Di-O-lauroyl-decitabine-lipid nanocapsules: toward extending decitabine activity

Autor: Briot, Thomas, Roger, Emilie, Bou Haidar, Naila, Bejaud, Jérôme, Lautram, Nolwenn, Guillet, Catherine, Thépot, Sylvain, LEGEAY, Samuel, Lagarce, Frédéric
Přispěvatelé: Bernardo, Elizabeth, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département de Pharmacie [CHU Angers] (Pôle Hippocrate), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de Biologie en Santé (PHB-IRIS) [CHU Angers] (IBS), Centre Hospitalier Universitaire d'Angers (CHU Angers), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Hématologie Biologique (Hémato - ANGERS), The authors are very grateful to the Ligue Contre le Cancer, particularly its Maine et Loire Committee for its financial support., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: International Journal of Nanomedicine
International Journal of Nanomedicine, 2019, 14, pp.2091-2102. ⟨10.2147/IJN.s190482⟩
International Journal of Nanomedicine, Dove Medical Press, 2019, 14, pp.2091-2102. ⟨10.2147/IJN.s190482⟩
ISSN: 1176-9114
DOI: 10.2147/IJN.s190482⟩
Popis: Thomas Briot,1,2 Emilie Roger,1 Naila Bou Haidar,1 Jerome Bejaud,1 Nolwenn Lautram,1 Catherine Guillet,3 Sylvain Thépot,4,5 Samuel Legeay,1 Frederic Lagarce1,2 1Micro & Nanomédecines Translationelles – MINT, UNIV Angers, INSERM 1066, CNRS 6021, University of Angers, MINT IBS-CHU, Larrey, 49933 Angers, France; 2University Hospital of Angers, Pharmacy Department, 49933 Angers, France; 3University of Angers, Molecular and Cellular Analysis Platform, IBS-CHU, 49933 Angers, France; 4University Hospital of Angers, Hematology, 49933 Angers, France; 5INSERM CRCINA, University of Angers, 49933 Angers, France Background: Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%–80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks. Methods: Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12)2 was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model. Results: Decitabine (C12)2 was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug. Conclusion: Decitabine (C12)2 as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics. Keywords: lipid nanocapsules, acute myeloid leukemia, decitabine, nanomedicines, prodrugs
Databáze: OpenAIRE
Externí odkaz: