Active Targeting Drug Delivery Systems Designed For Tumor EMT Cells

Drug resistance and metastasis are two major obstacles to successful tumor chemotherapy and therefore improving the sensitivity of tumor cells to chemotherapy drugs and inhibiting tumor metastasis have become the key to successful treatment of cancer.In recent years,studies on tumor revealed that epithelial-mesenchymal transition(EMT)is involved in drug-resistance and tumor metastasis.Primary tumor cells will obtain the ability of motility and invasiveness when they undergo EMT.The development of drug resistance in cancer cells is accompanied by a translation from an epithelial to a mesenchymal phenotype.Furthermore,the cells undergoing EMT often lost the sensitivity to chemotherapy drugs.Therfore,the targeted therapy of EMT cells could be a promising method for the effective chemotherapy of drug resistant and metastatic tumor cells.N-cadherin often over expression on cell membrance when tumor cells undergoing EMT,and studies have shown that it is an important maker of EMT.Hence,N-cadherin could be an ideal target for tumor EMT cells therapy.ADH-1 is a cyclic pentapeptide,which not could selectively and competitively bind to N-cadherin,but also is an effective antagonist of its mediated adhesion and migration.Therefore,ADH-1 was selected here as an antagonist for blocking N-cadherin and a targeting motif for EMT cells targeted delivery.Study on this project falls into two parts.In the first part,ADH-1 peptide-modified liposomes were designed and fabricated for exploring whether the targeted therapy of EMT cells is capable of reversing drug resistance.Paclitaxel(PTX)-resistant breast cancer cells line MCF7 cells(MCF7 PTX-R)were chosen here as the tumor cell model and the occurrence of EMT in MCF7 PTX-R cells was verified.The results showed that A-LP coule be used anticancer drug targeting delivery and has the capiable of enhancing chemosensitivity of tumor cells.In the second part,a dual targeting drug delivery system(ADH-1-HA-MSN)was constructed for exploring whether tumor cells undergoing EMT targeted therapy is in a position to inhibit tumor cell invasion and metastasis.Mesoporous silica nanoparticles was used here as drug vector.Hyaluronic acid(HA)and ADH-1 were selected here as targeting motif modified MSNs.Cellular uptake assays showed that HA significantly enhanced CD44-mediated endocytosis for ADH-1-HA-MSN/DOX.This nanocarrier exhibited higher cytotoxicity and markedly inhibited the migration and invasion of tumor cells.Finally,the mechanism research revealed that down-regulating N-cadherin expression was the reason for ADH-1-HA-MSN/DOX inhibited tumor cell metastasis and invasion by western blotting analysis.Taken together,tumor targeting therapy of tumor EMT cells could improve the sensitivity of tumor cells to chemotherapy drugs and inhibit tumor cell invasion and metastasis.