An effectively isolated chromophore with tetrapodal anionic pendants for hypoxia-triggered photothermal tumor therapy

The anionic tetrapodal perylene diimide (PDI-8COOH) was designed and synthesized to leverage the generation of PDI radical anions (PDI^●–) in response to tumor-specific hypoxic conditions, while addressing the aggregation of PDI and cytotoxicity challenges associated with cationic PDI-based photothermal agents. Four isophthalic acid moieties grafted onto the central PDI chromophore as pendant arms provide spatial separation and charge repulsion, effectively preventing chromophore aggregation even in high-concentration phosphate buffer solutions (PBS, up to 1.5 mM) and deuterium oxide (D₂O, up to 2.0 mM). This design significantly reduces cytotoxicity compared to cationic analogues, and achieves a fluorescence quantum yield of approximately 76.0 %. Under hypoxic conditions, PDI-8COOH^●– generated from PDI-8COOH exhibits strong near-infrared (NIR) photothermal effects with a conversion efficiency of 60.8 %. In vivo experiments demonstrate selective photothermal effects at tumor sites, achieving 98 % tumor inhibition upon 808 nm laser irradiation without significant damage to major organs or normal tissues. This study highlights the superior performance of anionic PDI design in developing safe and specific small-molecule phototheranostic agents, underscoring the importance of rational molecular design for hypoxia-targeted tumor therapy.