Development of a multi-target peptide for potentiating chemotherapy by modulating tumor microenvironment

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• 作者：Xu Song ; Zhuoya Wan ; Tijia Chen ; Yao Fu ; Kejun Jiang ; Xiaoli Yi ; Huan Ke ; Jianxia Dong ; Liuqing Yang ; Lin Li ; Xun Sun ; Tao Gong ; ^{gongtaoy@126.com" class="auth_mail" title="E-mail the corresponding author} ; Zhirong Zhang ; ^{zrzzl@vip.sina.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：nRGD ; iRGD ; Legumain ; Tumor associated macrophage ; Tumor microenvironment
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：108
• 期：Complete
• 页码：44-56
• 全文大小：5910 K

文摘

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.