GSH-responsive Drug/Gene Micelles With Targeted Function For Breast Cancer Research

Cancer is one of the highest rates of morbidity and mortality in the world.Conventional treatments are chemotherapy,radiation and surgery,but these treatments will bring some serious adverse effects and potential drug resistance can occur.Even worse,the acquired resistance often causes recurrence,cancer dissemination,and death.At this time,the nano-drug carrier is born,and by means of blood circulation,the carrier of the drug reaches the specific body part of the body,thereby reducing the toxic and side effects of the drug.But the long-term use of chemotherapy drugs can cause tumor cells to produce resistance,therefore,chemotherapy drugs and gene targeting by vehicle load to the specified target so that the tumor cell apoptosis,it also puts forward a new scheme for the treatment of cancer.The drug/gene codelivery is a promising strategy for cancer treatment.T7-conjugated redox sensitive amphiphilic micelles polyethylene glycol-polyethyleneimine-poly(caprolactone)-S-S-poly(caprolactone)-polyethyleneim ine-polyethylene glycol(PEG-PEI-PCL-S-S-PCL-PEG)(PPPT)was designed to realize the co-delivery of therapeutic gene encoding human tumor necrosis factor-related apoptosis-inducing ligand(pORF-hTRAIL)and doxorubicin(DOX)efficiently into tumor cells.PPPT was synthesized by ring opening polymerization(ROP)of ?-caprolactone followed by Michael addition polymerization and atom transfer radical polymerization(ATRP)of Maleic imide activity of MAL-PEG-NHS.The PPPT micelle presented a spherical or ellipsoidal geometry with an average diameter of about 100-120 nm.At the same time,it also demonstrated a character of redox-responsive drug release in vitro.Blood compatibility assays and complement activation tests revealed that PPPT micelles did not induce blood hemolysis,blood clotting,or complement activation.The T7 modified co-delivery system showed higher cellular uptake efficiency in human breast cancer MCF-7 cells than unmodified co-delivery systems and accumulated in tumor more efficiently in vitro.The in vivo anti-tumor effect was evaluated using a model of breast cancer.In addition,western blotting(WB),immunohistochemistry,and cell viability assays were used to study the mechanism of action and anti-tumor efficacy of combination therapy.These results demonstrate that a combined delivery system consisting of a T7-targeted co-delivery system of DOX and pORF-hTRAIL is a comprehensive delivery platform that can significantly improve the treatment of breast cancer.