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

Authors Briot T, Roger E, Bou Haidar N, Bejaud J, Lautram N, Guillet C, Thépot S, Legeay S, Lagarce F

Received 11 October 2018

Accepted for publication 4 December 2018

Published 26 March 2019 Volume 2019:14 Pages 2091—2102

DOI https://doi.org/10.2147/IJN.S190482

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Govarthanan Muthusamy

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo


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

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