PO-432 New combined nanoparticle therapy inhibits metastatic breast tumour growth with superior efficacy and lower side effect profile to docetaxel

• Published in: ESMO open Vol. 3; no. Suppl 2; pp. A191 - A192
• Main Authors: Alshaker, H, Pchejetski, D
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.07.2018
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1136/esmoopen-2018-EACR25.456

IntroductionCombining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine kinase 1 (SK1) is a proto-oncogene that is highly expressed in breast cancer, especially in oestrogen receptor (ER) negative tumours. SK1 inhibitor FTY720 has promising anticancer properties as monothrerapy. In this study, we have developed and tested polymer and silicon nanoparticles combining docetaxel and FTY720 for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity.Material and methodsDocetaxel, FTY720 and glucosamine were embedded or covalently conjugated to poly(lactic-co-glycolic acid) or silicon nanopores. Nanoparticles were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of nanoparticles were evaluated.Results and discussionsOur data indicate that in ER negative breast cancer cells FTY720 provides chemosensitisation to docetaxel, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in nanoparticles, with narrow size distribution of ~100 nm and excellent cancer cell uptake providing sequential, sustained release of both drugs. In mouse models of human ER negative breast cancer nanoparticles had superior efficacy to systemic free docetaxel. Both polymer and silicon nanoparticles had significantly lower side effect profile including reduction of chemotherapy-induced weight loss, liver toxicity and neutropenia.ConclusionHere we have shown for the first time that FTY720 can sensitise ER negative breast cancer to docetaxel. We further demonstrate that encapsulation of free drugs in nanoparticles can improve targeting, provide low off-target toxicity and enhance antitumour efficacy offering potential therapeutic use of FTY720 in clinical breast cancer treatment.