Long-circulating prostate-specific membrane antigen-targeted NIR phototheranostic agent

摘要

Targeted photodynamic therapy (PDT) combined with image-guided surgical resection is a promising strategy forprecision cancer treatment. Targeting the prostate-specific membrane antigen (PSMA) has drawn significant attention dueto its marked overexpression in a variety of malignant tissues, most notably in prostate cancer. Recently, we reported thedesign of a pyropheophorbide-based long-circulating PSMA-targeted phototheranostic agent for multimodalPET/fluorescence imaging and potent PDT of prostate cancer. While this agent is effective in a subcutaneous mouse model,the non-optimal optical properties of pyropheophorbide (Q_y absorption maximum at 671 nm) pose a limitation fortreatment of deep-seated solid tumors. To further advance PSMA-targeted PDT and enable effective treatment to thedeeper layers of tumor tissue, we developed a bacteriochlorophyll-based PSMA-targeted photosensitizer (BPP) whichconsists of three building blocks: 1) a urea-based PSMA-affinity ligand, 2) a peptide linker to prolong plasma circulationtime, and 3) a bacteriochlorophyll photosensitizer for NIR fluorescence imaging (Q_y absorption maximum at 750 nm).BPP demonstrated effective cell internalization as well as PDT activity in PSMA-expressing PC3-PIP cells. Furthermore,this agent possesses excellent targeting selectivity in vivo as demonstrated in a dual PSMA-positive and PSMA-negativesubcutaneous tumor model. The peptide linker in BPP allowed for its long plasma circulation time (12.65 hours), whichenabled its effective tumor accumulation. Overall, bright NIR fluorescence of BPP enables effective image guidance forsurgical resection, while the combination of its superb targeting and strong PDT activity allows for potent and precisephotodynamic treatment of deep-seated tumors.