Nanomedicine And Dietary Restriction Adjuvant Therapy For Tumor Metastasis-related Autophagy Regulation

Cancer has long been one of the major diseases that seriously threaten human life and health.The traditional cancer treatment methods are surgery,chemotherapy and radiotherapy,etc.The new cancer treatment methods include hormone therapy,phototherapy,nano catalytic therapy and immunotherapy.Nanomaterials have the advantages of high specific surface area,biofunctionalizable modification and high biosafety,which can effectively improve drug utilization efficiency,enhance drug targeting and reduce toxic side effects,and play a great role in improving the treatment of various cancers.In this thesis,we addressed the need for carrier and efficacy optimization of nanomaterials applied in tumor therapy,screened suitable polymeric carrier sizes,and developed nanodiamond-arsenic trioxide combination therapy to inhibit solid tumor growth and metastasis.Based on this,an optimized intermittent dietrestricted adjuvant therapy was proposed,and the mechanism of autophagy-regulated anti-tumor was explored.The work is specified as follows:(1)PLGA particle size-dependent cellular uptake and sustained drug releasePoly(lactic acid-hydroxyacetic acid)(PLGA),a polymeric carrier that is widely used for drug delivery and sustained release.Dexamethasone(DEX)is a waterinsoluble drug,and we prepared PLGA particles(DPs)loaded with DEX,ranging in size from submicron to micron,using an emulsification method and systematically compared the cellular uptake,intracellular sustained release and anti-inflammatory effects of the drug particles.The 200 nm DPs were found to have the highest uptake but lower drug encapsulation,while the 2000 nm DPs had the highest drug encapsulation but lower cellular uptake,thus affecting the anti-inflammatory effects of both.In contrast,the drug encapsulation rate and cellular uptake of 500 nm DPs are relatively high,which can achieve slow release and therefore not only achieve the best antiinflammatory effect in the short term,but also continue to exert significant antiinflammatory effects after drug discontinuation.(2)Nanodiamond combined with arsenic trioxide for anti-tumor metastasis studyArsenic trioxide(ATO)is a clinical agent for the treatment of acute promyelocytic leukemia,but drug resistance can occur when treating solid tumors.Our previous study found that ATO alone has limited efficacy in treating solid tumors and also induces metastasis in solid tumors of hepatocellular carcinoma.When administered in combination with NDs,it not only improved the therapeutic efficacy but also significantly inhibited distal tumor metastasis.By exploring the mechanism at the tissue level and verifying the mechanism at the cellular level,it was found that NDs combination treatment blocked cellular autophagy and inactivated the metastasisrelated signaling pathway TGF-β/Smad3,thus reversing the cellular metastasis process of epithelial-mesenchymal transition and reducing tumor metastasis.The NDs+ATO combination strategy demonstrated its good tumor growth inhibition and anti-tumor metastasis effect,and during the administration cycle within the administration cycle,100% of mice in the treatment group survived,showing good prospects for clinical application.(3)Intermittent dietary restriction adjuvant therapy inhibits the growth and mechanism of triple negative breast cancerDiet restriction is a new green,convenient and convenient anti-tumor method.We designed four diet restriction regimens: arbitrary diet AL group,daily 50% diet restriction DR group,alternate day fasting ADF group and alternate day 50% diet restriction ADR group,which were administered on normal nude mice for safety testing.We compared the body weight,survival,liver and kidney function indices and changes in body elements of each group of nude mice,and found that the average body weight of ADR group was normal,survival was not affected,liver and kidney function indices were maintained in a normal range as AL,and the distribution of important elements in the body in liver and kidney remained unchanged,indicating that the ADR regimen was safe and feasible.Subsequently,we used the green and safe ADR diet regimen in a study of the antitumor effects of triple-negative breast carcinoma in situ.We found that ADR treatment achieved effective inhibition of triple-negative breast cancer growth with a65% tumor suppression rate,which in turn effectively prolonged the life span of triplenegative breast cancer mice.Further investigation of the molecular mechanism revealed that this may be related to autophagic death of tumor cells induced by ADR treatment.The developed ADR intermittent diet restriction adjuvant therapy provides the basis for subsequent combination with other drugs to completely cure this tumor.