One-pot synthesis of conjugated small molecules for construction of NIR fluorescence/photoacoustic dual-modal imaging nanoagents with improved photothermal/photodynamic/chemodynamic effects

Theranostic nanoagents based on conjugated small molecules (CSMs) have attracted widespread interest in fluorescence (FL)/photoacoustic (PA) imaging and phototherapy for cancer, because CSMs exhibit not only excellent photophysical properties but also good synthetic repeatability and biosafety due to the small molecular weight, which are very important for further clinical applications. However, CSMs have rarely been studied for near-infrared (NIR) phototheranostics, especially in the NIR-II window, because of insufficient degree of conjugation. Herein, we employed bithiophenyl diketopyrrolopyrrole as acceptor (A), fluorene as donor (D), and vinylbenzene as it-bridge, two types of CSMs with D-it-A and D-it-A-it-D structure (FVD and FVDVF) were thus designed and simultaneously synthesized through a facile one-pot Heck reaction. Then, FVD@F127 nanoparticles (NPs) and FVDVF@F127 NPs were prepared by encapsulating the corresponding CSM with the hydrophilic polymer F127, achieving good water solubility, biocompatibility, and the CSMs-mediated synergistic photothermal/photodynamic effects. Subsequently, MnO2 NPs were loaded on their surface to obtain FVD@F127@MnO2 NPs and FVDVF@F127@MnO2 NPs, which responded to glutathione/H2O2 in the tumor microenvironment to produce cytotoxic center dot OH and in situ O2 supply, leading to enhanced photodynamic effect, additional photothermal and chemodynamic effects. In vitro and in vivo studies of the final two NPs demonstrated that they were both promising NIR FL/PA dual-modal imaging nanoagents with improved photothermal/ photodynamic/chemodynamic effects. Comparatively, FVD@F127@MnO2 NPs displayed better photodynamic effects because of the heavy atom Br in FVD, and FVDVF@F127@MnO2 NPs exhibited excellent NIR-II FL imaging capability (QY = 0.25 %), much better PA imaging performance and photothermal effects (eta = 68.5 %) owing to a larger molecular structure coplanarity of FVDVF.