed for breast cancer treatment as follows.1.Based on the TME of hypoxia and acidosis,a design of pH-responsive nano-drug delivery system was provided to enhance the anti-tumor effects by reducing the adaptation of tumor cells to the microenvironment.To alleviate the adaptation to the TME,hollow polydopamine(HPDA)with high biocompatibility and low cytotoxicity was selected as the carrier,and the pH gradient inside and outside the tumor cell membrane was reversed by modifying carbonic anhydrase Ⅸ(CAIX)inhibitor on the surface of HPDA.The phosphatidylinositol-3 kinase/mammalian target of rapamycin(PI3K/mTOR)inhibitor BEZ235 and Chlorin e6(Ce6)were loaded inside HPDA,and the reduction of hypoxia-inducible factor-1 alpha(HIF-1α)expression was achieved by intracellular acidification in combination with BEZ235.The experimental results confirmed that the customized nano-loading system was able to successfully accumulate in tumor tissues through enhanced permeability and retention(EPR)effect after tail vein injection,while enhancing the anti-tumor effects.2.The nanoformulation PCN(Fe)-Cu-HA-DQ(PFCHD)was designed in response to H2O2 in tumors.Diethyldithiocarbamate(DTC)is an anticancer metabolite of disulfiram.Firstly,DTC prodrug DQ was synthesized,which responded to H2O2 and then released DTC and quinone methide(QM).DTC chelated Cu2+to generate Cu(DTC)2 with high anticancer activity and the released QM worked as a glutathione(GSH)scavenger to inhibit GSH-mediated ROS elimination in cancer cells.Then,PCN(Fe)was used as a carrier to modify Cu2+,hyaluronic acid and DQ to synthesize PFCHD.PFCHD induced increased production of reactive oxygen species(ROS),which in combination with chemotherapy,activated caspase-3 to induce gasdermin E(GSDME)-dependent pyroptosis and facilitated the release of inflammatory factor interleukin-18(IL-18)leading to immune activation of the organism.Finally,PFCHD combined with anti-programmed cell death protein 1(PD-1)antibody to promote increased cytokine secretion.This H2O2-responsive nano-drug delivery system,based on the characteristics of the TME,provided a reference strategy for drug delivery with certain potential applications.In this dissertation,we designed and synthesized nanomaterials based on the microenvironmental characteristics of hypoxia,acidosis and the presence of reactive oxygen species in tumors,and validated their biological applications in breast cancer.Both nano-drug delivery systems exhibited significant biological effects with excellent biocompatibility as well as low off-tumor toxicity,providing a research direction to explore breast cancer treatment in some extent.