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Vascular damage photoinduced by liposomal formulations of mTHPC in xenografted CAM: influence of drug release
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Tumoricidal photodynamic therapy (PDT) efficacy implicates the combination of direct cellular and indirect vascular damage supported by an immune activation. It was demonstrated that the success of mTHPC-PDT depends particularly on tumoral vascular damage (Garrier et al., 2010). Recently developed liposomal formulations of mTHPC (Foslip®, Fospeg®) aim to improve the pharmacokinetic properties of the photosensitizer. However, it was shown in vitro, in human plasma, that the mTHPC release significantly depends on the liposomal formulation (Reshetov et al., 2011). Indeed, a part of mTHPC was released much faster from PEGylated liposomes compared to conventional ones. In this context, the kinetic of mTHPC release from lipid nanovesicles is an essential point in the estimation of the photoinduced vascular damage. The chick chorioallantoic membrane (CAM) model, particularly adapted for the study of vascular events, was used for the experiments. Foslip® and Fospeg® were either intravenously administered into CAM (in ovo) or incubated in chick plasma (ex ovo). In both cases, photosensitizer release was estimated by photoinduced fluorescence quenching technique in plasma (Kachatkou et al, 2009). PDT treatment was realized on xenografted CAM with EMT6 murine mammary carcinoma cells, a model developed in our laboratory in accordance with previous studies (Mitra et al, 2005). Vascular damage was evaluated by macroscopy and histology of CAM and tumors. Foslip® exhibited no significant difference in terms of mTHPC release when it was incubated in ovo and ex ovo. The plateau of release was obtained after 2 hours of incubation. In contrast, incubation with human plasma yielded a plateau after 6 hours, indicating an important influence of the plasma composition. Concerning Fospeg®, ex ovo studies confirmed the two-phase release of photosensitizer observed previously in human plasma. Different drug light intervals (DLIs) corresponding to partial or complete mTHPC redistribution were tested for Foslip® and Fospeg®-based PDT activity.
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