Fraser, B. | bioRxiv Science

bioRxiv2023

Neutron capture enhances dose and reduces cancer cell viability in and out of beam during helium and carbon ion therapy.

PurposeNeutron Capture Enhanced Particle Therapy (NCEPT) is a proposed augmentation of charged particle therapy which exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with two different targeted neutron capture agents (NCAs). Materials and MethodsHuman glioblastoma cells (T98G) were irradiated by carbon and helium ion beams in the presence of NCAs, [10B]-BPA and [157Gd]-DOTA-TPP. Cells were positioned within a PMMA phantom either laterally adjacent to, or within, a 100x100x60 mm spread out Bragg peak (SOBP). The impact of NCAs and location relative to the SOBP on the cells was measured by cell growth and survival assays in six independent experiments. Neutron fluence within the phantom was characterised by quantifying the neutron activation of gold foil. ResultsCells placed inside the treatment volume reached 10% survival by 2 Gy of C or 2-3 Gy of He in the presence of NCAs compared to 5 Gy of C and 7 Gy of He with no NCA. Cells placed adjacent to the treatment volume showed a dose-dependent decrease in cell growth when treated with NCAs, reaching 10% survival by 6 Gy of C or He (to the treatment volume), compared to a no detectable effect on cells without NCA. The mean thermal neutron fluence at the centre of the SOBP was approximately 2.2x109 n/cm2/Gy(RBE) for the carbon beam and 5.8x109 n/cm2/Gy(RBE) for the helium beam and gradually decreased in all directions. ConclusionsThe addition of NCAs to cancer cells during C and He beam irradiation has a measurable impact on cell survival and growth in-vitro. Through the capture of internally generated neutrons, NCEPT introduces the concept of a biochemically targeted radiation dose to charged particle therapy. NCEPT enables the established pharmaceuticals and concepts of neutron capture therapy to be applied to a wider range of deeply situated and diffuse tumours, by targeting this dose to micro-infiltrates and cells outside of defined treatment regions. These results also demonstrate the potential for NCEPT to provide an increased dose to tumour tissue within the treatment volume, with a reduction in radiation doses to off target tissue.

biophysics↗

bioRxiv2023

Development of peptides for targeting cell ablation agents concurrently to the Sertoli and Leydig cell populations of the testes: an approach to non-surgical sterilization

The surgical sterilization of cats and dogs has been used to prevent their unwanted breeding for decades, but this is an expensive and invasive procedure, and often impractical in wider contexts, for example the control of feral populations. A sterilization agent that could be administered in a single injection would not only eliminate the risks imposed by surgery but also be a much more cost-effective solution to this worldwide problem. In this study, we sought to develop a targeting peptide that would selectively bind to Leydig cells of the testes. Subsequently, after covalently attaching a cell ablation agent, Auristatin, to this peptide we aimed to apply this conjugated product (LH2Auristatin) to adult male mice in vivo, both alone and together with a previously developed Sertoli cell targeting peptide (FSH2Menadione). The application of LH2Auristatin alone resulted in an increase in DNA damage, reduced mean testes weights and mean seminiferous tubule size, along with extensive germ cell apoptosis and a reduction in litter sizes. Together with FSH2Menadione there was also an increase in embryo resorptions. These promising results were observed in around a third of all treated animals. Given this variability we discuss how these reagents might be adjusted in order to increase target cell ablation and improve their efficacy as sterilization agents.

biochemistry↗