Nanotubes as mitochondrial uncouplers

• US 7,919,699 B2
• Filed: 05/05/2006
• Issued: 04/05/2011
• Est. Priority Date: 05/06/2005
• Status: Expired due to Fees

• Current Assignee: University Of Kentucky Research Foundation (University of Kentucky)
• Original Assignee: University Of Kentucky Research Foundation (University of Kentucky)
• Inventors: Sullivan, Patrick G.
• Primary Examiner(s): Ford; Allison M
• Assistant Examiner(s): FERNANDEZ, SUSAN EMILY
• Application Number:
  US11/418,208
• Publication Number:
  US 20060275281A1
• Time in Patent Office: 1,796 Days
• Field of Search: None
• US Class Current: 435/4
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 31/717 Celluloses
• CPC Class Codes: A61K 31/718 Starch or degraded starch, e.g. amylose, amylopectin
• CPC Class Codes: A61K 31/722 Chitin, chitosan
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/242 Gold; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 33/38 Silver; Compounds thereof
• CPC Class Codes: A61K 33/44 Elemental carbon, e.g. charcoal, carbon black
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/1274 Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y10S 977/734 : Fullerenes, i.e. graphene-based structures, such as nanohorns, nanococoons, nanoscrolls or fullerene-like structures, e.g. WS2 or MoS2 chalcogenide nanotubes, planar C3N4, etc.
• CPC Class Codes: Y10S 977/773 : Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/788 : Of specified organic or carbon-based composition
• CPC Class Codes: Y10S 977/81 : Of specified metal or metal alloy composition
• CPC Class Codes: Y10S 977/902 : Specified use of nanostructure
• CPC Class Codes: Y10S 977/904 : for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/915 : Therapeutic or pharmaceutical composition

Abstract

A method of uncoupling mitochondria in a subject including administering nanotubes to the subject in a therapeutically effective amount, wherein the nanotubes are self-rectifying is provided. A method of decreasing reactive oxygen species and decreasing detrimental loading of Ca²⁺ into mitochondria is provided, including administering a pharmaceutically effective amount of nanotubes into the subject. A method of reducing weight, treating cancer, reducing the effects of traumatic brain injury, or reducing the effects of ageing, in a subject including administering a pharmaceutically effective amount of nanotubes into the subject is also provided.

Claims

1. A method of uncoupling mitochondria in a subject comprising:

administering nanotubes to the subject in a therapeutically effective amount, wherein the nanotubes are self-rectifying nanotubes, having a length of less than 50 nm and a conductance such that the nanotubes conduct protons only where a proton gradient of about 120-220 mV is present.

2. The method of claim 1, wherein the nanotubes are coated with a pKa reducing compound.

3. The method of claim 1, wherein the subject is a mammal.

4. The method of claim 1, wherein the nanotubes have an inner diameter suitable for uncoupling mitochondria.

5. The method of claim 1, wherein the nanotubes have an inner diameter which allows the nanotubes to self-rectify.

6. The method of claim 1, wherein the nanotubes comprise metals or polymers.

7. The method of claim 6, wherein the metal is gold or silver.

8. The method of claim 6, wherein the polymers are natural polymers or synthetic polymers.

9. The method of claim 6, wherein the polymers are selected from the group consisting of poly(vinyl alcohol), poly(esters), polyglycolide, polycaprolactone, polyethylene oxide), poly(butylene terephthalate), poly(hydroxyalkanoates), hydrogels, modified poly(saccharides), starch, cellulose, chitosan and combinations thereof.

18. The method of claim 1 wherein the nanotubes are less than 20 nm in length.

20. The method of claim 1 wherein the nanotubes are coated with polyethylene glycol or surrounded by lipid microspheres.

10. A method of decreasing reactive oxygen species and decreasing detrimental loading of Ca²⁺ into mitochondria of a subject comprising:

administering nanotubes to the subject in a therapeutically effective amount, wherein the nanotubes are self-rectifying, having a length of less than 50 nm and having a conductance such that the nanotubes conduct protons only where a proton gradient of about 120-220 mV is present.

11. The method of claim 10, wherein the subject is a mammal.

12. The method of claim 10, wherein the nanotubes have an inner diameter designed for uncoupling mitochondria.

13. The method of claim 10, wherein the nanotubes have an inner diameter which allows the nanotubes to self-rectify.

14. The method of claim 10, wherein the nanotubes comprise metals or polymers.

15. The method of claim 14, wherein the metal is gold or silver.

16. The method of claim 14, wherein the polymers are natural polymers or synthetic polymers.

17. The method of claim 14, wherein the polymers are selected from the group consisting of poly(vinyl alcohol), poly(esters), polyglycolide, polycaprolactone, poly(ethylene oxide), poly(butylene terephthalate), poly(hydroxyalkanoates), hydrogels, modified poly(saccharides), starch, cellulose, and chitosan.

19. The method of claim 10 wherein the nanotubes are less than 20 nm in length.

21. The method of claim 10 wherein the nanotubes are coated with polyethylene glycol or surrounded by lipid microspheres.