Mitochondrial delivery of 3-bromopyruvate

• US 10,398,663 B2
• Filed: 03/13/2015
• Issued: 09/03/2019
• Est. Priority Date: 03/14/2014
• 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
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Tcherkasskaya, Olga V.
• Application Number:
  US15/123,786
• Publication Number:
  US 20170014361A1
• Time in Patent Office: 1,635 Days
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/7004 Monosaccharides having only carbon, hydrogen and oxygen atoms
• CPC Class Codes: A61K 41/0042 Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
• CPC Class Codes: A61K 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• CPC Class Codes: A61K 47/6923 the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61N 5/062 Photodynamic therapy, i.e. excitation of an agent
• CPC Class Codes: A61N 5/067 using laser light

Abstract

A mitochondria targeted gold nanoparticle (T-3-BP-AuNP) decorated with 3-bromopyruvate (3-BP) and delocalized lipophilic triphenylphosphonium (TPP) cations to target the mitochondrial membrane potential (Δψm) was developed for delivery of 3-BP to cancer cell mitochondria by taking advantage of higher Δψm in cancer cell compared to normal cells. This construct showed remarkable anticancer activity in prostate cancer cells compared to non-targeted construct NT-3-BP-AuNP and free 3-BP. Anticancer activity of T-3-BP-AuNP was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3-BP chemotherapeutic and AuNP photothermal effects. T-3-BP-AuNPs showed markedly enhanced ability to alter cancer cell metabolism by inhibiting glycolysis and demolishing mitochondrial oxidative phosphorylation in prostate cancer cells. Our findings demonstrated that mitochondria targeted and concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP may have promise as a new anticancer therapy.

Claims

1. A nanoparticle, comprising:

a radiation excitable core;

hexokinase-2 inhibitor attached to the radiation excitable core; and

a mitochondrial targeting moiety attached to the radiation excitable core, wherein the mitochondrial targeting moiety comprises a lipophilic delocalized cation.

2. The nanoparticle according to claim 1, wherein the radiation excitable core comprises gold.

3. The nanoparticle according to claim 1, wherein the mitochondrial targeting moiety comprising the lipophilic delocalized cation comprises a moiety selected from the group consisting of a triphenyl phosphonium (TPP) moiety and a rhodamine cation.

4. The nanoparticle according to claim 1, wherein the mitochondrial targeting moiety comprising the lipophilic delocalized cation comprises a triphenyl phosphonium (TPP) moiety or a derivative thereof.

5. The nanoparticle according to claim 1, wherein the hexokinase-2 inhibitor is selected from the group consisting of 3-bromopyruvate, 2-deoxy-D-glucose, lonidamine, and combinations thereof.

6. A method for treating a patient at risk or suffering from cancer, comprising administering an effective amount of the nanoparticle according to claim 1 to the patient.

7. The method according to claim 6, wherein the cancer is prostate cancer.

8. The method according to claim 6, further comprising laser irradiating cells containing the nanoparticles after administering the nanoparticles to the patient to cause the radiation excitable core to heat.

9. A nanoparticle, comprising:

a core comprising gold, silver, or a quantum dot;

a hexokinase-2 inhibitor attached to the core; and

a mitochondrial targeting moiety attached to the core, wherein the mitochondrial targeting moiety comprises a triphenyl phosphonium moiety or a rhodamine cation.

10. The nanoparticle of claim 9, wherein the core comprises gold.

11. The nanoparticle of claim 10, wherein the mitochondrial targeting moiety comprises a triphenyl phosphonium moiety.

12. The nanoparticle of claim 9, wherein the mitochondrial targeting moiety comprises a triphenyl phosphonium moiety.

13. The nanoparticle according to claim 9, wherein the hexokinase-2 inhibitor is selected from the group consisting of 3-bromopyruvate, 2-deoxy-D-glucose, and lonidamine.

14. The nanoparticle according to claim 10, wherein the hexokinase-2 inhibitor is selected from the group consisting of 3-bromopyruvate, 2-deoxy-D-glucose, and lonidamine.

15. The nanoparticle according to claim 11, wherein the hexokinase-2 inhibitor is selected from the group consisting of 3-bromopyruvate, 2-deoxy-D-glucose, and lonidamine.

16. The nanoparticle according to claim 12, wherein the hexokinase-2 inhibitor is selected from the group consisting of 3-bromopyruvate, 2-deoxy-D-glucose, and lonidamine.