title: The effect of the acid-sensitivity of 4-(N)-stearoyl gemcitabine-loaded micelles on drug resistance caused by RRM1 overexpression.
abstract: 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.
authors.affiliation: The University of Texas at Austin, College of Pharmacy, Pharmaceutics Division, Austin, TX 78712, United States.
authors.forename: Saijie
authors.initials: S
authors.lastname: Zhu
authors.forename: Piyanuch
authors.initials: P
authors.lastname: Wonganan
authors.forename: Dharmika S P
authors.initials: DS
authors.lastname: Lansakara-P
authors.forename: Hannah L
authors.initials: HL
authors.lastname: O'Mary
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008823:Micelles; D036103:Nanotechnology; D012262:Ribonucleoside Diphosphate Reductase; D012264:Ribonucleotide Reductases / Q000235:genetics* / Q000378:metabolism
chemical_list: C525761:4-(N)-stearoylgemcitabine; D000143:Acids; D008823:Micelles; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D012262:Ribonucleoside Diphosphate Reductase; C498690:Rrm1 protein, mouse