Mitochondria-Targeting Multimodal Phototheranostics Based on Triphenylphosphonium Cation Modified Amphiphilic Pillararenes and A–D–A Fused-Ring Photosensitizers

Tumor-targeting phototheranostics has gradually developed as a powerful tool for the precise diagnosis and treatment of cancer. However, the designs of tumor-targeting phototheranostics agents with excellent multimodal phototherapy and fluorescence imaging (FLI) capability, as well as very few components, are still scarce and challenging for cancer treatment. Herein, a mitochondria-targeting multimodal phototheranostics system has been constructed by combining a designed amphiphilic pillararene WP5–2PEG–2TPP and the A–D–A fused-ring photosensitizer F8CA5. WP5–2PEG–2TPP is constructed by attaching the triphenylphosphonium cations to our previously reported dual PEG-functionalized amphiphilic pillararene, which can self-assemble into regular spherical nanocarriers with outstanding mitochondria targeting and water solubility. The A–D–A photosensitizer F8CA5 containing two methyl cyanoacetate group modified end groups displays superior photothermal conversion ability and dual type I/II photodynamic activity as well as strong NIR fluorescence emission. Through their strong union, multifunctional mitochondria-targeting phototheranostics agent F8CA5 NPs were obtained to be applied into FLI-guided synergistic photothermal and type I/II photodynamic therapy. As a result, F8CA5 NPs show good mitochondria-targeting and phototherapy effects in various tumor cells. Not only that, they can combat tumor hypoxia, which hinders the efficacy of photodynamic therapy. Therefore, this work provides a creative ideal for the construction of multifunctional tumor-targeting phototheranostic agents with excellent performance.