Schaal et al. report in Nature Biomedical Engineering a strategy to treat pancreatic tumours by combining systemic delivery of the chemotherapeutic drug paclitaxel with brachytherapy via intratumoral injection of a thermally responsive iodine-131 radionuclide-conjugated elastin-like polypeptide (131I-ELP) (top-left panel) (Nat. Biomed. Eng. 6, 1148–1166; 2022). Brachytherapy is a form of radiotherapy in which the radiation source is located proximally to the treatment area. 131I-ELP is liquid at room temperature and forms a coacervate at physiological temperature, leading to localized depots within the tumour. The authors had previously observed that 131I-ELP outperforms classical brachytherapy, thanks to its ability to deliver β-radiation instead of low-dose gamma emissions. Nonetheless, alone it fails to induce pancreatic tumour regression. In parallel, the authors optimized a nanoparticle formulation incorporating a chimeric ELP for paclitaxel delivery (CP-PTX). Then they combined 131I-ELP brachytherapy with either the clinically approved nab-paclitaxel or CP-PTX and obtained high efficacy across multiple human pancreatic subcutaneous (top right panel) and orthotopic (bottom left panel) tumour xenografts in mice, outperforming state-of-the-art EBRT combined with chemotherapy in a subcutaneous model (bottom right panel).
The team delivers 131I-ELP intratumorally, while multiple injections of CP-PTX are injected intravenously. The optimized 131I-ELP and CP-PTX treatment shows positive synergy, by maximizing the temporal overlap between radiotherapy and paclitaxel exposure, which could not be obtained with EBRT. Mechanistically, the exposure to paclitaxel leads to more cells in the radiation-sensitive G2/M phase. Therefore, the continuous release of 131I-ELP β-radiation, combined with multiple chemotherapeutic injections, increases the number of cells eventually exposed to the treatment, compared with the shorter radiation times of EBRT. Moreover, 131I-ELP treatment affects the tumour microenvironment, increasing chemotherapeutic delivery to the tumour. Notably, the team did not observe any sign of acute toxicity.
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