Synergistic effect of reduced polypeptide micelle for co-delivery of doxorubicin and TRAIL against drug-resistance in breast cancer

// Chuling Hu 1, * , Fenfen Gu 1, * , Zongguang Tai 1, * , Chong Yao 1 , Chunai Gong 1 , Qingming Xia 1 , Yuan Gao 1 , Shen Gao 1 1 Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China * These authors contributed equally to this work Correspondence to: Shen Gao, email: liullk@126.com Yuan Gao, email: gaoy82@hotmail.com Keywords: polyarginine, lipoic acid, reduction-sensitive, drug resistance, cancer therapy Received: May 02, 2016      Accepted: August 13, 2016      Published: August 20, 2016 ABSTRACT Cationic peptides as a non-viral gene vector have become a hotspot of research because of their high transfection efficcacy and safety. Based on our previous study, we synthesized a cationic reduction-responsive vector based on disulfide cross-linked L-arginine, L-histidine and lipoic acid (LHRss) as the co-carrier of both doxorubicin (DOX) and the necrosis factor-related apoptosis-inducing ligand (pTRAIL). The LHRss/DOX/TRAIL construct has reduction-sensitive behavior and an enhanced endosomal escape ability to increase the cytotoxicity of DOX and the transfection efficiency. Further, the LHRss/DOX/TRAIL construct increased the accumulation of DOX and promoted the expression of pTRAIL, thus increasing cellular apoptosis by 83.7% in MCF-7/ADR cells. In addition, the in vivo biodistribution results showed that the LHRss/DOX/TRAIL construct could target tumors well. The in vivo anti-tumor effect study demonstrated that the LHRss/DOX/TRAIL construct inhibited tumor growth markedly, with a tumor inhibitory rate of 94.0%. The co-delivery system showed a significant synergistic anti-tumor effect. The LHRss/DOX/TRAIL construct may prove to be a promising co-delivery vector for the effective treatment of drug resistant breast cancer.