👤 Li XL

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh₃, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh₃ exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC₅₀ value of 4.0 μM. Ru-TPE-PPh₃ could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh₃ also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation. Show less

Six polypyridyl Ru(II) complexes were designed for single-molecule photodynamic and sonodynamic therapy (PDT/SDT) synergistic multimodal anticancer toward cisplatin-resistant NSCLC. They demonstrated lowest 3ES with distinct intraligand transition nature, which is beneficial for singlet oxygen generation. Remarkable quantum yields of both singlet oxygen and superoxide anion under either 808 nm laser irradiation or ultrasonic treatment and could induce apoptosis and ferroptosis of A549R cells. Cytotoxicity experiments clearly demonstrated a synergistic effect between PDT and SDT. The relationship between the structures of these complexes and their cellular biological mechanisms has been explored in detail. Using a single-molecule sensitizer to achieve synergistic PDT/SDT may provide valuable insights for the treatment of drug-resistant tumors that located deeply and in hypoxic microenvironment. Show less

Title: Antitumor Cream: Transdermal Hydrogel Containing Liposome-Encapsulated Ruthenium Complex for Infrared-Controlled Multimodal Synergistic Therapy. Abstract: A transdermal drug delivery cream, which is non-invasive and painless, containing a liposome-encapsulated Ru(II) complex (LipoRu) is created for the treatment of skin cancer. This formulation capitalizes on the synergistic antitumor effects of two-photon excited photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy. LipoRu exhibits effective tumor accumulation, efficient cellular uptake, pH-sensitive and infrared-accelerated release, and dual localization to the nucleus and mitochondria. The released Ru(II) complexes within cells exert multiple antitumor mechanisms, such as DNA topoisomerase and RNA polymerase inhibition, Type I and II PDT, PTT, DNA photodamage, and apoptosis and ferroptosis induction. The biodistribution and therapeutic efficacy of LipoRu in vivo are systematically compared via three distinct administration routes: intratumoral injection, intravenous injection, and transdermal delivery through topical cream application. The positive therapeutic effects of the LipoRu cream fabricated here in subcutaneous tumor-bearing mice offer optimistic potential for the painless and non-invasive treatment of both early-stage and advanced skin cancers, as well as superficially located solid tumors. Show less

Title: Rhodium(III) Complex Noncanonically Potentiates Antitumor Immune Responses by Inhibiting Wnt/β-Catenin Signaling. Abstract: Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/β-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in β-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy. Show less

Title: Iridium(III)-Based Infrared Two-Photon Photosensitizers: Systematic Regulation of Their Photodynamic Therapy Efficacy. Abstract: Cyclometalated iridium(III) complexes are of significant importance in the field of antitumor photodynamic therapy (PDT), whether they exist as single molecules or are incorporated into nanomaterials. Nevertheless, a comprehensive examination of the relationship between their molecular structure and PDT effectiveness remains awaited. The influencing factors of two-photon excited PDT can be anticipated to be further multiplied, particularly in relation to intricate nonlinear optical properties. At present, a comprehensive body of research on this topic is lacking, and few discernible patterns have been identified. In this study, through systematic structure regulation, the nitro-substituted styryl group and 1-phenylisoquinoline ligand containing YQ2 was found to be the most potent infrared two-photon excitable photosensitizer in a 4 × 3 combination library of cyclometalated Ir(III) complexes. YQ2 could enter cells via an energy-dependent and caveolae-mediated pathway, bind specifically to mitochondria, produce 1O2 in response to 808 nm LPL irradiation, activate caspases, and induce apoptosis. In vitro, YQ2 displayed a remarkable phototherapy index for both malignant melanoma (>885) and non-small-cell lung cancer (>1234) based on these functions and was minimally deleterious to human normal liver and kidney cells. In in vivo antitumor phototherapy, YQ2 inhibited tumor growth by an impressive 85% and could be eliminated from the bodies of mice with a half-life as short as 43 h. This study has the potential to contribute significantly to the development of phototherapeutic drugs that are extremely effective in treating large, profoundly located solid tumors as well as the understanding of the structure-activity relationship of Ir(III)-based PSs in PDT. Show less

