Evolving an Ultra-Sensitive Near-Infrared ß-Galactosidase Fluorescent Probe for Breast Cancer Imaging and Surgical Resection Navigation.

Early diagnosis and therapy are clinically crucial in decreasing mortality from breast carcinoma. However, the existing probes have difficulty in accurately identifying the margins and contours of breast carcinoma due to poor sensitivity and specificity. There is an urgent need to develop high-sensitive fluorescent probes for the diagnosis of breast carcinoma and for differentiating tumors from normal tissues during surgery. ß-Galactosidase is a significant biomarker, whose overexpression is closely associated with the progression of breast tumors. Herein, we have constructed a ß-galactosidase-activated fluorescent probe NIR-ßgal-2 through rational design and molecular docking engineering simulations. The probe displayed superior sensitivity (detection limit = 2.0 × 10-3 U/mL), great affinity (Km = 1.84 µM), and catalytic efficiency (kcat/Km = 0.24 µM-1 s-1) for ß-galactosidase. Leveraging this probe, we demonstrated the differentiation of cancer cells overexpressing ß-galactosidase from normal cells and then applied the probe for intraoperative guided excision of breast tumors. Moreover, we exhibited the application of NIR-ßgal-2 for the successful resection of orthotopic breast tumors by "in situ spraying" and monitored a good prognostic recovery. This work may promote the application of enzyme-activated near-infrared fluorescent probes for the development of carcinoma diagnosis and image-guided surgery.

Enhancing the Release Efficiency of a Molecular Chemotherapeutic Prodrug by Photodynamic Therapy.

Tumor-specific, hypoxia-activated prodrugs have been developed to alleviate the side effects of chemotherapy drugs. However, the release efficiency of hypoxia-activated prodrugs is restricted by the degree of tumor hypoxia, which further leads to poor cancer treatment effects. On the other hand, oxygen is consumed gradually in photodynamic therapy (PDT), which aggravates hypoxia at the tumor site. In this study, we combined hypoxia-activated prodrugs with PDT agents to promote the prodrugs release, thereby improving their bioavailability and therapeutic effects. As a proof of concept, a mitochondria-targeted molecular prodrug, CS-P, was designed and synthesized. It can be selectively activated by tumor hypoxia to release chemotherapeutic drugs and photosensitizers, and then further discharge drugs after light irradiation. The design strategy proposed in this paper provides a new idea for enhancing hypoxia-activated prodrug release and real-time monitoring prodrug release.