Four-in-one multifunctional iron(iii) complex for cancer theranostics: unique integration of targeted delivery, photodynamic therapy, and dual imaging modalities

Abstract

3d transition metal complexes are increasingly valued for their theranostic roles in cancer, owing to their biocompatibility, cost-effectiveness, and multifunctional capabilities. We report a glucose-conjugated Fe(III) complex, Fe2, designed as a cancer theranostic agent by uniquely integrating four distinct functionalities: glucose-driven targeting, photodynamic therapy, optical imaging, and MRI contrast enhancement. Fe2 selectively targets cervical and breast cancer cells by capitalizing on the overexpression of glucose transporter-1 (GLUT-1) transmembrane protein. Its distinct ligand-to-metal charge transfer (LMCT) absorption band in the red region enables effective red-light photodynamic therapy for deep-tissue penetration, while its emission band supports optical cellular imaging. Additionally, its high-spin paramagnetic Fe(III) center facilitates T₁-weighted MRI contrast enhancement. Fe2 demonstrates good water solubility and high aqueous stability under dark and irradiated conditions and in reducing environments, such as in the presence of reduced glutathione (GSH). Fe2 shows significant red-light phototoxicity in cervical (HeLa) and breast (MCF-7) cancer cells (IC₅₀ ∼ 14.1 and 9.2 μM, respectively) while being non-toxic in the dark or healthy breast epithelial cells (MCF-10A, IC₅₀ > 200 μM). Cytotoxicity and cellular uptake studies confirm GLUT-1-mediated selective uptake of Fe2 in cancer cells over normal cells. Fe2 induces apoptosis via oxidative stress, activating both type-I and type-II photophysical pathways upon irradiation. Optical imaging studies confirm Fe2's mitochondrial localization in HeLa and MCF-7 cells. Fe2 exhibits impressive relaxivity (r_1p = 5.2 mM⁻¹ s⁻¹), attributed to interactions with human serum, and MRI phantom studies confirm significant contrast enhancement in MCF-7 cells. To our knowledge, Fe2 is the first complex to uniquely integrate these four functionalities, establishing it as a promising theranostic candidate and paving the way for designing carbohydrate-conjugated, photoactive paramagnetic complexes for targeted cancer theranostics.