Context‐Dependent Radioenhancement by Platinum Nanoparticles Under Conventional and Ultra‐High Dose‐Rate “FLASH” Radiotherapy

ABSTRACT Metallic nanoparticles (NPs) and ultra‐high dose rate (UHDR, FLASH) irradiation are being developed to widen the therapeutic index of radiotherapy, but their interaction remains poorly defined. We assessed PEGylated platinum nanoparticles (Pt‐NPs) in 4T1 tumor spheroids and syngeneic 4T1 and MC38 mouse models exposed to conventional (CONV, 0.125 Gy/s) or UHDR electron irradiation (∼200 Gy/s mean dose rate). Pt‐NPs penetrated throughout 4T1 spheroids and were mainly cytoplasmic. In clonogenic assays, Pt‐NPs increased radiation‐induced loss of reproductive capacity under both dose‐rate conditions. LQ analysis suggested dose‐dependent divergence between modalities, with significantly greater radioenhancement under UHDR only at 12 Gy (SER: 65.9% vs 40.8%, ΔSER = 25.1 percentage points, 95% CI, 2.1–48.1, p = 0.034). Pt‐NPs did not measurably alter apoptosis or γ‐H2AX kinetics. Micro‐CT confirmed intratumoral platinum at irradiation, but in vivo responses were heterogeneous. Pt‐NPs did not improve tumor control in the poorly immunogenic 4T1 model. In the more radiosensitive MC38 model, Pt‐NPs showed a nonsignificant trend toward improved tumor control and survival under CONV, with no comparable UHDR benefit. These findings identify an in vitro‐to‐in vivo disconnect and show that NP radioenhancement cannot be assumed to translate across dose‐rate regimens, tumor models, or host backgrounds.