Abstract 5702: NanoOxaza, pre-activated oxazaphosphorines prodrugs designed for drug delivery strategy with wide anticancer activity

Abstract

Abstract The oxazaphosphorines belong to the alkylating drug class with a wide spectrum of antineoplasic activity. Ifosfamide (IFO) demonstrated activity against various tumour types, from soft tissue sarcomas to lymphomas both in adult and paediatric patients. Oxazaphosphorines are metabolised by cytochromes, leading to ring opening and subsequent production of active nitrogen mustards, which display DNA cross-links. Associated toxicities of IFO are due to 1) acrolein, a urotoxic metabolite concomitantly generated with the release of the alkylating mustard and 2) chloroacetaldehyde, a metabolite derived from oxidation of side chains of the molecule via the action of cytochrome P450 (CYP) known to be responsible for neurotoxicity and nephrotoxicity (Kerbusch et al., 2001). To circumvent the oxidative related-toxicities, we have designed pre-activated oxazaphosphorines. (Paci et al., 2001) through electrochemical oxidation and engraftment of various moieties such as O-alkyl groups (fatty acids, alcohols, polyols, or sugars) and S-alkyl (thionyl) groups. Actually, IFO is activated by substitution at position 4 with labile moieties leading to the release of the cytotoxic entity without enzyme activity. These moieties can bring tissue specificity or physico-chemical characteristics leading to nanoassemblies for drug delivery purposes. Some of these pre-activated prodrugs may be constitutive of drug delivery systems, such as nanoparticles, aiming to address alkylating moieties to their target. We present here the use of squalene conjugation as squalene-based drug delivery systems have been favourably used for drug delivery (Couvreur et al. 2006). The designed compounds, SQ-IFO and SQ-thioIFO, have then two interesting properties. First, they are pre-activated formulations of IFO with C4-oxidation allowing to by-pass the CYP activation with the direct release of the alkylating mustard. The second property is the described capacity of squalenic derivatives for self-assembly in aqueous medium leading to nanoparticles. The SQ-IFO and SQ-thioIFO nanoparticles have been fully characterized with a mean diameter of 182 nm when prepared at 1mg/mL in 5% Dextrose. The cytotoxic activity of these nanoassemblies has been studied in vitro on a panel of 9 human and murine cancer lines (A549, MCF-7, B16F10, M109, MiaPaCa-2, KB 3.1, SK-N-MC, UW 479, IGR-OV1). Squalenoyl IFO derivatives present high activity in vitro while IFO has no activity on these cells even it is used in clinical practices to treat these cancers. This proves the pre-activated property of these new compounds and the lack of CYP activation needs. Their therapeutic activity is currently studied in vivo on human Ewing sarcoma xenografts in mice after i.v. administration. These new formulations of IFO could constitute promising candidates for both oral and IV administration in a wide panel of tumours. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5702. doi:1538-7445.AM2012-5702