Rational designed highly sensitive NQO1-activated near-infrared fluorescent probe combined with NQO1 substrates in vivo: An innovative strategy for NQO1-overexpressing cancer theranostics

Since NQO1 is overexpressed in many cancer cells, it can be used as a biomarker for cancer diagnosis and targeted therapy. NQO1 substrates show potent anticancer activity through the redox cycle mediated by NQO1, while the NQO1 probes can monitor NQO1 levels in cancers. High sensitivity of probes is needed for diagnostic imaging in clinic. In this study, based on the analysis of NQO1 catalytic pocket, the naphthoquinone trigger group 13 rationally designed by expanding the aromatic plane of the benzoquinone trigger group 10 shows significantly increased sensitivity to NQO1. The sensitivity of the naphthoquinone trigger group-based probe A was eight times higher than that of benzoquinone trigger group-based probe B in vivo. Probe A was selectively and efficiently sensitive to NQO1 with good safety profile and plasma stability, enabling its combination with NQO1 substrates in vivo for NQO1-overexpressing cancer theranostics for the first time. [Display omitted] •Novel NQO1-activated NIR probe with a naphthoquinone-based trigger group.•Significantly increased sensitivity for NQO1 imaging in vivo.•Probe A combined with NQO1 substrates for NQO1-overexpressing cancer theranostics.