Title: Bleeding the Excited State Energy to the Utmost: Single-Molecule Iridium Complexes for In Vivo Dual Photodynamic and Photothermal Therapy by an Infrared Low-Power Laser. Abstract: A series of cyclometalated Ir(III) complexes with morpholine and piperazine groups are designed as dual photosensitizers and photothermal agents for more efficient antitumor phototherapy via infrared low-power laser. Their ground and excited state properties, as well as the structural effect on their photophysical and biological properties, are investigated by spectroscopic, electrochemical, and quantum chemical theoretical calculations. They target mitochondria in human melanoma tumor cells and trigger apoptosis related to mitochondrial dysfunction upon irradiation. The Ir(III) complexes, particularly Ir6, demonstrate high phototherapy indexes to melanoma tumor cells and a manifest photothermal effect. Ir6, with minimal hepato-/nephrotoxicity in vitro, significantly inhibits the growth of melanoma tumors in vivo under 808 nm laser irradiation by dual photodynamic therapy and photothermal therapy and can be efficiently eliminated from the body. These results may contribute to the development of highly efficient phototherapeutic drugs for large, deeply buried solid tumors. Show less

Title: Ursolic acid-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes induced necroptosis in MGC-803 cells. Abstract: Three ursolic acid-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes Ru1-Ru3 were designed and synthesized for evaluating antitumor activity. All the complexes exhibited high in vitro cytotoxicity against MGC-803, T24, HepG2, CNE2, MDA-MB-231, MCF-7, A549, and A549/DDP cell lines. Ru1, Ru2, and Ru3 were 11, 8 and 10 times, respectively, more active than cisplatin against A549/DDP. An in vivo study on MGC-803 xenograft mouse models demonstrated that representative Ru2 exhibited an effective inhibitory effect on tumor growth, showing stronger antitumor activity than cisplatin. Biological investigations suggested that Ru2 entered MGC-803 cells by a clathrin-mediated endocytic pathway, initially localizing in the lysosomes and subsequently escaping and localizing in the mitochondria. Mitochondrial swelling resulted in vacuolization, which induced vacuolation-associated cell death and necroptosis with the formation of necrosomes (RIP1-RIP3) and the uptake of propidium iodide. These results demonstrate that the potential of Ru2 as a chemotherapeutic agent to kill cancer cells via a dual mechanism represents an alternative way to eradicate apoptosis-resistant forms of cancer. Show less

By rational altering the structure of CN auxiliary ligand, Near-infrared (NIR) phosphorescent cyclometalated platinum (II) and iridium (III) complexes with metformin (Met) have been successfully obtained and characterized. The dissociation of Met in aqueous solution can be accelerated by addition of Glutathione (GSH) and alleviated by drop of histidine, accompanied with a significant decay change of deep red phosphorescence. Besides, Pt3 and Ir1 with moiety of btpq mainly selectively targeted and located in Mitochondrial, while Pt1 of ppy and Pt2 with thpy mainly accumulated in endoplasmic reticulum. Moreover, Pt1-3 and Ir1 with metformin moiety all exert a significant enhanced anticancer activity, among them, Pt3 displays ca.66-fold, ca.147-fold and ca.588-fold higher cytotoxicity than cisplatin, Met-free analogue Pt3a and Met. Their relative anticancer mechanism was further investigated, both Pt2 and Pt3 could form covalent interaction with bovine serum albumin (BSA) and effectively induce reactive oxygen species (ROS) generation, arrest of cell cycle, loss of Mitochondrial membrane potential (MMP), display effective anti-metastasis activity and eventually induce apoptosis of cancer cell. Show less

Title: Mitochondria-targeted cyclometalated rhodium(III) complexes: synthesis, characterization and anticancer research. Abstract: Over the past few decades, the landscape of inorganic medicinal chemistry has been dominated by investigations on platinum or ruthenium, while the research based on other metal centers such as rhodium has been relatively insufficient. In this work, a series of cyclometalated rhodium(iii) complexes with imidazo[4,5-f][1,10]phenanthroline containing different aromatic rings were synthesized and characterized. Notably, all the complexes displayed stronger anticancer activity against various cancer cells compared with cisplatin. A mechanism study revealed that the rhodium complexes accumulated in the mitochondria, elevated the levels of mitochondrial reactive oxygen species (ROS) and released cytochrome c, indicating severe mitochondrial damage during the anticancer activity. Further studies illustrated that the rhodium complexes caused cell cycle arrest at the G2/M phase, upregulated the expression of p53 and reduced the ratio of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated x (Bax), which ultimately resulted in cellular apoptosis. Overall, through mitochondrial pathways, these Rh(iii) complexes could induce cellular apoptosis to a larger extent than cisplatin and should be paid close attention as promising chemotherapeutic drugs in anticancer research. Show less

