Gold Clusters, Compositions, and Methods for Treating Stroke - Patent application

Abstract

The present invention provides the use of ligand-conjugated gold clusters and compositions comprising said ligand-conjugated gold clusters in the treatment of stroke and in the manufacture of medicaments for treating stroke, and methods of treating stroke.

Description

[Technical field]

[0001] The present invention relates to the technical field of brain disease treatment, and in particular to ligand-conjugated gold clusters (AuCs), compositions comprising said ligand-conjugated AuCs, the use of said ligand-conjugated AuCs in the manufacture of medicaments for the treatment of stroke, and methods of treating stroke using said ligand-conjugated AuCs and compositions. [Background technology]

[0002] Stroke occurs when a blood vessel becomes blocked by a blood clot or ruptures. There are three types of stroke: hemorrhagic stroke, ischemic stroke, and transient ischemic attack (TIA).

[0003] Hemorrhagic stroke occurs when a blood vessel ruptures, cutting off blood flow to the brain. Common symptoms include sudden weakness, paralysis in some parts of the body, difficulty speaking, vomiting, difficulty walking, coma, loss of consciousness, stiff neck, and dizziness. There is no specific cure yet.

[0004] Ischemic stroke, also known as brain ischemia or cerebral ischemia, is one of the most common diseases in humans and a major cause of death and disability. Ischemic stroke accounts for approximately 87% of all strokes. Ischemic stroke occurs when a clot, such as a blood clot or plaque, forms in the artery that supplies blood to the brain, which then appears in the neck or skull, reducing blood flow and oxygen to the brain, causing damage and death of brain cells. If blood circulation is not restored quickly, it can result in permanent brain damage.

[0005] The specific symptoms of an ischemic stroke vary depending on the part of the brain that is affected. Common symptoms of most ischemic strokes include loss of vision, weakness or numbness in the arms or legs, dizziness or vertigo, confusion, loss of coordination, and drooping on one side of the face. If symptoms appear, it is important to seek treatment as soon as possible, as this can reduce the chance of permanent damage.

[0006] Treatment options for ischemic stroke are very limited. The main clinical treatment for ischemic stroke is tissue plasminogen activator (tPA), which breaks down blood clots, but tPA is only effective if administered intravenously within 4.5 hours of the onset of the stroke. However, because tPA causes bleeding, patients with a history of hemorrhagic stroke, intracerebral hemorrhage, recent major surgery, or head trauma cannot be treated with tPA. Long-term treatments include the use of aspirin and anticoagulants to prevent the progression of blood clots.

[0007] Amani et al. disclosed that OX26@GNPs, which are OX26-PEG conjugated to the surface of 25 nm colloidal gold nanoparticles, significantly increased necrotic brain tissue, while bare GNPs and PEGylated GNPs had no effect on the necrotic volume, indicating that OX26@GNPs are not suitable for the treatment of stroke.

[0008] Zheng et al. have shown that 20 nm Au-NPs can increase cell viability, alleviate neuronal apoptosis and oxidative stress, and improve mitochondrial respiration in a rat model of OGD / R injury. However, they also demonstrated that 5 nm AuNPs showed the opposite effect and were not suitable for the treatment of stroke.

[0009] TIAs are caused by temporary blood clots. Common symptoms include weakness, numbness or paralysis on one side of the body, slurred speech, loss of vision and dizziness. There is no cure yet.

[0010] Stroke treatment needs to be performed in a timely manner to avoid or reduce the patient's neurological dysfunction or death due to damage or death of brain nerve cells caused by cerebral ischemia or cerebral hemorrhage. There is no specific therapeutic drug for treating hemorrhagic stroke and TIA, and the main drugs for treating ischemic stroke, such as tPA, cause bleeding. Therefore, it is decided to use drugs for the treatment of ischemic stroke only when the patient is definitively diagnosed as having ischemic stroke rather than hemorrhagic stroke. However, this process of definitive diagnosis takes up valuable time to treat ischemic stroke in a timely manner.

