Context-Dependent Radioenhancement by Platinum Nanoparticles Under Conventional and Ultra-High Dose-Rate "FLASH" Radiotherapy.

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.