Alpha lipoic acid (LA) is a natural compound and coenzyme with sufficient safety information for serving as a promising anticancer agent. To further clarify the mechanism of action (MoA), two Ir(iii) complexes with the functionalized α-lipoic acid (N^∧N-LA, N^∧N, 2,2-bipyridine derivative), namely Ir1 and Ir2, were synthesized, where Ir1 possessed a half-sandwich structure with the formula [Ir(Cp*)(N^∧N-LA)Cl]PF₆ (Cp* = 1,2,3,4,5-pentamethyl-cyclopentadiene) and Ir2 possessed the cyclometalated structure with the formula [Ir(C^∧N)₂(N^∧N-LA)]PF₆ (C^∧N = 2-phenylpyridine). Even though both complexes were constructed based on the same N^∧N-LA ligand, Ir1 showed no cytotoxicity (IC₅₀ > 200 μM), which was due to its low lipophilicity for hard penetration into the cancer cells, easy hydrolysis, and reaction with GSH. Ir2 exhibited excellent cytotoxicity (IC₅₀ = 3.43-6.74 μM) toward diverse cancer cell lines in vitro and a promising ability to overcome the cisplatin-resistance in A549R cells. The anticancer mechanism of Ir2 in A549 cells was investigated in detail, and it was found it could localize and accumulate in the lysosomes of A549 cells, induce ROS, arrest the cycle at G₀/G₁, and lead to cell death by autophagy. Comparison with Ir-NH₂ ([Ir(C^∧N)₂(N^∧N-NH₂)]PF₆) demonstrated that introduction of the LA ligand to Ir2 could highly enhance the cytotoxicity and help to overcome the cisplatin-resistance. This study of the half-sandwich and cyclometalated Ir(iii)-based anticancer agents highlighted the different MoAs toward cancer cells and provided new insights for understanding their structure-property relationships. Show less

Three novel Ru(II) complexes, namely, (RuCl₂[L^a][DMSO]₂)·H₂O (Ru1), (RuCl₂[L^b][DMSO]₂) (Ru2), and (RuCl₂[L^c][DMSO]₂) (Ru3), which respectively contain 3-(2'-benzimidazolyl)coumarin (L^a), 3-(2'-benzimidazolyl)-7-fluoro-coumarin (L^b), and 3-(2'-benzimidazolyl)-7-methoxyl-coumarin (L^c), were first designed and characterized. Ru2 showed potent antitumor activity against NCI-H460 cells (IC₅₀ = 0.30 ± 0.02 μM) and high selectivity between NCI-H460 cancer cells and normal HL-7702 cells. Ru2 induced NCI-H460 apoptosis via telomerase inhibition, which involved DNA damage, cell-cycle distribution, and S phase-protein down-regulation. However, Ru1 did not demonstrate such effects in NCI-H460 cells, which is undoubtedly associated with the key regulatory role of the 7-fluoro substituted group in the L^b ligand of Ru2. Ru2 exhibited considerably higher anticancer efficacy (inhibition rate [IR] = 61.3%) compared with cisplatin (IR= 25.5%) in a NCI-H460 xenograft mouse model. Thus, this coumarin Ru(II) compound is a promising Ru2-targeting telomerase anticancer agent. Show less

Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1-4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, ¹H and ¹³C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin. Show less

Two new Ru(II) complexes, [Ru(Htip)3]Cl2 (1) and [Ru(Htip)2(dppz)]Cl2 (2), were synthesised and were characterised. The ground- and excited-state acid-base properties of 1 and 2 were studied and demonstrated that 1 acted as a pH-induced "on-off-on" luminescence switch. The binding behaviours of 1 and 2 to calf thymus DNA were studied with absorption and emission spectroscopy, DNA viscosities and density functional theory calculations. 2 was found to act as a DNA molecular light switch and as an efficient photocleaver of pUC 18 DNA. The cytotoxicities of the complexes were evaluated with the MTT method and it was found that 1 displayed apparent anticancer activity against MCF-7 cell, whereas 2 exhibited more potent and wider-spectrum antitumor activities against all cancer cell lines tested. Show less