Fluorinated Chitosan-Based Theranostic Nanocarrier System for Image-Guided Synergistic Treatment of Hepatocellular Carcinoma.

Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC), but its application is often limited by challenges such as inadequate drug accumulation in tumor tissue, the development of drug resistance, and significant toxic side effects. To address this, this study developed a fluorinated chitosan-based theranostic nanoplatform for the codelivery of the chemotherapeutic drug paclitaxel (PTX) and the photosensitizer 5,10,15,20-tetrakis[3,5-bis(trifluoromethyl)phenyl]porphyrin (FP) by leveraging chitosan's superior biocompatibility and degradability. Using a partial fluorination strategy, fluorinated chitosan (FCS) with a unique fluorine-19 magnetic resonance imaging (19F MRI) signal was effectively synthesized. Subsequently, stable and uniform nanoparticles (PTX-FP@FCS-NPs) were constructed with pH/laser-responsive drug release, which exhibit efficient uptake, laser-triggered reactive oxygen species generation, and synergistic killing effects in HCC cells (with an IC50 merely half that of PTX). PTX-FP@FCS-NPs accumulated selectively in xenograft HUH7 tumors and induced local photothermal heating (ΔT ≈ 30 °C), which enabled 19F MRI/FLI-guided synergistic chemotherapy (Chemo), photodynamic (PDT), and photothermal (PTT) therapy of HCC with high efficacy and favorable biosafety. This study not only developed an effective and safe novel strategy for HCC theranostics but also offers a reference design for constructing multifunctional nanoparticles based on natural polysaccharides.