Rational Design of a Hetero-multinuclear Gadolinium(III)–Copper(II) Complex: Integrating Magnetic Resonance Imaging, Photoacoustic Imaging, Mild Photothermal Therapy, Chemotherapy and Immunotherapy of Cancer

For more accurate diagnosis and effective treatment of cancer, we proposed to develop a hetero-multinuclear metal complex based on the property of apoferritin (AFt) for targeting tumor theranostics by integrating dual-modality imaging diagnosis and multimodality therapy. To this end, we rational designed and synthesized a trinuclear Gd(III)-Cu(II) thiosemicarbazone complex (<b>Gd-2Cu</b>) and then constructed a <b>Gd-2Cu</b>@AFt nanoparticle (NP) delivery system. <b>Gd-2Cu</b>/<b>Gd-2Cu</b>@AFt NPs not only had significant T₁-weighted magnetic resonance imaging and photoacoustic imaging of the tumor but also effectively inhibited tumor growth through a combination of mild photothermal therapy, chemotherapy, and immunotherapy. <b>Gd-2Cu</b>@AFt NPs optimized the behavior of imaging diagnosis and therapy of <b>Gd-2Cu</b>, improved its targeting ability, and reduced the side effects <i>in vivo</i>. Besides, we revealed and clarified the anticancer mechanism of <b>Gd-2Cu</b>: interrupting energy metabolism of the tumor cell, inducing apoptosis of the tumor cell, and activating a systemic immune response by inducing immunogenic cell death of cancer cells.