Photoinduction of Ferroptosis and cGAS-STING Activation by a HS-Responsive Iridium(III) Complex for Cancer-Specific Therapy.

Triggering ferroptosis represents a promising anticancer therapeutic strategy, but the development of a selective ferroptosis inducer for cancer-specific therapy remains a great challenge. Herein, a HS-responsive iridium(III) complex has been well-designed as a ferroptosis inducer. could selectively light up HS-rich cancer cells, primarily localize in mitochondria, intercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage, exhibiting higher anticancer activity under light irradiation.

Iridium(III) Photosensitizers Induce Simultaneous Pyroptosis and Ferroptosis for Multi-Network Synergistic Tumor Immunotherapy.

The integration of pyroptosis and ferroptosis hybrid cell death induction to augment immune activation represents a promising avenue for anti-tumor treatment, but there is a lack of research. Herein, we developed two iridium (III)-triphenylamine photosensitizers, IrC and IrF, with the capacity to disrupt redox balance and induce photo-driven cascade damage to DNA and Kelch-like ECH-associated protein 1 (KEAP1). The activation of the absent in melanoma 2 (AIM2)-related cytoplasmic nucleic acid-sensing pathway, triggered by damaged DNA, leads to the induction of gasdermin D (GSDMD)-mediated pyroptosis.

Effects of Polyethylene Terephthalate Particle Size on the Performance of Engineered Cementitious Composites.

This study utilizes polyethylene terephthalate (PET) aggregate of different particle sizes (21 μm, 107 μm, and 244 μm) to replace natural aggregate in the preparation of PET-modified engineered cementitious composite (P-ECC). The impact of PET aggregate particle size on the performance of P-ECC is examined herein from micro to macro levels. The focus is on the influence patterns and mechanisms of P-ECC's workability, its basic mechanical properties, and its microstructure.

Solution structures and effects of a platinum compound successively bound MYC G-quadruplex.

G-quadruplex (G4) structures play integral roles in modulating biological functions and can be regulated by small molecules. The MYC gene is critical during tumor initiation and malignant progression, in which G4 acts as an important modulation motif. Herein, we reported the MYC promoter G4 recognized by a platinum(II) compound Pt-phen.

G-quadruplex-guided cisplatin triggers multiple pathways in targeted chemotherapy and immunotherapy.

G-quadruplexes (G4s) are atypical nucleic acid structures involved in basic human biological processes and are regulated by small molecules. To date, pyridostatin and its derivatives [, PyPDS (4-(2-aminoethoxy)- , -bis(4-(2-(pyrrolidin-1-yl) ethoxy) quinolin-2-yl) pyridine-2,6-dicarboxamide)] are the most widely used G4-binding small molecules and considered to have the best G4 specificity, which provides a new option for the development of cisplatin-binding DNA. By combining PyPDS with cisplatin and its analogs, we synthesize three platinum complexes, named PyPDSplatins.

Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.

Mitochondria are dynamic organelles that undergo fusion and fission events, in which the mitochondrial membrane and DNA (mtDNA) play critical roles. The spatiotemporal organization of mtDNA reflects and impacts mitochondrial dynamics. Herein, to study the detailed dynamics of mitochondrial membrane and mtDNA, we rationally develop a dual-color fluorescent probe, mtGLP, that could be used for simultaneously monitoring mitochondrial membrane and mtDNA dynamics via separate color outputs.

Detection and tracking of cytoplasmic G-quadruplexes in live cells.

A TTPP probe was developed to distinguish G-quadruplexes (G4s) from other nucleic acid topologies through longer fluorescence lifetimes and higher quantum yields. In fluorescence lifetime imaging microscopy, TTPP enabled the visualization of cytoplasmic G4s in live cells, and showed the potential to detect cell apoptosis and ferroptosis by tracking cytoplasmic G4s.

Organic-Platinum Hybrids for Covalent Binding of G-Quadruplexes: Structural Basis and Application to Cancer Immunotherapy.

G-quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but the G4-mediated immune response remains unclear. We designed a novel class of G4-binding organic-platinum hybrids, L -cispt and L -transpt, with spatial matching for G4 binding and G4 DNA reactivity for binding site locking. The solution structure of L -transpt-MYT1L G4 demonstrated the effectiveness of the covalent binding and revealed the covalent binding-guided dynamic balance, accompanied by the destruction of the A5-T17 base pairs to achieve the covalent binding of the platinum unit to N7 of the G6 residue.

