Preparation And Study On Reversing Tumor Drug Resistance Of Plantinum Drug Nanoparticle Delivery System

Malignant tumors,also known as cancer,currently have three major treatments for malignant tumors,namely chemotherapy,radiotherapy,and surgical resection.Also,for ovarian cancer and breast cancer,the conventional treatments are surgery,chemotherapy,and rare radiotherapy.However,primary and secondary resistance to chemotherapy are the main causes of chemotherapy failure.Platinum chemotherapy drugs and doxorubicin are conventional drugs for the treatment of tumors.In recent years,nano-drug delivery systems have been proposed.Due to enhanced penetration and retention effect and different carriers,these systems can regulate the physicochemical properties of drugs.This research developed two nanoparticle drug delivery systems based on cisplatinum to reverse drug resistance.The research contains the following two aspects:1)Divalent cisplatin and oxaliplatin were oxidized and modified into tetravalent platinum prodrugs(CisPt(?)and OxaPt(?))with two long aliphatic chains coordinated axially.CisPt(?)and OxaPt(?)were encapsulated with amphiphilic polymer methoxy-poly(ethylene glycol)5000-block-poly(lactide)6000(mPEG5000-b-PLA6000),respectively.Finally,an spherical optimized formulation(M(CisPt)and M(OxaPt))with uniform particle sizes,negative charge,suitable encapsulation rate was prepared.Axially coordinated platinum prodrugs with long aliphatic chains can be encapsulated into amphiphilic polymers based on the rule of "like dissolves like".The average diameters of M(CisPt)and M(OxaPt)were 140 nm and 120 nm,respectively.The polymer dispersity indexs(PDI)are about 0.2,and the zeta potentials are about-20 mV which indicates that the nanomicelles are relatively stable in solution.In vitro release experiments demonstrated that this type of platinum-loaded prodrug nanomicelle is acid reduction sensitive.In vitro cytotoxicity experiments demonstrated that this type of platinum-loaded prodrug nanomicelles can effectively reverse the resistance of ovarian cancer cells to cisplatin.Cell cycle arrest analysis and apoptosis analysis showed that the M(CisPt)and M(OxaPt)mainly arrested the ovarian cancer cells in S phase,and promoted cell apoptosis.These experimental results indicate that this type of platinum prodrug nanomicelles can be an excellent drug delivery system that delivers and activates platinum drugs in cancer cells and overcomes cisplatin resistance.2)In this dissertation,cisplatin cross-linked hyaluronic acid-loaded doxorubicin nanogels(CDDPHANG/DOX),cisplatin cross-linked hyaluronic acid nanogels(CDDPHANG)and doxorubicin-loaded nanogels(HANG/DOX)were prepared through a green synthesis method.These hyaluronic acid nanogels were prepared for the treatment of breast cancer.With uniform sizes,the three nanogels are spherical.The average sizes of CDDPHANG/DOX,CDDPHANG and HANG/DOX were 115126 nm,151±19 nm and 75±18 nm,respectively.The PDI of CDDPHANG/DOX,CDDPHANG and HANG/DOX were 0.370,0.290,and 0.334,respectively.All PDIs were less than 0.4 indicating that the nanogels had a uniform size distribution.In vitro release experiments demonstrated that the nanogels(HANG)were acid-responsive.What's more,after cross-linked CDDP,the drug release was slower in different media,which indicated that CDDP cross-linked HANG have greater stability.Drug endocytosis experiments showed that compared with the free drug,more HANG were endocytosed by breast cancer resistant cells(MCF-7DOX),but less endocytosis in breast cancer doxorubicin-sensitive cells(MCF-7),indicating that HANG can effectively reduce drug efflux by cells.According to in vitro cell experiments,compared with free drug,HANG can effectively reduce the multiple drug resistance,and CDDPHANG/DOX is more toxic to MCF-7DOX.Accoerding to the above experiments and combining the various physical and chemical properties,CDDPHANG/DOX was chosen to perform in vivo experiments.Pharmacokinetic experiments showed that compared to the free drug,CDDPHANG/DOX showed significantly prolonged circulation time.In vivo experiments showed that compared to free drug group,CDDPHANG/DOX group were preferred to distribute in the tumor,and the tumor inhibitory effect was stronger than free drug.In addition,compared to free drug,BALB/c mice were more tolerant to CDDPHANG/DOX.In this dissertation,different carriers and anticancer drugs or prodrugs were used to construct drug-loaded nanomedicine system.According to the in vivo and in vitro evaluations,we concluded that these drug delivery systems have the ability to reverse the resistance of tumor cells and is expected to be used for the treatment of drug resistant tumors.