[0011] There is a need for effective methods and drugs for treating stroke, especially drugs that can treat both hemorrhagic stroke and ischemic stroke.Because the causes of hemorrhagic stroke and ischemic stroke are fundamentally different, all drug developments in the literature are either targeted at hemorrhagic stroke or ischemic stroke.Therefore, developing a drug that can treat stroke patients, regardless of hemorrhagic stroke or ischemic stroke, is an unimaginable challenge and can be taboo in the industry. Summary of the Invention

[0012] The present invention relates to including ligand-bound gold clusters, To treat stroke in a subject Pharmaceutical Compositions to provide.

[0013] In certain embodiments, A pharmaceutical composition for treating stroke in a subject is provided, comprising a ligand-conjugated gold cluster, The ligand-conjugated gold cluster comprises a gold core and a ligand bound to the gold core, and the stroke is selected from the group consisting of hemorrhagic stroke, ischemic stroke, and transient ischemic attack (TIA).

[0014] The above Pharmaceutical Compositions In a particular embodiment, the gold core has a diameter of 0.5 to 3 nm.

[0015] The above Pharmaceutical Compositions In a particular embodiment, the gold core has a diameter of 0.5 to 2.6 nm.

[0016] The above Pharmaceutical Compositions In certain embodiments, the ligand is a member selected from the group consisting of L-cysteine ​​and its derivatives, D-cysteine ​​and its derivatives, cysteine-containing oligopeptides and their derivatives, and other thiol-containing compounds.

[0017] The above Pharmaceutical Compositions In certain embodiments, the L-cysteine ​​and its derivatives are selected from the group consisting of L-cysteine, N-isobutyryl-L-cysteine ​​(L-NIBC), and N-acetyl-L-cysteine ​​(L-NAC), and the D-cysteine ​​and its derivatives are selected from the group consisting of D-cysteine, N-isobutyryl-D-cysteine ​​(D-NIBC), and N-acetyl-D-cysteine ​​(D-NAC).

[0018] The above Pharmaceutical Compositions In certain embodiments, the cysteine-containing oligopeptides and derivatives thereof are cysteine-containing dipeptides selected from the group consisting of L(D)-cysteine-L(D)-arginine dipeptide (CR), L(D)-arginine-L(D)-cysteine ​​dipeptide (RC), L(D)-histidine-L(D)-cysteine ​​dipeptide (HC), and L(D)-cysteine-L(D)-histidine dipeptide (CH).

[0019] The above Pharmaceutical Compositions In certain embodiments, the cysteine-containing oligopeptides and their derivatives are cysteine-containing tripeptides selected from the group consisting of glycine-L(D)-cysteine-L(D)-arginine tripeptide (GCR), L(D)-proline-L(D)-cysteine-L(D)-arginine tripeptide (PCR), L(D)-lysine-L(D)-cysteine-L(D)-proline tripeptide (KCP), and L(D)-glutathione (GSH).

[0020] The above Pharmaceutical CompositionsIn certain embodiments, the cysteine-containing oligopeptides and their derivatives are cysteine-containing tetrapeptides, said cysteine-containing tetrapeptides being selected from the group consisting of glycine-L(D)-serine-L(D)-cysteine-L(D)-arginine tetrapeptide (GSCR) and glycine-L(D)-cysteine-L(D)-serine-L(D)-arginine tetrapeptide (GCSR).

[0021] The above Pharmaceutical Compositions In certain embodiments, the cysteine-containing oligopeptides and derivatives thereof are cysteine-containing pentapeptides, the cysteine-containing pentapeptides being selected from the group consisting of cysteine-aspartic acid-glutamic acid-valine-aspartic acid (CDEVD) and aspartic acid-glutamic acid-valine-aspartic acid-cysteine ​​(DEVDC).