Simultaneous Photoactivation of cGAS-STING Pathway and Pyroptosis by Platinum(II) Triphenylamine Complexes for Cancer Immunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway is a potent anticancer immunotherapeutic strategy, and the induction of pyroptosis is a feasible way to stimulate the anticancer immune responses. Herein, two Pt complexes (Pt1 and Pt2) were designed as photoactivators of the cGAS-STING pathway. In response to light irradiation, Pt1 and Pt2 could damage mitochondrial/nuclear DNA and the nuclear envelope to activate the cGAS-STING pathway, and concurrently induce pyroptosis in cancer cells, which evoked an intense anticancer immune response in vitro and in vivo.

Solution structure of a thrombin binding aptamer complex with a non-planar platinum(ii) compound.

Thrombin Binding Aptamer (TBA) is a monomolecular well-defined two G-tetrad antiparallel G-quadruplex DNA that inhibits the activity of human α-thrombin. In this report, we synthesized a quasi-cross-shaped platinum(ii) compound (L'LPt) with one cyclometalated and two carbene ligands. We found L'LPt has selective affinity to bind the TBA G-quadruplex.

G-quadruplex structural transition driven by a platinum compound.

G-quadruplex (G4) transitions play integral roles in regulating biological functions and can be modified by ligands. However, little is known about G4 transitions. Herein, we reveal distinct pathways of a platinum(II) compound Pt-phen converting parallel-stranded MYC G4 to a hybrid-type structure.

Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes.

The nucleic acid G-quadruplex (G4) has emerged as a promising therapeutic target for a variety of diseases such as cancer and neurodegenerative disease. Among small-molecule G4-binders, pyridostatin (PDS) and its derivatives (, PyPDS) exhibit high specificity to G4s, but the structural basis for their specific recognition of G4s remains unknown. Here, we presented two solution structures of PyPDS and PDS with a quadruplex-duplex hybrid.

A Nuclear-Targeted AIE Photosensitizer for Enzyme Inhibition and Photosensitization in Cancer Cell Ablation.

The nucleus is considered the ideal target for anti-tumor therapy because DNA and some enzymes in the nucleus are the main causes of cell canceration and malignant proliferation. However, nuclear target drugs with good biosafety and high efficiency in cancer treatment are rare. Herein, a nuclear-targeted material MeTPAE with aggregation-induced emission (AIE) characteristics was developed based on a triphenylamine structure skeleton.

Spatial Matching Selectivity and Solution Structure of Organic-Metal Hybrid to Quadruplex-Duplex Hybrid.

The sequence-dependent DNA secondary structures possess structure polymorphism. To date, studies on regulated ligands mainly focus on individual DNA secondary topologies, while lack focus on quadruplex-duplex hybrids (QDHs). Here, we design an organic-metal hybrid ligand L Pt(dien), which matches and selectively binds one type of QDHs with lateral duplex stem-loop (QLDH) with high affinity, while shows poor affinity for other QDHs and individual G4 or duplex DNA.

A Continuous Add-On Probe Reveals the Nonlinear Enlargement of Mitochondria in Light-Activated Oncosis.

Oncosis, depending on DNA damage and mitochondrial swelling, is an important approach for treating cancer and other diseases. However, little is known about the behavior of mitochondria during oncosis, due to the lack of probes for in situ visual illumination of the mitochondrial membrane and mtDNA. Herein, a mitochondrial lipid and mtDNA dual-labeled probe, MitoMN, and a continuous add-on assay, are designed to image the dynamic process of mitochondria in conditions that are unobservable with current mitochondrial probes.

Selectivity and Targeting of G-Quadruplex Binders Activated by Adaptive Binding and Controlled by Chemical Kinetics.

G-quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) complex (Pt1), whose affinity to G4-DNA is activated by adaptive binding and selectivity controlled by binding kinetics.

Light-Driven Cascade Mitochondria-to-Nucleus Photosensitization in Cancer Cell Ablation.

Nuclei and mitochondria are the only cellular organelles containing genes, which are specific targets for efficient cancer therapy. So far, several photosensitizers have been reported for mitochondria targeting, and another few have been reported for nuclei targeting. However, none have been reported for photosensitization in both mitochondria and nucleus, especially in cascade mode, which can significantly reduce the photosensitizers needed for maximal treatment effect.

A Polarity-Sensitive Ratiometric Fluorescence Probe for Monitoring Changes in Lipid Droplets and Nucleus during Ferroptosis.

Ferroptosis regulates cell death through reactive oxygen species (ROS)-associated lipid peroxide accumulation, which is expected to affect the structure and polarity of lipid droplets (LDs), but with no clear evidence. Herein, we report the first example of an LD/nucleus dual-targeted ratiometric fluorescent probe, CQPP, for monitoring polarity changes in the cellular microenvironment. Due to the donor-acceptor structure of CQPP, it offers ratiometric fluorescence emission and fluorescence lifetime signals that reflect polarity variations.

