Dual stimuli-activatable versatile nanoplatform for photodynamic therapy and chemotherapy of triple-negative breast cancer

Photodynamic therapy (PDT) has emerged as an efficient cancer treatment method with minimal invasiveness. However, the majority of current photosensitizers (PSs) display severe dark toxicity and low tumor specificity due to their always-on photoactivity in blood circulation. To address this concern, we herein report a series of acid-activatable PSs for ultrasensitive PDT of triple-negative breast tumors. These set of novel PSs are synthesized by covalently modifying tetrakis(4-carboxyphenyl)porphyrin (TCPP) with a variety of tertiary amines for acidity-activatable fluorescence imaging and reactive oxygen species (ROS) generation. The resultant TCPP derivatives are grafted with a poly(ethylene glycol) (PEG) chain via a matrix metalloproteinase-2 (MMP-2)-liable peptide spacer and chelated with Mn 2 + for magnetic resonance imaging (MRI) capability. The PEGylated TCPP derivatives are amphiphilic and self-assemble into micellar nanoparticles to elongate blood circulation and for tumor-specific PDT. We further demonstrate that the PEGylated TCPP nanoparticles could serve as a nanoplatform to deliver the anticancer drug doxorubicin (DOX) and perform fluorescence image-guided combinatorial PDT and chemotherapy, which efficiently suppress the growth of 4T1 breast tumors and lung metastases in a mouse model. These acid-activatable PS-incorporated nanoparticles might provide a versatile platform for precise PDT and combinatorial breast cancer therapy.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

Photodynamic therapy (PDT) is an efficient and minimally invasive cancer treatment method. However, current photosensitizers often exhibit dark toxicity and low tumor specificity. To address this issue, researchers have developed a series of acid-activatable photosensitizers for highly sensitive PDT of triple-negative breast tumors. These novel photosensitizers can be activated in an acidic environment to generate reactive oxygen species (ROS) and emit fluorescence. They are also modified with a poly(ethylene glycol) (PEG) chain for prolonged blood circulation and magnetic resonance imaging (MRI) capability. The PEGylated photosensitizers can self-assemble into micellar nanoparticles for targeted tumor PDT. Furthermore, these nanoparticles can deliver the anticancer drug doxorubicin (DOX) and be used for fluorescence image-guided combination PDT and chemotherapy, effectively suppressing tumor growth in a mouse model. These acid-activatable photosensitizer-incorporated nanoparticles provide a versatile platform for precise PDT and combination breast cancer therapy.