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.

Most recent advances on enzyme‐activatable optical probes for bioimaging

“…Reproduced with permission. [ 122 ] Copyright 2020, American Chemical Society. (D) In ‐ vitro sensing ability of cathepsin B and the in ‐ vivo therapeutic applicability of 36 .…”

“…Considering the critical roles of cathepsin B in tumor-associated processes, a series of cathepsin Bactivatable probes have been recently reported for bioimaging or theranostics. [120][121][122][123][124] The most recently reported probes 35 and 36 are depicted in Figure 17 to elucidate the design principle, working mechanism, and performance of cathepsin Bactivatable probes.…”

“…Wang et al utilized a sequential strategy to improve the specificity of theranostics, that is, Pep-SQ@USPIO (35), for MR/NIR FL bimodal imagingguided PDT for triple negative breast cancer (Figure 17A and B). [122] In the cathepsin B-activatable theranostic system 35, the squaraine (SQ) derivative is both a photosensitizer and an NIR fluorophore, and the cleavable substrate of cathepsin B, namely Gly-Phe-Leu-Gly (GFLG) peptide, and the fibronectin-targetable Cys-Arg-Glu-Lys-Ala (CREKA) were conjugated to SQ. The resulting Pep-SQ was linked to maleimide-DSPE-PEG-decorated ultrasmall superparamagnetic iron oxide (USPIO) through covalent attachment between cysteine unit of Pep-SQ and maleimide to produce Pep-SQ@USPIO (35), where the MRI contrast agent USPIO also functions as the quencher or energy acceptor of SQ.…”

Rational design of aqueous conjugated polymer nanoparticles as potential theranostic agents of breast cancer

“…Among different types of superficial tumors, breast cancer represents the most commonly diagnosed cancer, accounting approximately for the 30% of all estimated new cancer cases globally in the female population and is regarded as the second leading cause of cancer-related mortality. [41][42][43] Based on immunohistochemistry, breast cancer can be divided into three main subtypes according to the expression of three crucial receptors, which are estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2). If the tumors do not express any of these three receptors it is the so-called triple negative breast cancers (TNBC), making it difficult to target.…”

<p>Facile Synthesis of Melanin-Dye Nanoagent for NIR-II Fluorescence/Photoacoustic Imaging-Guided Photothermal Therapy</p>

“…2 Recent studies, including those regarding the detection of metastatic lymph nodes, 3 tumor and vessel imaging, [4][5][6] and intraoperative guidance, 7,8 have shown that biological imaging advantages significantly improves as wavelengths increase. Thus far, quantum dots, [9][10][11] carbon nanotubes, 12,13 rare earth-doped nanoparticles, 14,15 squaraine dyes, 16,17 semiconducting polymer nanoparticles, 18 and small-molecule dyes 5,19,20 have all been actively used for NIR-II imaging. The recent rapid development of small molecule dyes, in particular, has led to the use of effective probes for NIR-II fluorescence bioimaging.…”