Developing a Copper(II) Isopropyl 2-Pyridyl Ketone Thiosemicarbazone Compound Based on the IB Subdomain of Human Serum Albumin-Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment.

To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed a copper (Cu) compound based on the properties of the human serum albumin (HSA)-indomethacin (IND) complex to remodel the tumor microenvironment (TME). We optimized a series of Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds to obtain a Cu(II) compound (C4) with significant cytotoxicity and then constructed an HSA-IND-C4 complex (HSA-IND-C4) delivery system. IND and C4 bind to the hydrophobic cavities of the IB and IIA domains of HSA, respectively. In vivo, the HSA-IND-C4 not only showed enhanced antitumor efficacy relative to C4 and C4 + IND but also improved their targeting ability and decreased their side effects. The antitumor mechanism of C4 + IND involved acting on the different components of the TME. IND inhibited tumor-related inflammation, while C4 not only induced apoptosis and autophagy of cancer cells but also inhibited tumor angiogenesis.

Developing a Hetero-Trinuclear Erbium(III)-Copper(II) Complex Based on Apoferritin: Targeted Photoacoustic Imaging and Multimodality Therapy of Tumor.

For the integration of targeted diagnosis and treatment of tumor, we innovatively designed and synthesized a single-molecule hetero-multinuclear Er(III)-Cu(II) complex (ErCu2) and then constructed an ErCu2@apoferritin (AFt) nanoparticle (NP) delivery system. ErCu2 and ErCu2@AFt NPs not only provided an evident photoacoustic imaging (PAI) signal of the tumor but also effectively inhibited tumor growth by integrating photothermal therapy, chemotherapy, and immunotherapy. ErCu2@AFt NPs improved the targeting ability and decreased the systemic toxicity of ErCu2 in vivo. Furthermore, we confirmed that ErCu2 and ErCu2@AFt NPs inhibited tumor growth by inducing apoptosis and autophagy of tumor cells and activating the immune system. The study not only provides a novel strategy to develop therapeutic metal agents but also reveals their potential for targeted accurate diagnosis and multimodality therapy of cancer.

Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis.

To develop next-generation metal drugs with high efficiency and low toxicity for targeting inhibition of gastric tumor growth and metastasis, we not only optimized a series of ruthenium (Ru, III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes to obtain a Ru(III) complex (4b) with remarkable cytotoxicity in vitro but also constructed a 4b-decitabine (DCT)/liposome (Lip) delivery system (4b-DCT-Lip). The in vivo results showed that 4b-DCT-Lip not only had a stronger capacity to inhibit gastric tumor growth and metastasis than 4b-DCT but also addressed the co-delivery problems of 4b-DCT and improved their targeting ability. Furthermore, we confirmed the mechanism of 4b-DCT/4b-DCT-Lip inhibiting the growth and metastasis of a gastric tumor. DCT-upregulated gasdermin E (GSDME) was cleaved by 4b-activated caspase-3 to afford GSDME-N terminal and then was aggregated to form nonselective pores on the cell membrane of a gastric tumor, thereby inducing pyroptosis and a pyroptosis-induced immune response.

Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin.

To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to develop a multitargeted palladium (Pd) agent to the tumor microenvironment (TME) based on the specific residue(s) of human serum albumin (HSA). To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.

Developing a Gadolinium(III) Compound Based on Apoferritin for Targeted Magnetic Resonance Imaging and Dual-Modal Therapy of Cancer.

To integrate targeted diagnosis and treatment of cancer, we proposed to develop a gadolinium (Gd) agent based on the properties of apoferritin (AFt). To this end, we not only optimized a series of Gd(III) 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazone compounds to obtain a Gd(III) compound (C4) with remarkable T1-weighted magnetic resonance imaging (MRI) performance and cytotoxicity to cancer cells in vitro but also constructed an AFt-C4 nanoparticle (NP) delivery system. Importantly, AFt-C4 NPs improved the targeting ability of C4 in vivo and showed enhanced MRI performance and tumor growth inhibition ratio relative to C4 alone. Furthermore, we confirmed that C4 and AFt-C4 NPs inhibited tumor growth through apoptosis, ferroptosis, and ferroptosis-induced immune response.

Developing a Copper(II) Agent Based on His-146 and His-242 Residues of Human Serum Albumin Nanoparticles: Integration To Overcome Cisplatin Resistance and Inhibit the Metastasis of Nonsmall Cell Lung Cancer.

To overcome the resistance of nonsmall cell lung cancer (NSCLC) cells to cisplatin and inhibit their metastasis, we proposed to develop a Cu(II) agent based on the specific residue(s) of HSA nanoparticles (NPs) for multitargeting the tumor microenvironment (TME). To this end, we not only synthesized four Cu(II) 2-hydroxy-3-methoxybenzaldehyde thiosemicarbazone compounds (C1-C4), obtaining a Cu compound (C4) with significant cytotoxicity by studying their structure-activity relationships, but also revealed the binding mechanism of C4 to HSA through X-ray crystallography and confirmed the successful construction of a new HSA-C4 NPs delivery system. C4 and HSA-C4 NPs inhibited the A549cisR tumor growth and metastasis, and HSA NPs optimized the anticancer behavior of C4. We further confirmed the anticancer mechanism of the C4/HSA-C4 NP multitargeting TME to overcome cisplatin resistance: killing tumor cells by acting on the mtDNA and inducing apoptosis, polarizing M2-type macrophages to the M1-type, and inhibiting angiogenesis.