par Levet, Vincent ;Wauthoz, Nathalie ;Amighi, Karim
Référence Journée des Doctorants de sciences biomédicales, dentaires, sciences médicales et pharmaceutiques 14th Erasme, Belgique 18/12/2014
Publication Non publié, 2014-12-18
Communication à un colloque
Résumé : Background: With 1,8M new cases and 1,6M deaths in 2012 worldwide, lung carcinoma is themost frequent cancer in men and the most fatal one in both males and females. Platinum-derivatives chemotherapy currently remains one of the most potent treatments available to physicians. Its main and first representative, cisplatin, is currently administered slowly by I.V. infusion and high hydration with mannitol 5% solution before and after treatment in order to reduce its cumulative dose-limiting nephrotoxicity. The pulmonary administration of chemotherapy is a promising route as it could increase drug concentration close to the tumor while decreasing its systemic concentration and the related adverse effects.Materials & Methods: Cisplatin solution was administered once to CD-1 female mice at a dose of 1.25 mg/kg, either intravenously through the caudal vein or under anesthesia by endotracheal instillation to the lungs with a Microsprayer IA-1C (Penn-Century Inc., Philadelphia, USA). Blood, lungs, kidneys, liver, spleen and mediastinum were removed at different times postadministration (n=5), weighted and digested in nitric acid at 60°C under ultrasonication. Samples were then analyzed for platinum concentration with a SpectrAA 300 absorption spectrometer equipped with a graphite furnace GTA-96 (Varian, Mulgrave, Australia) under specific electrothermic programs depending on the type of matrix.Results: The ETAAS appeared to be a reliable, fast and accurate method to quantify the platinum content in blood and different organs. The pharmacokinetic of cisplatin in mice lungs obtained after local delivery versus systemic delivery exhibits a 3-fold increase in total platinum concentration in the lungs associated with a 10-, 4- and 5-fold decrease in blood, kidneys and liver expositions, respectively. It also exhibits a 22-, 5- and 5-fold decrease of peak concentrations in blood, kidneys and liver, respectively.Conclusion and perspectives: The pulmonary route seems a promising approach to increase the therapeutic index of cisplatin in lung cancer as it increases its lung concentration and decreases its blood and kidney concentrations. The development of cisplatin-based dry powders for inhalation is now ongoing to assess their tolerance, toxicity, efficacy and convenience.