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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. [ABSTRACT FROM AUTHOR]

Liposomal formulations were made using Solvent-assisted active loading technology (SALT). Two formulations composed of HSPC:DPPG:Chol:DSPE-mPEG 2000 (PG-LipCUR) and HSPC:Chol:DSPE-mPEG 2000 (LipCUR) demonstrated good colloidal properties and the CUR-encapsulation of 82% and 89% for PG-LipCUR and LipCUR, respectively. The results showed that both formulations were stable during 6 months storage at 4 °C. The release study showed that the PG-LipCUR and LipCUR formulations are relatively stable at pH 7.4. Both formulations had higher cytotoxicity on TUBO and 4T1 cell lines in compassion with normal cells. PG-LipCUR had the higher amounts of CUR cellular uptake than LipCUR. Biodistribution studies showed that both formulations could enhance the half-life of the CUR 2–3 times compared to free CUR. The tumor accumulation of PG-LipCUR was significantly higher than LipCUR. The antitumor activities of liposomes on 4T1 tumor model demonstrated the efficacy of both formulations compared to PBS and free CUR. PG-LipCUR also was more potent in tumor growth delay in comparison with LipCUR. However, combination of the Caelyx® and PG-LipCUR had the most antitumor properties among other treatments. Based on the results, PG-LipCUR could be a promising formulation for the delivery of CUR which also significantly increased the efficacy of Caelyx® and merits further investigation. [ABSTRACT FROM AUTHOR]