Hypoxia-Responsive Aggregation of Gold Nanoparticles for Near-Infrared-II Photoacoustic Imaging-Guided Enhanced Radiotherapy.

By directly harming cancer cells, radiotherapy (RT) is a crucial therapeutic approach for the treatment of cancers. However, the efficacy of RT is reduced by the limited accumulation and short retention time of the radiosensitizer in the tumor. Herein, we developed hypoxia-triggered in situ aggregation of nanogapped gold nanospheres (AuNNP@PAA/NIC NPs) within the tumor, resulting in second near-infrared window (NIR-II) photoacoustic (PA) imaging and enhanced radiosensitization. AuNNP@PAA/NIC NPs demonstrated increased accumulation and retention in hypoxic tumors, mainly due to the hypoxia-triggered aggregation. After aggregation of AuNNP@PAA/NIC NPs, the absorption of the system extended from visible light to NIR-II light owing to the plasmon coupling effects between adjacent nanoparticles. Compared to the normoxic tumor, the PA intensity at 1200 nm in the hypoxic tumor increased from 0.42 to 1.88 at 24 h postintravenous injection of AuNNP@PAA/NIC NPs, leading to an increase of 4.5 times. This indicated that the hypoxic microenvironment in the tumor successfully triggered the in situ aggregation of AuNNP@PAA/NIC NPs. The in vivo radiotherapeutic effect demonstrated that this hypoxia-triggered in situ aggregation of radiosensitizers significantly enhanced radiosensitization and thus resulted in superior cancer radiotherapeutic outcomes.