Organic Theranostic Nanoplatform with Enhanced Fluorescence and Singlet Oxygen Quantum Yield for Tumor-Targeting Image-Guided Photodynamic/Photothermal Synergistic Therapy

The development of biocompatible therapeutic agents to achieve tumor-targeting photothermal/photodynamic synergistic therapy under imaging guidance is crucial for effective cancer phototherapy. Herein, we elaborately designed an organic theranostic nanoplatform, Ce6@HA-Cys-TTDTT nanoparticles (NPs), in which the active targeting moiety hyaluronic acid (HA) was conjugated with a hydrophobic conjugated oligomer TTDTT through the side chain of cystamine (Cys) to form an amphiphilic polymer, and then an excellent photosensitizer chlorin e6 (Ce6) was encapsulated by self-assembly. Bithiophenyl diketopyrrolopyrrole (TDPP) and triphenylamine were utilized as the acceptor (A) and donor (D), respectively, to construct the D–A–D molecule TTDTT, which served as an excellent photothermal agent with a moderate 1O2 quantum yield and quenched fluorescence (FL) in HA-Cys-TTDTT NPs. However, Ce6@HA-Cys-TTDTT NPs exhibited obviously higher 1O2 quantum yields (ΦΔ = 53.0%) and FL intensity than HA-Cys-TTDTT NPs (ΦΔ = 29.6%) and free Ce6 under laser irradiation at 635 nm and still maintained a high photothermal conversion efficiency (η = 37.7%). These results may be attributed to the efficient energy transfer from TTDTT to Ce6 in Ce6@HA-Cys-TTDTT NPs and the facilitation of the transition of singlet-to-triplet excited state via an intersystem crossing pathway. Ce6@HA-Cys-TTDTT NPs presented high tumor targeting capability in FL/thermal imaging in vivo and significant advantages over free Ce6 in long-term FL imaging in vivo. The remarkable antitumor efficacy of Ce6@HA-Cys-TTDTT NPs under a single wavelength laser irradiation was confirmed through in vitro and in vivo experiments. In this study, a multifunctional organic theranostic nanoplatform was designed to enhance the effect of tumor phototherapy, benefiting from the tumor-targeting multimodal imaging-guided photodynamic/photothermal synergistic therapy.