Disruption of Zinc Homeostasis by a Novel Platinum(IV)-Terthiophene Complex for Antitumor Immunity.

Zinc homeostatic medicine is of great potential for cancer chemo-immunotherapy; however, there are few reports on antitumor compounds that can trigger Zn2+ -mediated immune responses. In this work, we developed a novel cyclometalated PtIV -terthiophene complex, Pt3, that not only induces DNA damage and cellular metabolism dysregulation, but also disrupts zinc homeostasis as indicated by the abnormal transcriptional level of zinc regulatory proteins, excess accumulation of Zn2+ in cytoplasm, and down-regulation of metallothioneins (MTs), which further caused redox imbalance. The simultaneous disruption of zinc and redox homeostasis in response to Pt3 treatment activated gasdermin-D mediated pyroptosis accompanied by cytoskeleton remodeling, thus releasing pro-inflammatory cytokines to promote dendritic cell (DC) maturation and T cell tumor-infiltration, eventually eliminating both primary and distant tumors in vivo. As far as we know, this is the first metal complex that can regulate zinc homeostasis to activate antitumor immunity.

A Golgi-Targeted Platinum Complex Plays a Dual Role in Autophagy Regulation for Highly Efficient Cancer Therapy.

Regulating autophagy to control the homeostatic recycling process of cancer cells is a promising anticancer strategy. Golgi apparatus is a substrate of autophagy but the Golgi-autophagy (Golgiphagy) mediated antitumor pathway is rarely reported. Herein, we have developed a novel Golgi-targeted platinum (II) complex Pt3, which is ca. 20 times more cytotoxic to lung carcinoma than cisplatin and can completely eliminate tumors after intratumoral administration in vivo. Its nano-encapsulated system for tail vein administration also features a good anti-tumor effect. Mechanism studies indicate that Pt3 induces substantial Golgi stress, indicated by the fragmentation of Golgi structure, down-regulation of Golgi proteins (GM130, GRASP65/55), loss of Golgi-dependent transport and glycosylation. This triggers Golgiphagy but blocks the subsequent fusion of autophagosomes with lysosomes, that is a dual role in autophagy regulation, resulting in loss of proteostasis and apoptotic cell death. As far as we know, Pt3 is the first Golgi-targeted Pt complex that can trigger Golgi stress-mediated dual-regulation of autophagic flux and autophagy-apoptosis crosstalk for highly efficient cancer therapy.

A Carbonic Anhydrase IX (CAIX)-Anchored Rhenium(I) Photosensitizer Evokes Pyroptosis for Enhanced Anti-Tumor Immunity.

An ideal cancer treatment should not only destroy primary tumors but also improve the immunogenicity of the tumor microenvironment to achieve a satisfactory anti-tumor immune effect. We designed a carbonic anhydrase IX (CAIX)-anchored rhenium(I) photosensitizer, named CA-Re, that not only performs type-I and type-II photodynamic therapy (PDT) with high efficiency under hypoxia (nanomolar-level phototoxicity), but also evokes gasdermin D (GSDMD) mediated pyroptotic cell death to effectively stimulate tumor immunogenicity. CA-Re could disrupt and self-report the loss of membrane integrity simultaneously. This promoted the maturation and antigen-presenting ability of dendritic cells (DCs), and fully activated T cells dependent adaptive immune response in vivo, eventually eliminating distant tumors at the same time as destroying primary tumors. To the best of our knowledge, CA-Re is the first metal complex-based pyroptosis inducer.

Coordination-induced decomposition of luminescent gold nanoparticles: sensitive detection of H2O2 and glucose.

The surface inert of luminescent gold nanoparticles (AuNPs) toward biomolecules set a challenge to further exploit their bioanalytical applications using the direct luminescence response. Herein, we report a novel approach to induce significant luminescence quenching of the AuNPs upon the interaction with a metal coordination ligand tris(2-carboxyethyl)phosphine (TCEP), providing a strategy for the detection of H2O2 with a limit of detection (LOD) of 14 nM through the reaction between H2O2 and TCEP to protect the luminescence quenching of the AuNPs. Furthermore, this strategy is also extended for sensitive and selective detection of glucose with a LOD of 1.1 µM based on monitoring the production of H2O2 catalyzed from the oxidation of glucose. The highly extendable feature of this strategy can have great potential in the sensitive detection of other biomolecules. Graphical Abstract A facile and extendable strategy has been developed for the sensitive detection of H2O2 and glucose based on the interaction between luminescent gold nanoparticles and TCEP, a metal coordination ligand.

A platinum-ruthenium hybrid prodrug with multi-enzymatic activities for chemo-catalytic therapy of hypoxic tumors.

Regulation of tumor hypoxia and redox homeostasis is a promising strategy for cancer therapy. Nanocatalytic medicine has played more and more important roles in this field because it can cleverly convert the efficiency and selectivity of catalysis into high therapeutic efficiency. Herein, we developed a platinum(iv)-ruthenium hybrid prodrug, named as Pt-Ru, for efficient chemo-catalytic synergistic therapy of hypoxic tumors. The ruthenium hybridization endowed the Pt(iv) prodrug with multi-enzyme catalytic activity, that is, mimicking catalase (CAT) to generate O2 in situ, mimicking peroxidase (POD) to produce reactive oxygen species, and mimicking glutathione peroxidase (GPx) to deplete GSH, thus effectively overcoming tumor hypoxia and cisplatin resistance. As a result, Pt-Ru treatment led to a superior anticancer efficacy to cisplatin both in vitro and in vivo. This work suggested redox homeostasis regulation as a tantalizing angle for developing the next generation of platinum drugs.

pH-Guided Self-Assembly of Copper Nanoclusters with Aggregation-Induced Emission.

We here report a facile pH-guided strategy for the fabrication of water-soluble protein/copper nanoclusters (CuNCs) hybrid nanostructures with stable and bright luminescence resulted from aggregation-induced emission. Using l-cysteine as both the reducing and capping agents, the synthesized CuNCs showed a good reversible pH-responsive aggregation and dispersion in the solution. The CuNCs formed insoluble macroscopic aggregates with stable red-colored emission (620 nm) at pH 3.0 but became soluble with weak luminescence at pH <1.5 or pH >4.0. The highly reversible pH-responsive properties of the CuNCs made it feasible to achieve water-soluble protein/CuNCs hybrid nanostructures in the presence of protein without any external forces (e.g., sonication). The weak luminescent CuNCs were first mixed with protein under neutral condition (e.g., pH 7.0), followed by tuning of the pH to acidic conditions (e.g., pH 3.0) to form luminescent protein/CuNCs hybrid nanostructures, the sizes of which were much smaller than those of the protein-free macroscopic CuNC aggregates. This strategy was easily applicable to other dispersing agents (e.g., glucose oxidase), opening a new pathway for the construction of many other smart water-soluble luminescent biomolecule/nanocluster hybrid nanostructures with various applications.