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.