Lysosomal Delivery of a Lipophilic Gemcitabine Prodrug Using Novel Acid-Sensitive Micelles Improved Its Antitumor Activity

Stimulus-sensitive micelles are attractive anticancer drug delivery systems. Herein, we reported a novel strategy to engineer acid-sensitive micelles using a amphiphilic material synthesized by directly conjugating the hydrophilic poly(ethylene glycol) (PEG) with a hydrophobic stearic acid derivativ...

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Veröffentlicht in:Bioconjugate chemistry 2012-05, Vol.23 (5), p.966-980
Hauptverfasser: Zhu, Saijie, Lansakara-P, Dharmika S. P, Li, Xinran, Cui, Zhengrong
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container_issue 5
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container_title Bioconjugate chemistry
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creator Zhu, Saijie
Lansakara-P, Dharmika S. P
Li, Xinran
Cui, Zhengrong
description Stimulus-sensitive micelles are attractive anticancer drug delivery systems. Herein, we reported a novel strategy to engineer acid-sensitive micelles using a amphiphilic material synthesized by directly conjugating the hydrophilic poly(ethylene glycol) (PEG) with a hydrophobic stearic acid derivative (C18) using an acid-sensitive hydrazone bond (PHC). An acid-insensitive PEG-amide-C18 (PAC) compound was also synthesized as a control. 4-(N)-Stearoyl gemcitabine (GemC18), a prodrug of the nucleoside analogue gemcitabine, was loaded into the micelles, and they were found to be significantly more cytotoxic to tumor cells than GemC18 solution, likely due to the lysosomal delivery of GemC18 by micelles. Moreover, GemC18 in the acid-sensitive PHC micelles was more cytotoxic than in the acid-insensitive PAC micelles, which may be attributed to the acid-sensitive release of GemC18 from the PHC micelles in lysosomes. In B16–F10 melanoma-bearing mice, GemC18-loaded PHC or PAC micelles showed stronger antitumor activity than GemC18 or gemcitabine solution, likely because of the prolonged circulation time and increased tumor accumulation of the GemC18 by the micelles. Importantly, the in vivo antitumor activity of GemC18-loaded PHC micelles was significantly stronger than that of the PAC micelles, demonstrating the potential of the novel acid-sensitive micelles as an anticancer drug delivery system.
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source MEDLINE; American Chemical Society Journals
subjects Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Biochemistry
Cell Line, Tumor
Cells
Cytotoxicity
Delayed-Action Preparations - chemistry
Deoxycytidine - administration & dosage
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacokinetics
Deoxycytidine - therapeutic use
Drug Delivery Systems
Female
Hydrophobic and Hydrophilic Interactions
Lysosomes - metabolism
Lysosomes - pathology
Melanoma - drug therapy
Melanoma - metabolism
Melanoma - pathology
Mice
Mice, Inbred C57BL
Micelles
Polyethylene Glycols - chemistry
Prodrugs - administration & dosage
Prodrugs - pharmacokinetics
Prodrugs - therapeutic use
Rodents
Stearic Acids - chemistry
Tumors
title Lysosomal Delivery of a Lipophilic Gemcitabine Prodrug Using Novel Acid-Sensitive Micelles Improved Its Antitumor Activity
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