Combined Inorganic Nanodrugs For Tumor Therapy And Overcoming Tumor Drug Resistance

As a traditional systemic method to treat cancer,chemotherapy has some advantages over other methods.However,single-drug chemotherapy is far from satisfactory for current cancer treatment.Although combination therapy improves the plight of chemotherapy to a certain degree,the difference of drugs in delivery and metabolism restricts the effect of the combination therapy.Nanoplatform not only could act as a carrier for many kinds of drugs,but also could offer a means to deliver and release the drugs controllably,which provides a new approach for combination therapy.The thesis will focus on the improvement of anticancer efficacy of combination therapy based on urgent needs of developing novel anticancer nanodrugs.We designed and synthesized a novel nanodrug loading two inorganic drugs,cisplatin(CDDP)and arsenic trioxide(ATO),simultaneously.Then we explored the application of this nanodrug in combination cancer therapy and overcoming drug resistance.The main content is as follows:Chapter 1 describes current status of cancer in brief,analyzes advantages and disadvantages of traditional chemotherapy,introduces applications of combination therapy and nanodrugs in cancer treatment,and finally expounds the topic basis and research contents of this thesis.Chapter 2 mainly introduces the design and synthesis of nanodrugs and their application in hepatocellular carcinoma(HCC)treatment.We synthesized the PtAs@PAH-DXS nanodrugs by reverse microemulsion and layer-by-layer assembling,and investigated the structure,property and anticancer effect of these nanodrugs.The nanodrugs could load CDDP and ATO with high capacity,remain stable in physiological environment,and undergo acid-triggered controllable drug release.The nanodrugs prolonged the circulation time of drugs,improved drug accumulation in tumors,increased the synergistic effect and anticancer efficacy of CDDP and ATO,enhanced the suppression of hepatocellular carcinoma tumor growth without apparent side effects.The research in chapter 2 extends the application of CDDP and ATO to hepatocellular carcinoma(HCC)treatment.Chapter 3 mainly introduces the exploration of cellular mechanism for enhanced anticancer efficacy,overcoming drug resistance of nanodrugs,and the synergy of CDDP and ATO.The nanodrugs could increase cellular DNA damage,enhance cellular apoptosis,and suppress cellular migration.Tumor drug-resistant cells usually acquire drug resistance by changing expression levels of membrane transport proteins to reduce the concentration of drugs in cells and enhancing cellular DNA damage repair to weaken anticancer efficacy of drugs.Due to the difference in cellular uptake between nanodrugs and traditional drugs,the nanodrugs were able to overcome the drug resistance induced by changes in expression levels of membrane transport proteins and increase cellular uptake of drugs.In addition,ATO inside the nanodrugs could block cellular DNA damage repair by inhibiting the activities of DNA damage repair related enzymes,generate a synergistic effect with CDDP,and therefore overcome the drug resistance induced by the enhancement of cellular DNA damage repair.The research in chapter 3 extends the potential application of nanodrugs to overcome tumor drug resistance and provides a new approach for solving the challenges in tumor drug resistance.