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 Mn2+ 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. A library of tetrakis (4-carboxyphenyl) porphyrin (TCPP)-based photosensitizers (PS) with tunable pKa values were synthesized to reduce dark toxicity and improve tumor specificity. A dual-modal imaging-guided multifunctional nanoplatform was thereafter developed by self-assembling poly(ethylene glycol)-modified TCPP derivatives for tumor-specific distribution and combinatory therapy. [Display omitted]