2026-10-14T05:19:36Z https://api.figshare.com/v2/oai

oai:figshare.com:article/32641341 2026-10-01T16:23:57Z portal_1172 item_type_8 month_year_10_2026

Enhancing the effectiveness of radiotherapy by targeting tumour metabolism: a microfluidic approach to nanotherapeutic formulation Meabh Doherty (21158211) PUREID: 642266849 Radiotherapy tumour metabolism tumour microenvironment microfluidics nanoparticles liposomes radiosensitisation Metabolic flexibility is a major hallmark of cancer that allows tumour cells to thrive in challenging environments, while conferring resistance to conventional treatments such as radiotherapy. The work presented within investigated metabolic modulation strategies to enhance tumour cell radiosensitivity by inhibiting the monocarboxylate transporters (MCT1/4) and the mitochondrial pyruvate carrier (MPC), whilst exploring liposomal delivery systems to improve therapeutic efficacy.<br><br>Initial studies demonstrated the radiosensitising potential of MPC inhibition using the small molecule inhibitor 7ACC2. We report that 7ACC2 altered cell metabolism by reducing oxygen consumption rate (OCR) and increasing extracellular acidification (ECAR). Additionally, we demonstrate enhanced radiosensitivity in both prostate (PC3) and head and neck (FaDu) tumour models, a mechanism underpinned by local reoxygenation. By blocking pyruvate transport, 7ACC2 increased intracellular oxygen availability during radiation, leading to elevated ROS levels and increased DNA double strand break damage.<br><br>Subsequently, we developed a novel liposomal formulation (Lipo-7ACC2) using microfluidics. DPPC liposomes demonstrated optimal characteristics in terms of size and homogeneity, achieving high 7ACC2 encapsulation, controlled drug release and good stability. Finally, we investigated cellular uptake mechanisms using a model fluorescent liposome system. Whilst Lipo-7ACC2 demonstrated promising radiosensitising potential in 3D tumourspheres, reduced efficacy compared to free drug indicated opportunities for formulation enhancement.<br><br>In conclusion, this work demonstrates that metabolic modulation can enhance radiotherapy effectiveness in cancer treatment. The work presented highlights 7ACC2 mediated MPC inhibition as an effective metabolic radiosensitiser. While the liposomal formulation shows potential, further optimisation is needed. These findings lay groundwork for developing future metabolic radiosensitisers.<br><br><i>Thesis is embargoed until 31 July 2030.</i> 2026-10-01T16:23:57Z Text Thesis 10.17034/32641341.v1 https://figshare.com/articles/thesis/Enhancing_the_effectiveness_of_radiotherapy_by_targeting_tumour_metabolism_a_microfluidic_approach_to_nanotherapeutic_formulation/32641341 All Rights Reserved Open Access after 2030-07-31