Carbon Ion FLASH Dose-Rate Radiotherapy: First Investigation in Human Brain Organoids

Abstract

<h3>Purpose/Objective(s)</h3> In this work, we investigated and compared the effects of carbon ion ultra-high dose-rate (uHDR; FLASH) vs standard dose-rate (SDR) beams on brain organoids. <h3>Materials/Methods</h3> For testing the effects of high dose-rate radiotherapy using carbon ions, dose rates of ∼40 Gy/s (uHDR) and 0.15 Gy/s (SDR) were applied at 7.4 Gy dose (LETd = 12 keV µm-1). The effectiveness of uHDR vs. SDR carbon ion beams was tested using brain organoids generated from human induced pluripotent stem cells (iPS). Brain organoids were evaluated for their cellular composition and radiation induced DNA-damage repair using immunofluorescence. Quantitative analysis was performed using semi-automated imaging software. <h3>Results</h3> Multicellular brain organoids were characterized by the presence of neuronal progenitor cells (nestin positive), more differentiated neurons (Tuj1 positive), and astrocytic cells (GFAP positive). Following irradiation, the cells were further evaluated for presence of radiation induced DNA double strand breaks surrogated by nuclear γH2AX foci (RIF). While both uHDR and SDR irradiations led to RIF formation, uHDR markedly expressed reduced RIF vs. SDR at 1-hour post-irradiation. <h3>Conclusion</h3> This study indicates feasibility of brain organoids as a healthy brain tissue model for studying the effects of particle radiation. Here reported encouraging normal tissue sparing effect of uHDR carbon ion beams, at relevant plateau LET level, warrants further investigation of carbon ion FLASH radiotherapy.