title: Therapeutic modalities of squalenoyl nanocomposites in colon cancer: an ongoing search for improved efficacy.
abstract: Drug delivery of combined cytotoxic and antivascular chemotherapies in multidrug nanoassemblies may represent an attractive way to improve the treatment of experimental cancers. Here we made the proof of concept of this approach on the experimental LS174-T human colon carcinoma xenograft nude mice model. Briefly, we have nanoprecipitated the anticancer compound gemcitabine conjugated with squalene (SQ-gem) together with isocombretastatin A-4 (isoCA-4), a new isomer of the antivascular combretastatin A-4 (CA-4). It was found that these molecules spontaneously self-assembled as stable nanoparticles (SQ-gem/isoCA-4 NAs) of ca. 142 nm in a surfactant-free aqueous solution. Cell culture viability tests and apoptosis assays showed that SQ-gem/isoCA-4 NAs displayed comparable antiproliferative and cytotoxic effects than those of the native gemcitabine or the mixtures of free gemcitabine with isoCA-4. Surprisingly, it was observed by confocal microscopy that the nanocomposites made of SQ-gem/isoCA-4 distributed intracellularly as intact nanoparticles whereas the SQ-gem nanoparticles remained localized onto the cell membrane. When used to deliver these combined chemotherapeutics to human colon cancer model, SQ-gem/isoCA-4 nanocomposites induced complete tumor regression (by 93%) and were found superior to all the other treatments, whereas the overall tolerance was better than the free drug treatments. This approach could be applied to other pairs of squalenoylated nanoassemblies with other non-water-soluble drugs, thus broadening the application of the "squalenoylation" concept in oncology.
authors.affiliation: Faculté de Pharmacie, Université Paris-Sud , Institut Galien Paris Sud, UMR CNRS 8612, 5 rue J.-B. Clément, Châtenay-Malabry, Paris, F-92296, France.
authors.forename: Andrei
authors.initials: A
authors.lastname: Maksimenko
authors.forename: Mouad
authors.initials: M
authors.lastname: Alami
authors.forename: Fatima
authors.initials: F
authors.lastname: Zouhiri
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Brion
authors.forename: Alain
authors.initials: A
authors.lastname: Pruvost
authors.forename: Julie
authors.initials: J
authors.lastname: Mougin
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamze
authors.forename: Tanguy
authors.initials: T
authors.lastname: Boissenot
authors.forename: Olivier
authors.initials: O
authors.lastname: Provot
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D053761:Nanocomposites / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use; D013185:Squalene / Q000737:chemistry*; D013267:Stilbenes / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D013267:Stilbenes; D003841:Deoxycytidine; D013185:Squalene; C058728:fosbretabulin; D000093542:Gemcitabine