title: Polyisoprenoyl gemcitabine conjugates self assemble as nanoparticles, useful for cancer therapy.
abstract: A series of new polyisoprenoyl prodrugs of gemcitabine, which can be formulated as nanoassemblies are described. These prodrugs were designed to improve gemcitabine efficacy and to overcome the limitations due to the systemic toxicity of this anticancer compound. In vitro biological assessment showed that these polyisoprenoyl gemcitabine nanoassemblies displayed notable cytotoxicity on several cancer cell lines, including murine melanoma cell line B16F10, human pancreatic carcinoma cell line MiaPaCa-2, human lung carcinoma cell line A549 and human breast adenocarcinoma cell line MCF7. Interestingly, it was observed that the anticancer efficacy of these nanoassemblies was dependant on the size of polyisoprenoyl moiety. The polyisoprenoyl prodrug of gemcitabine containing three isoprene units (2d) was the more active on all the cancer cell lines tested. The antitumor efficacy of the nanoassemblies (NAs) constructed with the most active prodrug 2d was further evaluated on a human pancreatic (MiaPaCa-2) carcinoma xenograft model in mice. The prodrug 2d NAs showed an increased antitumor efficacy as compared to free gemcitabine or to squalene-gemcitabine (SQ-gem, 2a) nanoassemblies. Interestingly, MiaPaCa-2 tumors that did not respond to gemcitabine were inhibited by 76% after treatment with prodrug 2d NAs, whereas SQ-gem-treated MiaPaCa-2 tumor xenografts decreased only by 41% compared to saline or to gemcitabine-treated mice. Together, these findings demonstrated that the modulation of the length of nanoassemblies polyisoprenoyl moiety made tumor cells more sensitive to gemcitabine treatment without flagrant toxicity, thus providing a significant improvement in the drug therapeutic index.
authors.affiliation: Univ Paris-Sud, Faculté de Pharmacie, 5, rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France. andrey.maksimenko@u-psud.fr
authors.forename: Andrei
authors.initials: A
authors.lastname: Maksimenko
authors.forename: Julie
authors.initials: J
authors.lastname: Mougin
authors.forename: Simona
authors.initials: S
authors.lastname: Mura
authors.forename: Eric
authors.initials: E
authors.lastname: Sliwinski
authors.forename: Elise
authors.initials: E
authors.lastname: Lepeltier
authors.forename: Claudie
authors.initials: C
authors.lastname: Bourgaux
authors.forename: Sinda
authors.initials: S
authors.lastname: Lepêtre
authors.forename: Fatima
authors.initials: F
authors.lastname: Zouhiri
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D061986:MCF-7 Cells; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry; D011897:Random Allocation; D013729:Terpenes / Q000008:administration & dosage / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D013729:Terpenes; D003841:Deoxycytidine; D000093542:Gemcitabine