Design of benzo[1,2-b:4,3-b′]dithiophene-4,5-dione based donor-acceptor-donor small molecules for efficient near-infrared photothermal therapy

The development of high-performance organic photothermal conversion agents (PTCAs) with strong near-infrared (NIR) absorption, high photothermal conversion efficiency (PCE), and excellent biocompatibility remains a critical challenge in photothermal therapy (PTT). In this study, we designed and synthesized a series of novel donor-acceptor-donor (D-A-D) small molecules based on a benzo[1,2-b:4,3-b']dithiophene-4,5-dione (BDTD-4,5-dione) core as a strong electron-accepting unit, symmetrically functionalized with triphenylamine (TPA) derivatives as tunable electron donors. By focusing on the strong electron-donating N,N-dimethylaniline (NPA) unit-contrasted with a methoxy-substituted analog-we achieved effective modulation of the HOMO energy, bandgap, and supramolecular aggregation, underscoring the advantage of enhanced donor strength for photothermal applications. Spectroscopic and electrochemical analyses revealed that electron-rich substituents significantly redshifted the intramolecular charge transfer (ICT) absorption into the NIR region (650-900 nm) and enhanced molar extinction coefficients. Among the derivatives, the dimethylamino-functionalized compound (BDQ-NPA) exhibited the most redshifted absorption, a narrow bandgap (2.0 eV), and an outstanding PCE of 35.05% under 808 nm laser irradiation. Theoretical calculations confirmed strong D-A interactions and efficient charge separation in the excited state. BDQ-NPA self-assembled into stable nanoparticles with excellent photostability and biocompatibility, facilitating efficient cellular uptake and NIR-triggered photothermal ablation of cancer cells in vitro. In vivo studies demonstrated significant tumor growth inhibition in a murine model following a single dose of BDQ-NPA and 808 nm irradiation, with no observable systemic toxicity. This work establishes BDTD-4,5-dione as a promising acceptor core for NIR-absorbing organic PTCAs and highlights the efficacy of substituent engineering in optimizing photothermal performance for cancer theranostics.