👤 Wu XX

Lipid-mediated phase separation is crucial for the formation of lipophilic spontaneous domain to regulate lipid metabolism and homeostasis, furtherly contributing to multiple cell death pathways. Herein, a series of Ru(II) lipid-mimics based on short chains or midchain lipids are developed. Among them, Ru-LipM with two dodecyl chains significantly induces natural lipid phase separation via hydrocarbon chain-melting phase transitions. Accompanied by the aggregation of Ru-LipM-labeled lipophilic membrane-less compartments, most polyunsaturated lipids are increased and the autophagic flux is retarded with the adaptor protein sequestosome 1 (p62). Upon low-dose irradiation, Ru-LipM further drives ferritinophagy, providing an additional source of labile iron and rendering cells more sensitive to ferroptosis. Meanwhile, the peroxidation of polyunsaturated lipids occurs due to the deactivation of glutathione peroxidase 4 (GPX4) and the overexpression of acyl-CoA synthetase long-chain family member 4 (ACSL4), leading to the immunogenic ferroptosis. Ultimately, both innate and adaptive immunity are invigorated, indicating the tremendous antitumor capability of Ru-LipM in vivo. This study presents an unprecedented discovery of small molecules capable of inducing and monitoring lipid phase separation, thereby eliciting robust immune responses in living cells. It provides a biosimulation strategy for constructing efficient metal-based immune activators. 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

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

Description

Two new ruthenium(II) complexes containing guanidinium as ligands, [Ru(dip)2 (L1)]3+ (Ru1) and [Ru(dip)2(L2)]3+ (Ru2) (dip=4,7-diphenyl-1,10-phenanthroline; L1=1-(4-(1H-imidazo[4,5- f][1,10]phenanthrolin-2-yl)phenyl)guanidine cation; L2 = 1-(3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl) phenyl)guanidine cation) have been synthesized and characterized. Both complexes display higher cytotoxicity against several cancer cell lines compared to cisplatin and are less cytotoxic on the nontumorigenic cell line LO2. Intracellular distribution studies show that these complexes are selectively localized in the cytoplasm.

Findings

Further analysis revealed that Ru1 and Ru2 had no obvious effects on the cell cycle and induced apoptosis in HeLa cells via the mitochondrial pathway, which involved reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and Bcl-2 family member activation. Taken together, the two complexes have the potential to be utilized as anticancer agents. Show less