CN-118344406-B - Lysosome-targeted ruthenium complex and preparation and application thereof

Abstract

The invention belongs to the crossing field of disciplines of coordination chemistry, biology, medicine and the like, and relates to a lysosome-targeted metal ruthenium complex, and preparation and application thereof. The metal ruthenium complex prepared by the invention has novel structure, lysosome targeting property and phosphorescence characteristic, can realize phosphorescence imaging of cells and tissues, can be used as a photosensitizer, can generate active oxygen under illumination, and is used for photodynamic therapy of tumors. Under weakly acidic conditions, the phosphorescence of the complex is significantly enhanced, and the singlet oxygen generating capacity and NADH catalyzing capacity are also increased, so that the complex has more effective killing capacity on lysosomes and tumors. The preparation method has the advantages of simple preparation process, high yield, good repeatability and the like. The metal ruthenium complex prepared by the invention can be used for biological imaging and photodynamic therapy of tumors.

Inventors

• RU JIAXI
• ZHANG FANGMEI
• CHEN YU
• LIANG CHAO

Assignees

• 温州医科大学慈溪生物医药研究院

Dates

Publication Date

20260505

Application Date

20240326

Claims (1)

1. 1. Application of metal ruthenium complex in preparing optical imaging reagent and tumor photodynamic therapy reagent; The metal ruthenium complex has phosphorescence luminescence property of pH response and lysosome targeting, and the optical imaging reagent is used for optical imaging of breast cancer 4T1 cells, wherein the tumor is breast cancer; The metal ruthenium complex is 。

Description

Lysosome-targeted ruthenium complex and preparation and application thereof Technical Field The invention belongs to the field of interdisciplinary chemistry, biology, medicine and the like, and particularly relates to a lysosome-targeted metal ruthenium complex, a preparation method thereof and application thereof in biological imaging and tumor photodynamic therapy. Background Tumor treatment strategies targeting organelles have become a new paradigm for future precision medicine, drawing great attention. These strategies deliver drugs precisely to critical or fragile subcellular organelles such as mitochondria, lysosomes, and golgi. By precisely destroying the structure and function of subcellular organelles, therapeutic effects can be significantly improved, drug resistance prevented, drug dosage reduced, and side effects minimized. Among the various subcellular organelles, lysosomes function as the essential subcellular organelles of human and mammalian cells, playing an important role in a variety of physiological and signaling processes, such as intracellular trafficking, protein degradation, endocytosis, and cell death. Cancer cells possess more lysosomes and lower acidity (pH 4.5-5.5) than normal cells. At the same time, once lysosomes are damaged, protons and tens of hydrolases within the lysosomes are released into the cytoplasm, which can trigger apoptosis by cleaving various substrates within the cell, such as cysteine proteases and several members of the bcl-2 protein family. The characteristics make lysosomes ideal targets for tumor diagnosis and treatment. Therefore, the development of lysosomal targeting drugs is a key goal. Transition metal complexes are receiving increasing attention as probes or drugs targeting organelles. This is due to the fact that metal complexes have a rich and tunable structure and excellent photophysical properties, providing a variety of alternatives for the design of unique drugs/probes. Among transition metal complexes, ruthenium complexes have been widely used for bioimaging, biosensing, and photoactivated tumor therapy. TLD1433 has shown promising results in recent clinical trials as an outstanding representation of ruthenium complexes. Due to their high solubility and stability, tunable structure and redox potential, excellent photophysical properties, and their subcellular organelle targeting capability, ru (ii) complexes have become promising targeted organelle metal drugs in cancer treatment. Photodynamic therapy (PDT) has found wide application in preclinical and clinical studies due to its non-invasive, light-specific toxicity and space-time controllability. Many ruthenium polypyridine complexes have been explored as Photosensitizers (PSs) for PDT. Recently Huang Huaiyi et al developed a photo-redox catalyst (PC) based on iridium complexes for the treatment of hypoxic tumors (nat. Chem.2019,11, 1041-1048). This strategy differs from conventional PSs in that energy is directly transferred to surrounding oxygen molecules under light to produce highly toxic reactive oxygen species, but instead directly catalyzes the substrate (NADH) via the electron transfer pathway, in a manner independent of oxygen concentration. This catalytic process breaks the mitochondrial Electron Transport Chain (ETC) and disrupts the redox homeostasis of the cell, ultimately leading to death of the damaged cell. Although a variety of ruthenium complex photosensitizers have been designed and synthesized for preclinical and basic scientific studies of photodynamic therapy (PDT) of tumors, many of these complexes exhibit high affinity to DNA and thus are capable of targeting the nucleus. However, such nuclear-targeted drugs may cause potential genotoxicity problems. In contrast, lysosomal targeting drug strategies are considered a relatively safe and effective approach. Nevertheless, metallic ruthenium complexes capable of specifically targeting lysosomes are still very limited. In addition, the hypoxic nature of the tumor microenvironment significantly inhibits the activity of photosensitizers, while both tumor cells and lysosomes exhibit typical weak acidic characteristics, which present challenges for developing new therapeutic strategies. The invention aims to prepare a lysosome targeted metal ruthenium complex, realizes the treatment of hypoxic tumor by a photocatalytic NADH approach independent of oxygen concentration, and shows higher PDT and photocatalytic activity under weak acidic conditions, so that the research can obviously increase the tumor treatment effect, and provides an important tool for developing a new lysosome targeted treatment strategy. Disclosure of Invention In view of the above, the invention provides a lysosome-targeted metal ruthenium complex, and a preparation method and application thereof. The metal ruthenium complex provided by the invention consists of a ruthenium complex cation unit shown in a formula I or I I and a coordination anion, The coordina