title: Lysosomal delivery of a lipophilic gemcitabine prodrug using novel acid-sensitive micelles improved its antitumor activity.
abstract: 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.
authors.affiliation: College of Pharmacy, Pharmaceutics Division, The University of Texas at Austin , Austin, Texas, 78712, United States.
authors.forename: Saijie
authors.initials: S
authors.lastname: Zhu
authors.forename: Dharmika S P
authors.initials: DS
authors.lastname: Lansakara-P
authors.forename: Xinran
authors.initials: X
authors.lastname: Li
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013229:Stearic Acids / Q000737:chemistry; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D008823:Micelles; D011355:Prodrugs; D013229:Stearic Acids; D003841:Deoxycytidine; D011092:Polyethylene Glycols; C031183:stearic acid; D000093542:Gemcitabine