Activable Cell-Penetrating Peptide Conjugated Prodrug for Tumor Targeted Drug Delivery

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• 作者：Hong Cheng ; Jing-Yi Zhu ; Xiao-Ding Xu ; Wen-Xiu Qiu ; Qi Lei ; Kai Han ; Yin-Jia Cheng ; Xian-Zheng Zhang
• 刊名：ACS Applied Materials & Interfaces
• 出版年：2015
• 出版时间：July 29, 2015
• 年：2015
• 卷：7
• 期：29
• 页码：16061-16069
• ISSN：1944-8252

文摘

In this paper, an activable cell-penetrating peptide (CR₈G₃PK₆, ACPP) with a shielding group of 2,3-dimethylmaleic anhydride (DMA) was conjugated with antitumor drug doxorubicin (DOX) to construct a novel prodrug (DOX-ACPP-DMA) for tumor targeted drug delivery. The shielding group of DMA linked to the primary amines of K₆ through the amide bond was used to block the cell-penetrating function of the polycationic CPP (R₈) through intramolecular electrostatic attraction at physiological pH 7.4. At tumor extracellular pH 6.8, the hydrolysis of DMA led to charge reversal, activating the pristine function of CPP for improved cellular uptake by tumor cells. Confocal laser scanning microscopy (CLSM) and flow cytometry studies revealed that the cellular uptake of DOX-ACPP-DMA was significantly enhanced after acid-triggered activation in both HeLa and COS7 cells. After cell internalization, the overexpressed intracellular proteases would further trigger drug release in cells. Both in vitro and in vivo investigations showed that the peptidic prodrug exhibited significant tumor growth inhibition and demonstrated great potential for tumor therapy.