Optimization of a novel and improved thermosensitive liposome formulated with DPPC and a Brij surfactant using a robust in vitro system

The combination of thermosensitive liposomes and local heating has been shown to improve anticancer drug delivery in both animal models and human patients. The lyso-lipid temperature sensitive liposomes (LTSL) consisting of DPPC, MSPC and DSPE-PEG2000 is currently under evaluation in clinical trials. We hypothesized that Brij surfactants resembling the chemical structures of MSPC and DSPE-PEG2000 could be utilized for generating a thermosensitive formulation with DPPC. Here, we report using a robust in vitro system to efficiently screen a series of liposomal candidates composed of DPPC and a Brij surfactant for thermosensitive delivery of doxorubicin. The data indicated that the optimal acyl chain length of the surfactant was between C16 and C18 with a saturated carbon chain, a PEG repeating unit ranging between 10 and 100 and a molecule weight above 600 Da. The linking chemistry between the acyl chain and the PEG chain did not influence thermosensitivity. In the panel of surfactants tested, Brij78 was optimal and could be incorporated into the liposomes by the thin film hydration or the post-insertion method with an optimal range of 1 to 8 mol%. Doxorubicin was incorporated into the formulation by pH gradient with > 95% loading efficiency at drug/lipid of 1/20 (w/w). The transition temperature of the Brij78-liposomes was slightly lower than that of LTSL (41 v.s. 41.5 °C), leading to enhanced drug release at the low end of the hyperthermic temperatures (40 °C) with similar stability at 37 °C, which was confirmed by cell based assays. Finally, the Brij78-liposomes and LTSL displayed comparable blood compatibility with mild hemolytic activity. This in vitro system allowed for efficient screening and optimization to produce an optimal formulation.

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