Abstract 4386: Docetaxel-trastuzumab stealth immunoliposome: design and non-clinical study in HER2+ and HER2- breast cancer models

Abstract

Abstract Targeted liposomal drug delivery is expected to enhance the therapeutic effects of anti-cancer agents through both active and passive targeting of tumor cells. We have developed a stealth liposomal formulation of docetaxel anchored with trastuzumab (HER2-ANC) to target HER2+ breast cancers. Pegylated SUV liposomes with 95% docetaxel encapsulation yield were obtained using the thin-film method. Homogenous distribution in liposome size of 100-150 nm diameter was achieved by extrusion, prior to anchoring trastuzumab through maleimide coupling. Anchoring was evidenced by electronic microscopy with anti-mouse gold antibody. HER2-ANC antiproliferative activity was assessed on a representative panel of human breast cancer cells expressing (SKBR3, MDA-MB451) or not expressing HER2 (MDA-MB231). Free docetaxel and trastuzumab combination was used as control. Cytotoxicity was evaluated in vitro on 2D culture cells by MMT assay, and in 3D spheroids co-cultured with HMEC endothelial cells. HER2-ANC proved to have a similar efficacy than the free combination, including in triple negative MDA-MB231 cells in 2D models. In 3D models, the immunoliposome displayed higher efficacy as compared with the free combination, possibly because of a better and deeper diffusion of the antibody inside the spheroids. Surprisingly, and although less marked, this difference in favor of HER2-ANC was observed as well with the triple negative MDA-MB231 cells, thus suggesting that a better delivery of docetaxel was achieved with the liposomal form. Fluorescence imaging showed that HER2-ANC was internalized inside tumor cells. Measurement of HER2 expression and immunofluorescence staining of alpha-microtubulline supported this increase in efficacy observed in vitro. After tagging HER2-ANC with DIR fluorescent probe, in vivo preliminary distribution studies in nude mice bearing both the HER2+ SKBR3 and HER2- MDA-MB231 tumors showed that a more specific tumor uptake is achieved in HER2+ tumors, thus suggesting that higher antiproliferative effect and lower toxicities can be expected in further efficacy studies. Overall, this proof of concept study strongly suggest that redesigning existing combinations of biologics and cytotoxics as immunoliposomes could help to optimize the efficacy/toxicity balance of anticancer treatments. Citation Format: Raphaelle R. Fanciullino, Jean-Michel Brunel, Florian Correard, Sarah Giacometti, Joseph Ciccolini. Docetaxel-trastuzumab stealth immunoliposome: design and non-clinical study in HER2+ and HER2- breast cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4386. doi:10.1158/1538-7445.AM2015-4386