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

• Published in: International journal of pharmaceutics Vol. 532; no. 2; pp. 748 - 756
• Main Authors: Skarbek, Charles, Delahousse, Julia, Pioche-Durieu, Catherine, Baconnais, Sonia, Deroussent, Alain, Renevret, Patrice, Rivard, Michael, Desmaele, Didier, Martens, Thierry, Le Cam, Eric, Couvreur, Patrick, Paci, Angelo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.11.2017; Elsevier
• Subjects: Animals; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - pharmacokinetics; Cancer drug delivery; Cell Line, Tumor; Cell Survival - drug effects; Humans; Ifosfamide; Ifosfamide - administration & dosage; Ifosfamide - analogs & derivatives; Ifosfamide - chemistry; Ifosfamide - pharmacokinetics; Life Sciences; Male; Maximum Tolerated Dose; Mice, Nude; Nanoassemblies; Nanostructures - administration & dosage; Nanostructures - chemistry; Prenylation; Prodrug; FF; NAs; CAA; DMSO; Ifosfamide; Nanoassemblies; EPR; IP; Prodrug; IV; LC–MS/MS; AUC; Cancer drug delivery; DDS; IFO; NA; PdI; DNA; MTD; TEM
• ISSN: 0378-5173; 1873-3476; 1873-3476
• DOI: 10.1016/j.ijpharm.2017.05.044

[Display omitted] 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.