title: A new nanomedicine of gemcitabine displays enhanced anticancer activity in sensitive and resistant leukemia types.
abstract: Gemcitabine is an anticancer nucleoside analogue active against various solid tumors. However, it possesses important drawbacks like a poor biological half-life and the induction of resistance. With the objective of overcoming the above drawbacks, we designed a new nanomedicine of gemcitabine and studied its anticancer efficacy against leukemia at preclinic. Gemcitabine has been covalently coupled with 1,1',2-tris-nor-squalenic acid to obtain the new anticancer nanomedicine 4-(N)-Tris-nor-squalenoyl-gemcitabine (SQdFdC NA). The SQdFdC NA exhibited, in comparison to gemcitabine, 3.26- and 3.22-folds higher cytotoxicity respectively, in murine resistant leukemia L1210 10K cells and in human leukemia resistant cell line CEM/ARAC8C. Following intravenous treatment of murine aggressive metastatic leukemia L1210 wt bearing mice, the SQdFdC NA caused significant increase in survival time compared to gemcitabine and also led to long-term survivals, which was not the case after gemcitabine treatment. This was attributed to significantly higher deposition of SQdFdC NA in spleen and liver (P<0.05), the major metastatic organs. In comparison to gemcitabine, SQdFdC NA displayed greater ability to induce S-phase arrest of the cancer cells followed by increased apoptotic induction. Interestingly, like gemcitabine, SQdFdC NA didn't induce appreciable differences in blood parameters even at doses higher than those used for anticancer evaluation. The preclinical data obtained in vitro and in vivo with SQdFdC NA demonstrate that this nanomedicine represents a new therapeutic system for the effective treatment of leukemia.
authors: Université Paris-Sud XI, Faculté de Pharmacie, UMR CNRS 8612, IFR 141, 92296 Châtenay-Malabry Cedex, France.
authors: L Harivardhan
authors: LH
authors: Reddy
authors: Catherine
authors: C
authors: Dubernet
authors: Sinda Lepetre
authors: SL
authors: Mouelhi
authors: Pierre Emmanuel
authors: PE
authors: Marque
authors: Didier
authors: D
authors: Desmaele
authors: Patrick
authors: P
authors: Couvreur
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D013185:Squalene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: C525919:4-(N)-tris-nor-qualenoyl-gemcitabine; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D013185:Squalene