title: 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.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Zhu
authors.forename: Xiao-Ding
authors.initials: XD
authors.lastname: Xu
authors.forename: Wen-Xiu
authors.initials: WX
authors.lastname: Qiu
authors.forename: Qi
authors.initials: Q
authors.lastname: Lei
authors.forename: Kai
authors.initials: K
authors.lastname: Han
authors.forename: Yin-Jia
authors.initials: YJ
authors.lastname: Cheng
authors.forename: Xian-Zheng
authors.initials: XZ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000493:pharmacokinetics*; D002522:Chlorocebus aethiops; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage*; D006367:HeLa Cells; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D058726:Nanoconjugates / Q000737:chemistry / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D057846:Cell-Penetrating Peptides; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D058726:Nanoconjugates; D011355:Prodrugs; D004317:Doxorubicin
keywords: cell-penetrating peptide; cellular uptake; prodrug; targeted drug delivery; tumor therapy