| Cancer is one of the major diseases threatening human life and health.Currently,there are clinical therapeutic strategies such as surgery,radiotherapy,immunotherapy and chemotherapy,among which chemotherapy is the most basic cancer treatment,but it faces scientific problems such as low treatment efficiency,strong toxic and side effects.This is mainly attributed to the low stability,low drug solubility and bioavailability,low pharmacological and pharmacodynamic parameters,low delivery efficiency,non-specific distribution/lack of specificity(unintended off-target effects),accumulation in normal tissues and organs(such as liver and spleen),and high systemic toxicity due to immune stimulation.In order to improve the therapeutic efficacy of chemotherapy,multiple biological obstacles in drug delivery must be overcome,such as lack of targeting to specific physiological sites,low cell uptake efficiency and poor escape from the endosome.The nanotechnology based drug delivery system can effectively improve the biological distribution of drugs,endow chemotherapy drugs with high loading capacity,long blood circulation,good solid tumor enhanced permeability and retention effect(EPR effect),achieve controllable targeting of drugs to cancer cells that need their activity,and minimize the damage to normal cell activities.Therefore,chemotherapeutic drugs are often used as "base drugs" for different delivery systems,combined with different "formulations" to evaluate the efficacy and efficiency of the new system,improve the therapeutic effect of chemotherapy,and reduce the dose restriction and cardiotoxicity associated with the drug.In this dissertation,starting from the construction of chemotherapy drug delivery system,and aimed to achieve controlled drug release in response to tumor microenvironment and improve drug therapeutic effect.Two drug delivery system of chemotherapy were designed and constructed,with specific contents as follows:(1)In response to the high concentration of glutathione(GSH)in tumor microenvironment,a class of GSH-responsive prodrug nanogel(HHNP)was designed to enhance tumor chemotherapy.The 10-hydroxycamptothecin(HCPT)in HHNP was the key building block in apoptosis of cancer cells.Through covalent cross-linking of hydroxyl group and cross-linker containing disulfide bond,and cross-linking aminosylated polyethylene glycol for surface modification,HHNP nanogel with outstanding water dispersion and nanometer size,which significantly prolongated the half-life of the drug.Moreover,HHNP can be highly enriched to the tumor tissue and can be retained for a long time,thus realized the controlled release of HCPT drugs.HHNP nanogel strategy can effectively preserve the biological activity of drugs,introduce passive targeting,stimulus response release,biometabolizable and other functions,significantly improve the therapeutic efficiency of drugs,and reduce their toxic and side effects,providing a new enlightenment for the construction of an efficient drug delivery platform.(2)In order to further improve the therapeutic efficiency of chemotherapy,a supramolecular assembly(DAS@CD-Ox Pt NPs)has been constructed to exhibit additive or synergistic antitumor efficacy by conjugated the chemotherapeutic drug oxaliplatin(Ox Pt)to beta-cyclodextrin(β-CD)and supramolecular assembly with the guest molecule Dasatinib(DAS).The experiment showed that DAS@CD-Ox Pt NPs has glorious blood compatibility and long blood circulation.In addition,the acidic tumor cell microenvironment can destroy the host and guest force of the assembly,control the release of DAS molecules,and restore the high expression of p53 in the cell.Meanwhile,high concentration of GSH in the tumor cells reduced the low-toxicity CD-Ox Pt(IV)prodrug to the highly toxic Ox Pt(Ⅱ)molecular form,induced double damage of DNA in the cell.And enhanced chemotherapy was achieved in mouse CT26 colon cancer model.This supramolecular assembly can effectively enhance the effect of chemotherapy and has a broad application prospect. |
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