Patents

Microemulsions As Precursors To Solid Nanoparticles


United States Patent

7,153,525

Mumper , et al.

December 26, 2006

The preparation of novel microemulsions to be used as precursors for solid nanoparticles is described. The microemulsion precursors consist of either alcohol-in-fluorocarbon microemulsions, liquid hydrocarbon-in-fluorocarbon microemulsions, or liquid hydrocarbon-in-water microemulsions. The formed solid nanoparticles have diameters below 200 nanometers and can be made to entrap various materials including drugs, magnets, and sensors. The solid nanoparticles can be made to target different cells in the body by the inclusion of a cell-specific targeting ligand. Methods of preparing the novel microemulsion precursors and methods to cure solid nanoparticles are provided.


Inventors: Mumper; Russell John (Lexington, KY), Jay; Michael (Lexington, KY)
Assignee: The University of Kentucky Research Foundation (Lexington, KY)
Appl. No.: 09/812,884
Filed: March 21, 2001

CONTINUING DATA

The present application claims the benefit of priority to U.S. Provisional Application No. 60/191,112, filed Mar. 22, 2000, which is incorporated by reference herein in its entirety.


Claims

What is claimed is:

1. A method of making solid nanoparticles, comprising: making an oil-in-water microemulsion by heating, the microemulsion comprising: a liquid nanoparticle matrix material formed by heating a solid matrix material until melted; a surfactant or a co-surfactant or a mixture thereof, and a molecule of interest, wherein the molecule is a drug molecule; wherein the microemulsion is formed essentially spontaneously by heating at a temperature of between about 35 degree. C. and about 100 degree. C.; and cooling the microemulsion while stirring to form solid nanoparticles having a diameter of less than about 300 nanometers, wherein said solid nanoparticles are formed by cooling the microemulsion without aqueous dilution, and where the molecule of interest is either entrapped in or adsorbed to the solid nanoparticles.

2. The method according to claim 1, wherein the nanoparticle matrix material comprises one or more of the following materials: emulsifying wax, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene stearates, phospholipids, fatty acids or fatty alcohols or their derivatives, or combinations thereof.

3. The method according to claim 1, wherein the liquid nanoparticle matrix material is present in the microemulsion at a concentration from about 0.1 to about 30 mg/mL.

4. The method according to claim 1, wherein the microemulsion comprises an oil phase that is present as liquid droplets having a diameter of less than about 100 nanometers.

5. The method according to claim 1, wherein the microemulsion comprises a continuous phase comprising water or an aqueous buffer at a concentration of greater than about 95% w/w.

6. The method according to claim 1, wherein the surfactant or co-surfactant comprises polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, hexadecyltrimethylammonium bromide, fatty alcohol and their derivatives, or combinations, thereof.

7. The method according to claim 1, wherein the surfactant is present at a total concentration of about 1 5000 mM.

8. The method according to claim 1, wherein the molecule of interest is present at a total concentration in the range of about 20 mu.g/mL to about 5 mg/mL.

9. The method according to claim 1, wherein the nanoparticle is coated with a cell-specific ligand such as an antibody, carbohydrate, peptide, protein, or derivatives or combinations thereof.

10. The method of claim 1, wherein the nanoparticles and molecule of interest are formulated into a pharmaceutical composition suitable for intravenous, intramuscular or subcutaneous administration.

Nanoscintillation Systems For Aqueous-Based Liquid Scintillation Counting


United States Patent

6,855,270

Mumper , et al.

February 15, 2005

 

The present invention relates to the use of nanoscintillation systems, or nanoparticles containing fluor molecules, that can be used to detect an electron-emitting or alpha-particle-emitting radioisotope in the absence of organic-solvents commonly used in organic-based liquid scintillation cocktails. The invention also relates to compositions and use of three oil-in-water microemulsion precursors that can be engineered rapidly, reproducibly, and cost-effectively to produce useful nanoparticles less than 100 nanometers.


