Document Detail

The effect of the acid-sensitivity of 4-(N)-stearoyl gemcitabine-loaded micelles on drug resistance caused by RRM1 overexpression.
MedLine Citation:
PMID:  23261218     Owner:  NLM     Status:  MEDLINE    
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.
Saijie Zhu; Piyanuch Wonganan; Dharmika S P Lansakara-P; Hannah L O'Mary; Yue Li; Zhengrong Cui
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-20
Journal Detail:
Title:  Biomaterials     Volume:  34     ISSN:  1878-5905     ISO Abbreviation:  Biomaterials     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-01-21     Completed Date:  2013-07-22     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  8100316     Medline TA:  Biomaterials     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  2327-39     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
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MeSH Terms
Acids / metabolism
Apoptosis / drug effects
Blotting, Western
Cell Line, Tumor
Deoxycytidine / analogs & derivatives*,  chemistry,  pharmacokinetics
Drug Resistance, Neoplasm / drug effects*,  genetics*
Gene Expression Regulation, Neoplastic
Ribonucleotide Reductases / genetics*,  metabolism
Grant Support
Reg. No./Substance:
0/4-(N)-stearoylgemcitabine; 0/Acids; 0/Micelles; 0W860991D6/Deoxycytidine; EC 1.17.4.-/Ribonucleotide Reductases; EC protein, mouse

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