From Small Molecules to Polymers: Developing Non-Fullerene Acceptors for Efficient NIR Photothermal Cancer Therapy

Developing organic photothermal agents that are highly stable and have tunable electronic properties is important for advancing low-invasive cancer therapy. In this study, we present the synthesis and evaluation of three conjugated photothermal agents inspired by non-fullerene Y-series acceptors: the small molecule BTPT-OD, as well as two of its polymer derivatives with regular (<i>r</i>-BTPT) and irregular (<i>ir</i>-BTPT) structures. All of the compounds absorb light effectively in the red and near-infrared spectral ranges, with absorption maxima from 734 to 746 nm, and form stable nanoparticles (NPs) via nanoprecipitation, ranging in size from 13 to 39 nm. NPs exhibited negative surface charges, with <i>ζ</i>-potentials of -12.9, -15.5, and -17.9 mV for BTPT-OD, <i>r</i>-BTPT, and <i>ir</i>-BTPT NPs, respectively. Irradiation at a wavelength of 730 nm revealed that <i>r</i>-BTPT and <i>ir</i>-BTPT polymer NPs exhibited a 22- to 40-fold greater phototoxicity against A-549, Sk-Br-3, and MCF-7 human carcinoma cells than the non-polymeric analogue BTPT-OD. The measured photothermal conversion efficiencies ranged from 24 to 27 ± 5%. At the same time, the intracellular ROS generation quantified by the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay was low, allowing us to propose heat-mediated photothermal therapy as a more significant cell death predictor than ROS-mediated photodynamic therapy. This work is one of the first to compare small and polymeric non-fullerene acceptor materials for phototherapy purposes, demonstrating the advantages of using polymers.