Inventors: Mumper; Russell John (Lexington, KY), Jay; Michael (Lexington, KY)
Assignee: The University of Kentucky Research Foundation (Lexington, KY)
Appl. No.: 10/165,201
Filed: June 6, 2002

The patent application claims priority to U.S. Provisional Patent Application Serial No. 60/296,124 filed Jun. 7, 2001 entitled, “Nanoscintillation Systems for Aqueous-Based Liquid Scintillation Counting” by Russell J. Mumper and Michael Jay. That application is incorporated herein by reference in its entirety.

U.S. patent 7,153,525 entitled, “Microemulsions as Precursors to Solid Nanoparticles” by Russell J. Mumper and Michael Jay is incorporated herein by reference in its entirety.


Claims

What is claimed is:

1. A nanoscintillation system comprising nanoparticles suspended in an aqueous vehicle, the nanoparticles comprising: at least one nanoparticle matrix material at least one surfactant or co-surfactant or a mixture thereof, and at least one primary or secondary fluor molecule or a mixture thereof.

2. The nanoscintillation system of claim 1, the nanoparticles having a diameter less than 300 nanometers.

3. The nanoscintillation system of claim 1, the nanoparticles having a diameter less than 100 nanometers.

4. The nanoscintillation system of claim 1, further comprising an electron-emitting or alpha-particle-emitting radioisotope.

5. The nanoscintillation system of claim 4, the electron-emitting or alpha-particle-emitting radioisotope being free or attached to one or more molecules in the aqueous vehicle.

6. The nanoscintillation system of claim 1, further comprising one or more ligands coupled to one or more of the nanoparticles.

7. The nanoscintillation system of claim 6, the one or more ligands comprising a protein, carbohydrate, or a combination thereof.

8. The nanoscintillation system of claim 1, the nanoparticle matrix material comprising emulsifying wax, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, a polyoxyethylene stearte, or polystyrene or its derivative or copolymer thereof.

9. The nanoscintillation system of claim 1, the nanoparticle matrix material being present at a concentration from 0.1 to 300 mg/mL.

10. The nanoscintillation system of claim 1, the aqueous vehicle comprising water or an aqueous buffer.

11. The nanoscintillation system of claim 1, the surfactant or co-surfactant comprising a polyoxyethylene alkyl ether, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene stearate, an alkoxylated alcohol or its derivative thereof, or an alcohol.

12. The nanoscintillation system of claim 1, surfactants being present at a total concentration of 1-5000 mM.

13. The nanoscintillation system of claim 1, the primary fluor molecule comprising 2,5-diphenyloxazole (PPO), 2-(4-biphenylyl)-5-phenyl-1,3,4-oxadiazole (PBD), 2-(4-biphenylyl)-5-(4tert-butylphenyl)-1,3,4-oxadiazole (butyl-PBD), 2,5-bis(5-tert-butyl-2-benzoxazolyl)thiophene (BBOT), or derivatives or combinations thereof.

14. The nanoscintillation system of claim 1, the secondary fluor molecule comprising 1,4-bis(5-phenyloxazol-2yl)benzene (POPOP), 1,4-bis(2-methylstyryl)benzene(bis-MSB), or derivatives or combinations thereof.

15. The nanoscintillation system of claim 1, primary fluor molecules being present at a total concentration of at least 1 mg/mL.

16. The nanoscintillation system of claim 1, water comprising at least 50% of the total weight of the nanoscintillation system.

17. A method for scintillation measurement, comprising: obtaining a nanoscintillation system according to claim 1; and measuring scintillation associated with the nanoscintillation system.

18. A nanoparticle comprising: at least one nanoparticle matrix material; at least one surfactant or co-surfactant or a mixture thereof, and at least one primary or secondary fluor molecule or a mixture thereof; wherein the nanoparticle is made from an oil-in-water microemulsion precursor.

19. The nanoparticle of claim 18, the nanoparticle being made by cooling the oil-in-water microemulsion to room temperature while stirring.

