A Smart Photosensitizer:Tumor-triggered Oncotherapy By Self-Assembly Photodynamic Nanodots

Photodynamic therapy(PDT)is a promising therapeutic modality for various malignant cancers.Compared to surgery,chemo-and radio-therapies,which bring severe suffering to patients,PDT causes much milder systemic damage for the non-invasive nature.PDT eliminates tumors through the generation of the highly cytotoxic reactive oxygen species(ROS)and the shutdown of angiogenesis.In addition,in contrast to chemotherapies,which suppress the natural immune systems,PDT stimulates immune responses to facilitate the clearance of cancers.Clinical photosensitizers suffer from the disadvantages of fast photobleaching and high systemic toxicities due to the off-target photodynamic effects.To address these problems,we report a self-assembled pentalysine-phthalocyanine assembly nanodots(PPAN)fabricated by an amphipathic photosensitizer-peptide conjugate.We triggered the PDT effects of photosensitizers by precisely controlling the assembly and disintegration of the nanodots.In physiological aqueous conditions,PPAN exhibited a size-tunable spherical conformation with a highly positive shell of the polypeptides and a hydrophobic core of theπ-stacking Pc moieties.The assembly conformation suppressed the fluorescence and the reactive oxygen species(ROS)generation of the monomeric photosensitizer molecules(mono-Pc),and thus declined the photobleaching and off-target photodynamic effects.However,tumor cells disintegrated PPAN and released mono-Pc molecules,which performed fluorescence and the photodynamic effects for the detection and elimination of tumor tissues.The molecular dynamics(MD)simulation revealed the various assembly configurations of PPAN and illustrated the assembly mechanism.In cellular level,PPAN exhibited remarkable phototoxicity to breast cancer cells with the IC50 values in low nanomolar range.By using a subcutaneous and an orthotopic breast cancer animal models,we also demonstrated the excellent antitumor efficacies of PPAN in vivo.