Preparation And Characterization Of Antitumor Prodrugs With Redox Dual Response

Hypoxia makes tumor cells several times more resistant to radiation and chemotherapy drugs than aerobic cells.Therefore,the treatment of hypoxic tumor cells is one of the focuses of current research.Enhancing targeting and reducing the resistance of tumor cells to chemotherapy drugs has become a new way of treating tumors.Tirapazamine（TPZ）is a new anti-tumor drug,which has the characteristics of hypoxic sensitivity,when in the hypoxic environment,it can become a powerful free radical to cells.SN-38,the active metabolite of CPT-11,has a significant inhibitory effect on DNA topoisomerase I,and.induced the strongest inhibition of DNA topoisomerase I and could be used in combination with Tirapazamine.In this paper,the polymerization of anticancer drugs is used to prepare polymer prodrugs to achieve target and improve the therapeutic effect on tumor cellsThe polymer prodrug m PEG₅₀₀₀-EDA-b-P（LA-g-S-TPZ）was synthesized by condensation reaction with the carboxylated Tirapazamine（TPZ-S-COOH）obtained by functionalization.The average particle size of the polymer nanomicelle was 93.8nm and the drug loading was 11.51 wt%.By simulating tumor microenvironment,the redox group of GSH and H₂O₂ was set at p H=7.4PBS buffer（2%DMSO V/V）at 37℃which was proved that the polymer prodrug had redox response performance and could release the drug quickly.MTT results showed that TPZ prodrug had an inhibitory effect on Hep G2 cell activity.The 7-ethyl-10-hydroxycamptothecin（SN-38）was modified and functionalized to obtain SN-38-S-COOH.Then TPZ-S-COOH and SN-38-S-COOH one-pot reaction obtained the intelligent polymer prodrug m PEG₅₀₀₀-EDA-b-P（LA-g-S-TPZ-g-S-SN-38）with synergistic effect.In the p H=7.4 environment,the particle size of the nanoparticles formed by TPZ basically remained 113.7 nm within 24 h,the drug loading of TPZ was 8.12 wt%,and the drug loading of SN-38 was 8.46 wt%.In vitro drug release experiments proved that the prodrug had redox responsiveness and could release the drug rapidly.MTT results showed that TPZ/SN-38 dual drug prodrug had a stronger inhibitory effect on HepG2 cell activity which also proved their excellent synergistic effect.