20. The nanoparticle of claim 18, the nanoparticle comprising an emulsifying wax, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, a polyoxyethylene stearate, polystyrene, or derivatives or combinations thereof.

21. The nanoparticle of claim 18, the nanoparticle comprising polystyrene, a copolymer of polystyrene, or a derivative thereof and having a melting point between 40.degree. C. and 80.degree. C.

22. The nanoparticle of claim 18, the nanoparticle comprising styrene, divinyl benzene, toluene, an aromatic or unsaturated monomer capable of being polymerized by one or more free radicals, or a derivative or combination thereof.

23. The nanoparticle of claim 18, the nanoparticle being present at a concentration from 0.1 to 300 mg/mL.

24. The nanoparticle of claim 18, the surfactant or co-surfactant comprising a polyoxyethylene alkyl ether, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene stearate, an alkoxylated alcohol or its derivative thereof, or an alcohol.

25. The nanoparticle of claim 18, surfactants being present at a total concentration of 1-5000 mM.

26. The nanoparticle of claim 25, surfactants being present at a total concentration of 1-300 mM.

27. The nanoparticle of claim 18, the primary fluor molecule comprising 2,5-diphenyloxazole (PPO), 2-(4-biphenylyl)-5-phenyl-1,3,4-oxadiazole (PBD), 2-(4-biphenylyl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole (butyl-PBD), 2,5-bis(5-tert-butyl-2-benzoxazolyl)thiophene (BBOT), or derivatives or combinations thereof.

28. The nanoparticle of claim 18, the secondary fluor molecule comprising 1,4-bis(5-phenyloxazol-2yl)benzene (POPOP), 1,4-bis(2-methylstyryl)benzene (bis-MSB), or derivatives or combinations thereof.

29. The nanoparticle of claim 18, primary fluor molecules being present at a total concentration of at least 1 mg/mL.

30. The nanoparticle of claim 18, the nanoparticle being made by polymerizing the nanoparticle matrix material within the oil-in-water microemulsion precursor by free-radical polymerization.

31. The nanoparticle of claim 30, free-radical polymerization being performed by heating the oil-in-water microemulsion precursor, by adding a free-radical initiator, or by a combination thereof.

32. A method for scintillation measurement, comprising: obtain a nanoparticle according to claim 18; and measuring scintillation associated with the nanoparticle.

33. A method of making a nanoscintillation system, comprising: dispersing a liquid nanoparticle matrix material with a fluor molecule in an aqueous continuous phase to form a surfactant stabilized microemulsion; and cooling the surfactant stabilized microemulsion to room temperature while stirring.

34. A method of making a nanoparticle useful for scintillation, comprising: obtaining a nanoparticle matrix material; melting the nanoparticle matrix material to form a liquid dispersed phase; dispersing a fluor molecule into the liquid dispersed phase; dispersing the liquid dispersed phase, including the fluor molecule, in an aqueous continuous phase to form a surfactant stabilized microemulsion; and cooling the microemulsion while stirring to form a solid stable nanoparticle having a diameter of less than about 300 nanometers, which includes the fluor molecule either entrapped in or adsorbed to the nanoparticle.

35. The method of claim 34, the melting occurring at a temperature between about 35.degree. C. and about 100.degree. C.

36. The method of claim 34, the cooling comprising cooling with no dilution in water.

37. A method of making a nanoscintillation system, comprising: dispersing a liquid nanoparticle matrix material with a fluor molecule in an aqueous continuous phase to form a surfactant stabilized microemulsion; and polymerizing the liquid nanoparticle matrix material by free-radical polymerization.

38. The method of claim 37, the free-radical polymerization being performed by heating the surfactant stabilized microemulsion, by adding a free-radical initiator, or by a combination thereof.

39. The method of claim 37, further comprising concentrating the nanoscintillation system.

40. The method of claim 39, the concentrating comprising centrifugal ultrafiltration.