Development of a multi-target peptide for potentiating chemotherapy by modulating tumor microenvironment.
Finding effective cures against aggressive malignancy remains a major challenge in cancer chemotherapy. Here, we report a "tadpole"-like peptide by covalently conjugating the alanine-alanine-asparagine "tail" residual to the cyclic tumor homing peptide iRGD (CCRGDKGPDC) to afford nRGD, which significantly enhanced tumoricidal effects of doxorubicin, by either co-administered as a physical mixture or as a targeting ligand covalently conjugated to the liposomal carrier. Given twice at an equivalent dose of 5 mg/kg, doxorubicin loaded liposomes modified with nRGD (nRGD-Lipo-Dox) showed excellent antitumor efficacy in 4T1 breast cancer mice, of which 44.4% remained alive for over 90 days without recurrence during the period of investigation. The dramatic improvement in antitumor efficacy was attributed to nRGD-Lipo-Dox which appeared to specifically interact with tumor vascular endothelial cells to achieve efficient tumor penetration, and modulate tumor microenvironment with depletion of tumor associated macrophages.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Xu
X
Song
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Zhuoya
Z
Wan
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Tijia
T
Chen
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Yao
Y
Fu
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Kejun
K
Jiang
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Xiaoli
X
Yi
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Huan
H
Ke
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Jianxia
J
Dong
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Liuqing
L
Yang
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Lin
L
Li
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Xun
X
Sun
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China. Electronic address: gongtaoy@126.com.
Tao
T
Gong
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China. Electronic address: zrzzl@vip.sina.com.
Zhirong
Z
Zhang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000138:chemical synthesis; D015202:Protein Engineering / Q000379:methods; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects*
D000903:Antibiotics, Antineoplastic; D004338:Drug Combinations; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin
Legumain; Tumor associated macrophage; Tumor microenvironment; iRGD; nRGD