A NIR iridium(III) complex-based luminescence probe for imaging mitochondria pyruvate dehydrogenase kinase 1 in triple-negative breast cancer cells

Abstract

The aberrant expression of mitochondrial pyruvate dehydrogenase kinase 1 (PDK1) is highly associated with tumorigenesis and metastasis of triple-negative breast cancer (TNBC). However, because of the dearth of highly sensitive and targetable probes for PDK1, the precise imaging of mitochondrial PDK1 in TNBC cells remains challenging. We herein describe the first near-infrared (NIR) luminescence probe for visualizing PDK1 in TNBC living cells through conjugating a PDK1 inhibitor, dichloroacetic acid (DCA), to an iridium(III) complexes. This probe retains not only the favorable optical characteristics of iridium complexes, but also the specific binding ability of DCA for PDK1. The probe can sensitively and specifically detect mitochondria PDK1 in TNBC cells, as verified by cellular thermal shift assay (CETSA), knockdown and selectivity experiments. Moreover, complex 1 has the capability for imaging TNBC spheroids and zebrafish models with good imaging contrast and penetration, presumably benefiting from its PDK1 targetability and NIR property. Importantly, the probe shows negligible luminescence in normal cell lines with low expression of PDK1, demonstrating its ability to discriminate TNBC cells from normal cells. This probe, which acts through the interplay of both low oxygen diffusion and a rigid microenvironment upon binding to PDK1, could provide mechanistic insights into the biological roles of PDK1 in TNBC and support the development of PDK1-based TNBC diagnostic probes in vivo.