Ultrasound-responsive lactic acid based agents for the delivery of targeted radiotherapy to solid tumours


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Irini Skaripa-Koukelli1,Ole Tietz1,Christophoros Mannaris2,Jason Brown3,Joshua Owen2,Robert Carlisle2,Katherine Vallis1
1CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology,2Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford,3Department of Physics, University of Oxford

Abstract

Background

Penetration of therapeutics into solid tumours following extravasation through the porous vasculature is a major limiting factor for treatment efficacy. Nanomedicine improved selective accumulation but the distribution of particles, unlike small molecules, in the tumour is severely inhibited. The aim of this work is to exploit the lactate shuttling mechanism of cancer cells, via the monocarboxylate transporter 1 (MCT1), to deliver a small molecule radiotherapeutic. This radiolabelled lactate mimetic (RLM) will be incorporated in ultrasound-responsive, biodegradable particles which will release it, following inertial cavitation in response to externally applied ultrasound and polymer degradation.

Method

Two RLM candidates were synthesized by electrophilic aromatic substitution (RLM1) and halogen exchange (RLM2) reaction, chromatographically purified,  and characterised by nuclear magnetic resonance (NMR) spectroscopy. MCT1 positive and negative cell lines were identified by Western blotting. MTT assay was used to assess the relative toxicity of the closest lactate mimetic, 3-bromopyruvate. Ultrasound responsive particles were fabricated by a double emulsion – solvent evaporation method, followed by characterisation by optical and scanning electron microscopy and a high-intensity focused ultrasound - passive cavitation detector (HIFU-PCD) set up. 

Results

Iodination of p-hydroxyphenyllactate (RLM1) and exchange of chlorine for iodine on 3-chlorolactate (RLM2) was confirmed by NMR (peaks in the aromatic region at 6.84, 7.10 and 7.62 ppm for RLM1, and peaks at 4.31 and 3.56 ppm for RLM2). MCT1 positive (BT20) and negative (MDA-MB-231) breast cancer cell lines were identified (band ≈40 kDa). 3-bromopyruvate decreased viability of BT20 cells by 42% and 91% in 3 and 24 h respectively, as compared to 9% for the MDA-MB-231 cells. Acoustically responsive particles of sizes between 0.5-6 μm were fabricated using PLGA polymer of different molecular weights.  

Conclusion

Agents with the potential for concurrent non-invasive imaging and therapy via the targeting of a widespread metabolic trait of cancer cells are under development.