Side-chain engineering of organic photothermal agents for boosting further red-shifted absorption and higher photothermal therapeutic effect

Although organic photothermal agents (PTAs) have been extensively studied in preclinical cancer photothermal therapy (PTT), the internal mechanism, particularly the impact of side chains on photothermal performance, remains inadequately investigated. Herein, we conducted a systematic comparison of the photothermal properties between two organic molecules, namely O-IDTBR with four n-octyl chains and EH-IDTBR with four 2-ethylhexyl chains. With the same conjugated main structure, both O-IDTBR and EH-IDTBR exhibited nearly identical absorption properties (with a peak at 629 nm) in their molecular states. Interestingly, after the formation of nanoparticles (NPs), O-IDTBR NPs with linear alkyl chains exhibit a further red-shifted absorption onset (peak at 711 nm) compared to EH-IDTBR NPs (peak at 662 nm) with branched alkyl chains. Additionally, the photothermal conversion efficiency of O-IDTBR NPs was calculated of 33.7%, which is higher than that of EH-IDTBR NPs (27.7%). This can be attributed to the fact that linear alkyl chains of O-IDTBR NPs promote more intramolecular motions at the aggregated state by extending intermolecular distance and distorting molecular conformation. Therefore, the nonradiative thermal deactivation-induced photothermal property can be further enhanced. Through both in vitro and in vivo experiments, O-IDTBR NPs exhibit effective PTT effect and excellent biocompatibility. This study not only introduces a novel PTA but also opens new avenues for exploring organic optical nano-agents through side-chain engineering to adjust intramolecular motions at the aggregated state.