Products and methods for organ protection with noble nanoparticles

Patent metadata

Field	Value
Publication number	US-2024415879-A1
Application number	US-202418757037-A
Country	US
Kind code	A1
Filing date	Jun 27, 2024
Priority date	Apr 8, 2020
Publication date	Dec 19, 2024
Grant date	—

Abstract

Products and methods for redirecting the pathological biochemical process of accumulation of reduced pyridine nucleotides under deleterious hypoxia conditions toward the reduction of the precursor salt and the biosynthesis of biologically compatible, antioxidant noble metal nanoparticles and the simultaneous restoring of the tissue redox state are provided. The products and methods have application in the treatment of hypoxia and hypoxia-related diseases and disorders. Such products and methods are also useful in organ transplantation and recovery, in screening of anti-hypoxia agents, and in detecting elevated levels of the reducing equivalents of the redox state, for example, NADH, NADPH, GSH, and TrxSH 2 , in cells, tissues, or organs.

First claim

1 . A method of changing an oxidation-reduction (redox) state of a non-cancerous cell undergoing or at risk of undergoing hypoxia not resulting from Alzheimer's disease, the method comprising administering to the cell an effective amount of a noble metal precursor.

2 . The method of claim 1 , wherein changing the redox state of the cell comprises increasing the ratio of oxidized to reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH), nicotinamide adenine dinucleotide phosphate (NADP+/NADPH), glutathione (GSSG/GSH), or thioredoxin (TrxSS/TrxSH 2 ) in the cell.

3 . The method of claim 2 , wherein increasing the ratio of NAD+/NADH, NADP+/NADPH, GSSG/GSH, or TrxSS/TrxSH 2 reduces production of reactive oxygen species, reduces reactive nitrogen species, and/or reduces apoptosis.

4 . The method of claim 2 , wherein changing the redox state of the cell comprises conversion of the noble metal precursor to a noble metal nanoparticle in the cell or in the vicinity of the cell.

5 . The method of claim 4 , wherein the noble metal nanoparticle reduces the accumulation of reduced pyridine nucleotides in the cell or in the vicinity of the cell.

6 . The method of claim 1 , wherein the cell is suffering from or is at risk of suffering from a deficiency of oxidized forms of nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate (NADP+), glutathione (GSSG), or thioredoxin (TrxSS).

7 . The method of claim 2 , wherein NADH is converted to NAD+, NADPH is converted to NADP+, GSH is converted to GSSG, or TrxSH 2 is converted to TrxSS.

8 . The method of claim 1 , wherein the noble metal precursor is gold (Au), silver (Ag), platinum (Pt), palladium (Pd), ruthenium (Ru), rhodium (Rh), osmium (Os), or iridium (Ir), or wherein the noble metal precursor a noble metal halide, hydroxide, chloride, or a complex thereof with one or more organic ligands, or combinations thereof.

9 . The method of claim 1 , wherein the noble metal precursor is a gold chloride.

10 . The method of claim 9 , wherein the gold chloride is gold monochloride (AuCl), gold dichloride (AuCl 2 ), gold trichloride (AuCl 3 ), tetragold octachloride (Au 4 Cl 8 ), or chloroauric acid (HAuCl 4 ).

11 . The method of claim 1 , wherein the hypoxia results from oxidative stress, oxygen free radical damage, or ischemia-reperfusion injury.

12 . The method of claim 1 , wherein the cell is a brain cell, a cardiac cell, a kidney cell, a lung cell, a liver cell, a stomach cell, an intestinal cell, a pancreatic cell, a blood cell, a retinal cell, a skin cell, or other cell of the eye.

13 . The method of claim 1 , wherein the cell is a non-cancerous tumor cell.

14 . The method of claim 1 , wherein the cell undergoing or at risk of undergoing hypoxia is in a tissue or organ that is being preserved for transplantation.

15 . The method of claim 1 , wherein the cell undergoing or at risk of undergoing hypoxia is in a tissue or organ in a subject suffering from a hypoxia-related disease or disorder.

16 . The method of claim 1 , wherein the cell is in a subject.

17 . A method of ameliorating, treating, or preventing hypoxia or a hypoxic condition in a subject, the method comprising administering an effective amount of a noble metal precursor to the subject.

18 . The method of claim 17 , wherein the noble metal precursor forms noble metal nanoparticles in the subject and thereby changes the redox state of cells, tissues, and/or organs in the subject suffering from the hypoxic condition.

19 . A method for screening an agent for its antioxidant activity, the method comprising exposing a cell, a plurality of cells, or a tissue to a noble metal precursor in the presence or absence of an agent indicated to have antioxidant activity;
exposing the cell, the plurality of cells, or the tissue to a hypoxic condition or an oxidative stress; and measuring the conversion of the noble metal precursor to noble metal nanoparticles in or near the vicinity of the cell, the plurality of cells, or the tissue, wherein the agent is considered to have antioxidant activity if there is (i) a decrease in the concentration of noble metal precursor in the presence but not in the absence of the agent, (ii) an increase in the formation of noble metal nanoparticles in the presence but not in the absence of the agent, (iii) a decrease in the level of NADH, NADPH, GSH, or TrxSH 2 in the presence but not in the absence of the agent, and/or (iv) an increase in the level of NAD+, NADP+, GSSG, or TrxSS in the presence but not in the absence of the agent.

20 . The method of claim 19 , wherein the agent is a candidate drug or therapeutic agent which either affects the redox state of the cell or affects the rate of formation of noble metal nanoparticles from the noble metal precursor.

Assignees

• Uchicago Argonne Llc

Inventors

• Rozhkova Elena A
• Shevchenko Elena

Classifications

• G01N33/502

  for testing non-proliferative effects · CPC title

• A61K9/5115

  Inorganic compounds · CPC title

• A61P39/06 Primary

  Free radical scavengers or antioxidants · CPC title

• G01N33/5008

  for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics · CPC title

• A61K9/0048

  Eye, e.g. artificial tears · CPC title