Introduction Targeting the altered cancer metabolism has opened new therapeutic opportunities. Upregulation of the expression of the monocarboxylate transporter 1 (MCT1) has been shown in various cancers, including breast tumours. MCT1 is responsible for the transport of lactate and pyruvate. Lactate/pyruvate analogues, such as 3-bromopyruvate, have been shown to be toxic to cells overexpressing MCT1.
However, in order to successfully treat the tumour, the therapeutic must be shielded from the immune system, target the tumour and penetrate it. To overcome these challenges we have encapsulated lactate/pyruvate analogues inside ultrasound labile liposomes. These will protect the therapeutic and extend its circulation time, enabling delivery and triggered release at the tumour site using externally applied ultrasound, whereas MCT1 expression offers selective uptake of the compounds.
Material and methods Western blotting was used to identify cell lines with high and low expression of MCT1. Cell viability after treatment was tested with an MTT assay. Chromatography techniques were used to measure encapsulation efficiency into the liposomes. A novel iodinated lactate analogue, 3-iodolactate (3IL), was synthesised via Finkelstein reaction and characterised by NMR spectroscopy and mass spectrometry. Ultrasound-labile liposomes were synthesised by dispersion of a lyophilised lipid film (DOPE, cholesterol and DSPC-PEG(2000) in 65:25:10 molar ratio) in an aqueous solution of the compound, followed by extrusion and size exclusion chromatography.
Results and discussions Breast cancer cell lines with low, intermediate and high expression of MCT1 have been identified (MDA-MB-231, MDA-MB-468 and BT20, respectively). 3 BP toxicity correlated with MCT1 expression. BT20 had an LD50 of 87.10±0.03 µM, while MDA-MB-231, were 90% viable even up to concentrations of 300 µM 3 BP. Toxicity is reversed with MCT1 inhibition. 3IL has been synthesised and purified. Ultrasound labile liposomes with an average hydrodynamic diameter of 120 nm have been synthesised and encapsulation of 3 BP has been confirmed and tested with cells with and without ultrasound.
Conclusion Cell toxicity of halogenated lactate/pyruvate analogues has been confirmed. A novel iodinated analogue has been synthesised. These molecules have been encapsulated within ultrasound labile liposomes. A novel drug delivery system has been engineered for the delivery of metabolic inhibitors targeting the lactate/pyruvate transporter (MCT1) for targeted cancer therapy.
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