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

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 t...

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Bibliographic Details
Published in:ACS applied materials & interfaces 2015-07, Vol.7 (29), p.16061-16069
Main Authors: Cheng, Hong, Zhu, Jing-Yi, Xu, Xiao-Ding, Qiu, Wen-Xiu, Lei, Qi, Han, Kai, Cheng, Yin-Jia, Zhang, Xian-Zheng
Format: Article
Language:English
Subjects:
Animals
Antimetabolites, Antineoplastic - administration & dosage
Antimetabolites, Antineoplastic - chemistry
Apoptosis - drug effects
Cell Survival - drug effects
Cell-Penetrating Peptides - chemistry
Cell-Penetrating Peptides - pharmacokinetics
Cercopithecus aethiops
COS Cells
Delayed-Action Preparations - administration & dosage
Delayed-Action Preparations - chemical synthesis
Diffusion
Doxorubicin - administration & dosage
HeLa Cells
Humans
Molecular Targeted Therapy - methods
Nanocapsules - chemistry
Nanocapsules - ultrastructure
Nanoconjugates - chemistry
Nanoconjugates - ultrastructure
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Prodrugs - administration & dosage
Prodrugs - chemistry
Treatment Outcome
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Summary: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.
ISSN:1944-8244
1944-8252
DOI:10.1021/acsami.5b04517