Photostable Mn(II) Complex of Curcumin for Effective Photodynamic Therapy and Precise Three-Dimensional <i>In Vivo</i> Tumor Imaging

Photoactive complexes of first-row transition metals with emission properties offer a dual approach to cancer treatment, enabling precise optical tumor detection and subsequent eradication using light. We report a photostable and photoactive mixed-ligand Mn(II) complex, <b>Mn4</b>, featuring a naturally occurring curcumin ligand and dipyridophenazine base. <b>Mn4</b> demonstrates significant visible and red light-triggered phototoxicity against cancer cells and precise tumor imaging capability <i>in vivo</i>. The complex exhibits an absorption band in the visible region, extending its tail into the red region, and shows excellent dark and photostability in solution. <b>Mn4</b> induces significant phototoxicity against HeLa (cervical), A549 (lung), and MCF-7 (breast) cancer cells (IC₅₀ ≈ 1.0 μM), as well as 3D multicellular tumor spheroids, under low-energy visible (400-700 nm) and red-light (660 nm). This effect is mediated by cytotoxic singlet oxygen and proceeds via an apoptotic mechanism. Importantly, <b>Mn4</b> displays significantly lower toxicity toward normal HPL1D lung and HEK-293 kidney cells under similar conditions. Cellular uptake studies reveal selective accumulation of <b>Mn4</b> in A549 cancer cells, with mitochondrial localization, and negligible accumulation in BEAS-2B normal lung cells. Furthermore, 3D optical tumor imaging demonstrated <b>Mn4</b>'s selective tumor accumulation in a 4T1 breast tumor-bearing <i>in vivo</i> mouse model. <i>In vivo</i> efficacy studies using a 4T1 tumor-bearing orthotopic mouse model show that <b>Mn4</b> significantly reduces tumor volume and weight in a dose-dependent manner under low-energy blue laser (450 nm) irradiation, highlighting its potential as an effective photodynamic therapy (PDT) agent. Toxicological studies confirm that <b>Mn4</b> does not induce abnormal biochemical or hematological parameters in healthy mice. To our knowledge, this is the first report of a Mn(II) complex with curcumin and the first example of a metal complex with curcumin for combined <i>in vivo</i> PDT and noninvasive 3D optical tumor imaging, paving the way for nonmacrocyclic Mn-based cancer phototheranostics.