Nanoparticles for mitochondrial trafficking of agents

• US 10,416,167 B2
• Filed: 02/15/2013
• Issued: 09/17/2019
• Est. Priority Date: 02/17/2012
• Status: Active Grant

• Current Assignee: The University of Georgia Research Foundation, Inc.
• Original Assignee: The University of Georgia Research Foundation, Inc.
• Inventors: Dhar, Shanta, Marrache, Sean M.
• Primary Examiner(s): Cabral, Robert S
• Application Number:
  US14/378,813
• Publication Number:
  US 20160022825A1
• Time in Patent Office: 2,405 Days
• CPC Class Codes: A61K 31/06 the aromatic ring being substituted by nitro groups
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 49/0067 quantum dots, fluorescent nanocrystals
• CPC Class Codes: A61K 49/0093 Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: G01N 33/587 Nanoparticles
• CPC Class Codes: G01N 33/588 : with semiconductor nanocrystal label, e.g. quantum dots

Abstract

Nanoparticles include a core, a hydrophilic layer around the core, and one or more mitochondrial targeting moieties, and may optionally include one or more contrast agents or one or more therapeutic agents. For effective mitochondrial targeting the nanoparticles have a diameter of about 200 nm or less or have a zeta potential of about 0 mV or more.

Claims

1. A nanoparticle, comprising:

a hydrophobic nanoparticle core;

a hydrophilic layer surrounding the core; and

a mitochondria targeting moiety tethered to the core,

wherein the nanoparticle has a diameter of from about 10 nanometers to about 200 nanometers or less and has a zeta potential of about 0 mV or greater.

2. A nanoparticle according to claim 1, wherein the nanoparticle has a diameter of from about 80 nanometers to about 100 nanometers.

3. A nanoparticle according to claim 1, wherein the nanoparticle has a zeta potential of about 1 mV or greater.

4. A nanoparticle according to claim 1, wherein the nanoparticle has a zeta potential of about 7 mV or greater.

5. A nanoparticle according to claim 1, wherein the nanoparticle has a zeta potential of about 20 mV or greater.

6. A nanoparticle according to claim 1, wherein the nanoparticle has a zeta potential of about 25 mV or greater.

7. A nanoparticle according to claim 1, wherein the mitochondria targeting moiety comprises a moiety selected from the group consisting of a triphenylphosphonium (TPP) moiety, a Szeto-Shiller peptide, and a rhodamine cation.

8. A nanoparticle according to claim 1, wherein the mitochondria targeting moiety comprises a triphenylphosphonium (TPP) moiety or a derivative thereof.

9. A nanoparticle according to claim 1, wherein the mitochondria targeting moiety is attached to the core via a hydrophilic polymer moiety.

10. A nanoparticle according to claim 9, wherein the hydrophilic polymer moiety comprises PEG.

11. A nanoparticle according to claim 9, wherein the hydrophilic polymer moiety is attached to a hydrophobic polymer moiety that forms at least a portion of the core.

12. A nanoparticle according to claim 1, wherein the hydrophilic layer comprises a hydrophilic polymer moiety attached to the core.

13. A nanoparticle according to claim 12, wherein the hydrophilic polymer moiety comprises polyethylene glycol (PEG).

14. A nanoparticle according to claim 12, wherein hydrophilic polymer moiety is attached to the core via a hydrophobic polymer moiety that forms at least a part of the core.

15. A nanoparticle according to claim 14, wherein the hydrophobic polymer that forms at least a part of the core is selected from a polymer comprising polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), and polylactic-co-glycolic acid (PLGA).

16. A nanoparticle according to claim 14, wherein the hydrophobic polymer that forms at least a part of the core comprises polylactic-co-glycolic acid (PLGA).

17. A nanoparticle according to claim 1, further comprising a contrast agent.

18. A nanoparticle according to claim 17, wherein the contrast agent is selected from a quantum dot, iron oxide, and combinations thereof.

19. A nanoparticle according to claim 17, wherein the contrast agent is embedded in, or contained within, the core.

20. A nanoparticle according to claim 17, wherein the contrast agent is attached to a hydrophilic polymer moiety that is attached to the core.

21. A nanoparticle according to claim 1, wherein the nanoparticle further comprises a therapeutic agent.

22. A nanoparticle according to claim 21, wherein the therapeutic agent is selected from the group consisting of an anticancer agent, a mitochondrial uncoupling agent and an agent configured to reduce amyloid beta.

23. A nanoparticle according to claim 21, wherein the therapeutic agent is selected from the group consisting of 2,4-dinitrophenol (DNP), lonidamine (LND), α

-tocopherylsuccinate (TOS), and curcumin.

24. A method for treating a patient at risk or suffering from a disease associated with mitochondrial dysfunction, comprising administering a nanoparticle according to claim 21 to the patient.