[0022] The above Pharmaceutical Compositions In certain embodiments, the other thiol-containing compound is selected from the group consisting of 1-[(2S)-2-methyl-3-thiol-1-oxopropyl]-L(D)-proline, thioglycolic acid, mercaptoethanol, thiophenol, D-penicillamine, N-(2-mercaptopropionyl)-glycine, dodecyl mercaptan, 2-aminoethanethiol (CSH), 3-mercaptopropionic acid (MPA), and 4-mercaptobenzoic acid (p-MBA). JPEG0007638373000001.jpg232158JPEG0007638373000002.jpg237158JPEG0007638373000003.jpg237158JPEG0007638373000004.jpg237158JPEG0007638373000005.jpg237158JPEG0007638373000006.jpg237158JPEG0007638373000007.jpg237158JPEG0007638373000008.jpg237159JPEG0007638373000009.jpg237159JPEG0007638373000010.jpg232158JPEG0007638373000011.jpg234164JPEG0007638373000012.jpg237164JPEG0007638373000013.jpg237158JPEG0007638373000014.jpg237158JPEG0007638373000015.jpg237158JPEG0007638373000016.jpg237158JPEG0007638373000017.jpg237158JPEG0007638373000018.jpg232158JPEG0007638373000019.jpg237158JPEG0007638373000020.jpg237158JPEG0007638373000021.jpg237158JPEG0007638373000022.jpg237159JPEG0007638373000023.jpg237158JPEG0007638373000024.jpg178158

Claims

1. 1. A pharmaceutical composition for treating stroke in a subject, comprising a ligand-conjugated gold cluster, the ligand-conjugated gold cluster comprising: Gold core and and a ligand bound to said gold core; the gold core has a diameter of 0.5 to 3 nm; the ligand is one selected from the group consisting of L-cysteine ​​and its derivatives, D-cysteine ​​and its derivatives, cysteine-containing oligopeptides and their derivatives, and other thiol-containing compounds; The L-cysteine ​​and its derivatives are selected from the group consisting of L-cysteine, N-isobutyryl-L-cysteine ​​(L-NIBC), and N-acetyl-L-cysteine ​​(L-NAC), and the D-cysteine ​​and its derivatives are selected from the group consisting of D-cysteine, N-isobutyryl-D-cysteine ​​(D-NIBC), and N-acetyl-D-cysteine ​​(D-NAC), The cysteine-containing oligopeptide and its derivatives are a cysteine-containing dipeptide, a cysteine-containing tripeptide, a cysteine-containing tetrapeptide, or a cysteine-containing pentapeptide; the other thiol-containing compound is selected from the group consisting of 1-[(2S)-2-methyl-3-thiol-1-oxopropyl]-L(D)-proline, thioglycolic acid, mercaptoethanol, thiophenol, D-penicillamine, N-(2-mercaptopropionyl)-glycine, dodecyl mercaptan, 2-aminoethanethiol (CSH), 3-mercaptopropionic acid (MPA), and 4-mercaptobenzoic acid (p-MBA); The pharmaceutical composition, wherein the stroke is selected from the group consisting of hemorrhagic stroke, ischemic stroke, and transient ischemic attack (TIA).

2. 2. The pharmaceutical composition of claim 1, wherein the gold core has a diameter of 0.5-2.6 nm.

3. 2. The pharmaceutical composition of claim 1, wherein the cysteine-containing dipeptide is selected from the group consisting of L(D)-cysteine-L(D)-arginine dipeptide (CR), L(D)-arginine-L(D)-cysteine ​​dipeptide (RC), L(D)-histidine-L(D)-cysteine ​​dipeptide (HC), and L(D)-cysteine-L(D)-histidine dipeptide (CH).

4. 2. The pharmaceutical composition of claim 1, wherein the cysteine-containing tripeptide is selected from the group consisting of glycine-L(D)-cysteine-L(D)-arginine tripeptide (GCR), L(D)-proline-L(D)-cysteine-L(D)-arginine tripeptide (PCR), L(D)-lysine-L(D)-cysteine-L(D)-proline tripeptide (KCP), and L(D)-glutathione (GSH).

5. 2. The pharmaceutical composition of claim 1, wherein the cysteine-containing tetrapeptide is selected from the group consisting of glycine-L(D)-serine-L(D)-cysteine-L(D)-arginine tetrapeptide (GSCR) and glycine-L(D)-cysteine-L(D)-serine-L(D)-arginine tetrapeptide (GCSR).

6. 2. The pharmaceutical composition of claim 1, wherein the cysteine-containing pentapeptide is selected from the group consisting of cysteine-aspartic acid-glutamic acid-valine-aspartic acid (CDEVD) and aspartic acid-glutamic acid-valine-aspartic acid-cysteine ​​(DEVDC).

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