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

Abstract

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.

• Authors: Hong Cheng, Jing-Yi Zhu, Xiao-Ding Xu, Wen-Xiu Qiu, Qi Lei, Kai Han, Yin-Jia Cheng, Xian-Zheng Zhang
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 7 Issue 29 Pg. 16061-9 (Jul 29 2015) ISSN: 1944-8252 [Electronic] United States
• PMID: 26161578 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Cell-Penetrating Peptides
• Delayed-Action Preparations
• Nanocapsules
• Nanoconjugates
• Prodrugs
• Doxorubicin

Topics

• Animals
• Antimetabolites, Antineoplastic (administration & dosage, chemistry)
• Apoptosis (drug effects)
• COS Cells
• Cell Survival (drug effects)
• Cell-Penetrating Peptides (chemistry, pharmacokinetics)
• Chlorocebus aethiops
• Delayed-Action Preparations (administration & dosage, chemical synthesis)
• Diffusion
• Doxorubicin (administration & dosage)
• HeLa Cells
• Humans
• Molecular Targeted Therapy (methods)
• Nanocapsules (chemistry, ultrastructure)
• Nanoconjugates (chemistry, ultrastructure)
• Neoplasms (drug therapy, metabolism, pathology)
• Prodrugs (administration & dosage, chemistry)
• Treatment Outcome