Poly-isoprenylated ifosfamide analogs: Preactivated antitumor agents as free formulation or nanoassemblies

Charles Skarbek, Julia Delahousse, Catherine Pioche-Durieu, Sonia Baconnais, Alain Deroussent, Patrice Renevret, Michael Rivard, Didier Desmaele, Thierry Martens, Eric Le Cam, Patrick Couvreur, Angelo Paci

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

1 Citation (Scopus)

Résumé

Oxazaphosphorines including cyclophosphamide, trofosfamide and ifosfamide (IFO) belong to the alkylating agent class and are indicated in the treatment of numerous cancers. However, IFO is subject to limiting side-effects in high-dose protocols. To circumvent IFO drawbacks in clinical practices, preactivated IFO analogs were designed to by-pass the toxic metabolic pathway. Among these IFO analogs, some of them showed the ability to self-assemble due to the use of a poly-isoprenyloxy chain as preactivating moiety. We present here, the in vitro activity of the nanoassembly formulations of preactivated IFO derivatives with a C-4 geranyloxy, farnesyloxy and squalenoxy substituent on a large panel of tumor cell lines. The chemical and colloidal stabilities of the geranyloxy-IFO (G-IFO), farnesyloxy-IFO (F-IFO) and squalenoxy-IFO (SQ-IFO) NAs were further evaluated in comparison to their free formulation. Finally, pharmacokinetic parameters and maximal tolerated dose of the most potent preactivated IFO analog (G-IFO) were determined and compared to IFO, paving the way to in vivo studies.

langue originaleAnglais
Pages (de - à)748-756
Nombre de pages9
journalInternational Journal of Pharmaceutics
Volume532
Numéro de publication2
Les DOIs
étatPublié - 5 nov. 2017
Modification externeOui

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