Fibronectin-Targeting and Cathepsin B-Activatable Theranostic Nanoprobe for MR/Fluorescence Imaging and Enhanced Photodynamic Therapy for Triple Negative Breast Cancer

Abstract

Because of the lack of specific targets, the highly aggressive triple negative breast cancer (TNBC) is unable to benefit from endocrine therapy or conventional targeting therapy. Even worse, current diagnostic and therapeutic approaches have limited value for TNBC. Therefore, developing TNBC-specific theranostic probes for accurate diagnosis and further selective therapy will build a powerful toolbox for TNBC management. In this contribution, we developed a sequential strategy to enhance the specificity of TNBC theranostics. In this theranostic system, a versatile nanoprobe (Pep-SQ@USPIO) was integrated legitimately for the fibronectin-targeting MR imaging and CTSB-activatable fluorescence imaging, followed with enhanced photodynamic therapy (PDT) of TNBC. First, the fibronectin overexpressed in the extracellular matrix (ECM) of TNBC was used as a biomarker for targeting theranostics using the Cys-Arg-Glu-Lys-Ala (CREKA) peptide. For another, the fluorescence and PDT capacity of self-developed squaraine photosensitizer (SQ) were prequenched by ultrasmall superparamagnetic iron oxide (USPIO), an MR imaging contrast agent. Once the linker, Gly-Phe-Leu-Gly (GFLG) peptide, was selectively cleaved by TNBC-derived CTSB, the liberated SQ photosensitizer allowed light-up fluorescence imaging and enhanced PDT of TNBC. Remarkably, this research demonstrates that tumor-ECM-targeting and endogenous enzyme-activated nanoprobes open a new avenue for TNBC theranostics.