Ratiometric Fluorescence Imaging for the Distribution of Nucleic Acid Content in Living Cells and Human Tissue Sections.

The misregulation of nucleic acids behavior leads to cell dysfunction and induces serious diseases. A ratiometric fluorescence probe is a powerful tool to study the dynamic behavior and function relationships of nucleic acids. However, currently, no such effective probe has been reported for , real-time tracking of nucleic acids in living cells and tissue sections.

Optimization of the supercritical fluidized bed process for sirolimus coating and drug release.

Directly coating an active pharmaceutical ingredient (API) onto excipient granules has been a common approach to prepare solid dosage forms. The combination of supercritical anti-solvent (SAS) and fluidized bed (FB) coating technology (SAS-FB) has the advantages of preventing nanoparticles aggregation, oxidation and light exposure. However individual operating parameters and factors which contribute to the overall coating efficiency remain to be defined.

Multiple-Color Platinum Complex with Super-Large Stokes Shift for Super-Resolution Imaging of Autolysosome Escape.

It is of great significance to track the platinum drugs in real time with super-resolution to elucidate their mechanism of action, such as their behavior and distribution in live cells. Such information is required for further drug development. However, it is always challenging to design platinum complexes suitable for such research.

Two novel fan-shaped trinuclear Pt(ii) complexes act as G-quadruplex binders and telomerase inhibitors.

Two new trinuclear Pt(ii) complexes {[Pt(dien)]3(tib)}(NO3)6 (1) and {[Pt(dpa)]3(tib)}(NO3)6 (2) (dien: diethylenetriamine, dpa: bis-(2-pyridylmethyl)amine, tib: 1,3,5-tris(1H-imidazol-1-yl)benzene) have been designed, synthesized, characterized and applied to a series of biochemical studies. We found that both of the Pt(ii) complexes exhibited much better selectivity for human telomeric G-quadruplex sequence than promoter G-quadruplexes (c-kit, c-myc, and bcl2) or duplex DNA. Both complexes displayed comparative stability and affinity towards human telomeric G-quadruplex by the studies from surface plasmon resonance, fluorescence resonance energy transfer and polymerase chain reaction stop assays.

Quantitative Detection of G-Quadruplex DNA in Live Cells Based on Photon Counts and Complex Structure Discrimination.

G-quadruplex DNA show structural polymorphism, leading to challenges in the use of selective recognition probes for the accurate detection of G-quadruplexes in vivo. Herein, we present a tripodal cationic fluorescent probe, NBTE, which showed distinguishable fluorescence lifetime responses between G-quadruplexes and other DNA topologies, and fluorescence quantum yield (Φ ) enhancement upon G-quadruplex binding. We determined two NBTE-G-quadruplex complex structures with high Φ values by NMR spectroscopy.

Charge-driven tripod somersault on DNA for ratiometric fluorescence imaging of small molecules in the nucleus.

Although fluorescence tracing of small bioactive molecules in living cells has been extensively studied, it is still a challenging task to detect their variations in the nucleus mainly due to the impermeable nuclear membrane and nucleic acid interference. Herein, we take advantage of the nucleic acid enriched environment in the nucleus to establish a strategy, named "charge-driven tripod somersault on DNA", for ratiometric fluorescence imaging of small bioactive molecules in the nucleus. Taking SO derivatives as a typical target analyte, a tripodal probe has been constructed by conjugating two DNA binding groups containing a SO derivative reaction site.

Rigid dinuclear ruthenium-arene complexes showing strong DNA interactions.

Six novel dinuclear Ru(II)-arene complexes [Ru(η-p-cymene)(1,3-bib)Cl]×·Solvent (X = Cl (1), I (2), NO (3), BF (4), PF (5), CFSO (6); 1,3-bib = 1,3-di(1H-imidazol-1-yl) benzene) were synthesized and fully characterized by FT-IR, H NMR, ESI-MS, Elemental Analysis (EA) and Powder X-ray Diffraction (PXRD). Single crystal X-ray diffractions studies showed that 3 and 4 have rigid bowl-like structures, where one counter-anion (NO for 3 and BF for 4) was trapped inside the cavity to balance the charge, respectively. Even complexes 1-6 showed only moderate or little anti-proliferative activity toward cancer cells, strong interactions with DNA molecules through intercalation, however, were confirmed by UV-Vis, CD and fluorescence spectroscopy.