The effect of the acid-sensitivity of 4-(N)-stearoyl gemcitabine-loaded micelles on?drug resistance caused by RRM1 overexpression

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• 作者：Saijie Zhu^a ; Piyanuch Wonganan^a ; Dharmika S.P. Lansakara-P.^a ; Hannah L. O'Mary^a ; Yue Li^b ; Zhengrong Cui^a ; ^{zhengrong.cui@austin.utexas.edu}
• 关键词：Hydrazone ; Nucleoside analogs ; Cell uptake ; Intracellular metabolism ; Lysosomes ; dFdCTP/dNTP ratio
• 刊名：Biomaterials
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：34
• 期：9
• 页码：2327-2339
• 全文大小：2147 K

文摘

Chemoresistance is a major issue for most gemcitabine-related chemotherapies. The overexpression of ribonucleotide reductase subunit M1 (RRM1) plays a key role in gemcitabine resistance. In this study, we synthesized a new highly acid-sensitive amphiphilic micelle material by conjugating hydrophilic polyethylene glycol with a hydrophobic stearic acid derivative (C18) using a hydrazone bond, which was named as PHC-2. A lipophilic prodrug of gemcitabine, 4-(N)-stearoyl gemcitabine (GemC18), was loaded into micelles prepared with PHC-2, a previously synthesized less acid-sensitive PHC-1, and their acid-insensitive counterpart, PAC. GemC18 loaded in acid-sensitive micelles can overcome gemcitabine resistance, and GemC18 in the highly acid-sensitive PHC-2 micelles was more cytotoxic than in the less acid-sensitive PHC-1 micelles. Mechanistic studies revealed that upon cellular uptake and lysosomal delivery, GemC18 in the acid-sensitive micelles was released and hydrolyzed more efficiently. Furthermore, GemC18 loaded in the highly acid-sensitive PHC-2 micelles inhibited the expression of RRM1 and increased the level of gemcitabine triphosphate (dFdCTP) in gemcitabine resistant tumor cells. The strategy of delivering lipophilized nucleoside analogs using highly acid-sensitive micelles may represent a new platform technology to increase the antitumor activity of nucleoside analogs and to overcome tumor cell resistance to them.