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

For more accurate diagnosis and effective\ntreatment of cancer,\nwe proposed to develop a hetero-multinuclear metal complex based on\nthe property of apoferritin (AFt) for targeting tumor theranostics\nby integrating dual-modality imaging diagnosis and multimodality therapy.\nTo this end, we rational designed and synthesized a trinuclear Gd(III)–Cu(II)\nthiosemicarbazone complex (<b>Gd-2Cu</b>) and then constructed\na <b>Gd-2Cu</b>@AFt nanoparticle (NP) delivery system. <b>Gd-2Cu</b>/<b>Gd-2Cu</b>@AFt NPs not only had significant\nT<sub>1</sub>-weighted magnetic resonance imaging and photoacoustic\nimaging of the tumor but also effectively inhibited tumor growth through\na combination of mild photothermal therapy, chemotherapy, and immunotherapy. <b>Gd-2Cu</b>@AFt NPs optimized the behavior of imaging diagnosis\nand therapy of <b>Gd-2Cu</b>, improved its targeting ability,\nand reduced the side effects <i>in vivo</i>. Besides, we\nrevealed and clarified the anticancer mechanism of <b>Gd-2Cu</b>: interrupting energy metabolism of the tumor cell, inducing apoptosis\nof the tumor cell, and activating a systemic immune response by inducing\nimmunogenic cell death of cancer cells.