title: Nanosuspension for the delivery of a poorly soluble anti-cancer kinase inhibitor.
abstract: We hypothesized that nanosuspensions could be promising for the delivery of the poorly water soluble anti-cancer multi-targeted kinase inhibitor, MTKi-327. Hence, the aims of this work were (i) to evaluate the MTKi-327 nanosuspension for parenteral and oral administrations and (ii) to compare this nanosuspension with other nanocarriers in terms of anti-cancer efficacy and pharmacokinetics. Therefore, four formulations of MTKi-327 were studied: (i) PEGylated PLGA-based nanoparticles, (ii) self-assembling PEG₇₅₀-p-(CL-co-TMC) polymeric micelles, (iii) nanosuspensions of MTKi-327; and (iv) Captisol solution (pH=3.5). All the nano-formulations presented a size below 200 nm. Injections of the highest possible dose of the three nano-formulations did not induce any side effects in mice. In contrast, the maximum tolerated dose of the control Captisol solution was 20-fold lower than its highest possible dose. The highest regrowth delay of A-431-tumor-bearing nude mice was obtained with MTKi-327 nanosuspension, administered intravenously, at a dose of 650 mg/kg. After intravenous and oral administration, the AUC₀₋∞ of MTKi-327 nanosuspension was 2.4-fold greater than that of the Captisol solution. Nanosuspension may be considered as an effective anti-cancer MTKi-327 delivery method due to (i) the higher MTKi-327 maximum tolerated dose, (ii) the possible intravenous injection of MTKi-327, (iii) its ability to enhance the administered dose and (iv) its higher efficacy.
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmaceutics and Drug Delivery, Brussels, Belgium.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Danhier
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmaceutics and Drug Delivery, Brussels, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ucakar
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmaceutics and Drug Delivery, Brussels, Belgium.
authors.forename: Marie-Lyse
authors.initials: ML
authors.lastname: Vanderhaegen
authors.affiliation: Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Brewster
authors.affiliation: Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Tina
authors.initials: T
authors.lastname: Arien
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Pharmaceutics and Drug Delivery, Brussels, Belgium. Electronic address: veronique.preat@uclouvain.be.
authors.forename: Véronique
authors.initials: V
authors.lastname: Préat
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D019540:Area Under Curve; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006863:Hydrogen-Ion Concentration; D047028:Macrocyclic Compounds / Q000008:administration & dosage*; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D011108:Polymers / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D012995:Solubility; D013535:Suspensions; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; C553025:JNJ-26483327; D047028:Macrocyclic Compounds; D008823:Micelles; D011108:Polymers; D047428:Protein Kinase Inhibitors; D013535:Suspensions; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin
keywords: Anti-cancer drug; Kinase inhibitor; MTKi-327; Micelles; Nanoparticles; Nanosuspension; Tumor targeting