PO-440 Targeting of triple negative breast tumours using liposomes as drug delivery systems for siRNA and HSP90 inhibitor

Abstract

IntroductionFor Triple Negative Breast Cancers (TNBC) there are no effective specific targeted therapy readily available. CD44 is found overexpressed in many tumours, in particular TNBC, making this an attractive receptor for therapeutic targeting. Besides, Hsp90 inhibitors (Hsp90i) have been shown as promising molecules to treat cancer. Here we show our both drug delivery approaches to target TNBC. First, we describe a unique non-cationic liposome-based siRNA delivery system with a core composed of siRNA:protamine complexes and a shell designed for the active targeting of CD44-expressing cells using for the first time an anti-CD44 aptamer as targeting ligand. This was evaluated for the silencing of the luciferase reporter gene (luc2) in a TNBC breast cancer model in vitro and in vivo (orthotopically implanted) (Alshaer, 2015, 2018). Secondly, we succeeded to use the inhibition of the chaperone Hsp90 against breast cancer. A promising Hsp90i derived from Novobiocin (6BrCaQ) has been encapsulated in liposomes and liposomal 6BrCaQ displayed a good activity on prostate cancer cells in vitro (apoptosis induction, cell cycle arrest, slowed down of migration) and synergized with doxorubicin (Sauvage, 2016). In the same in vivo TNBC model as above we evaluated the anti-tumour activity of these liposomes.Material and methodNanocarriers were characterised and assessed in vitro using the CD44 +MDA MB-231-luc2. The CD44 targeting and gene silencing were investigated in vivo at the mRNA and protein levels, on an orthotopic MDA-MB-231-luc2 xenograft model in nude mice. The liposomal 6BrCaQ was evaluated in vitro in the same model to investigate the anti-proliferative effect) and in vivo for the anti-tumour effect.Results and discussion1) We show the possibility of conjugating an aptamer to siRNA-containing liposomes for an efficient gene silencing therapy in CD44-expressing tumour cells in vivo. 2) In vitro, liposomal 6BrCaQ blocked the cell cycle of MDA-MB-231-luc2 cells and retarded, in vivo, the tumour growth at a low dose (1 mg/kg, once a week for 4 weeks). Histological analysis of tumours revealed necrosis and a lower proportion of proliferative cells in treated mice indicating that this drug has potential for breast cancer therapy when encapsulated in liposomes.ConclusionOur work gives evidences that liposomes can be used to target CD44 positive cells in resistant TNBC breast tumours and to deliver an anti-tumour but poorly soluble inhibitor of Hsp90.