Amphiphilic compound assisted nanoparticles for targeted delivery

Patent metadata

Field	Value
Publication number	US-9333179-B2
Application number	US-57359109-A
Country	US
Kind code	B2
Filing date	Oct 5, 2009
Priority date	Apr 4, 2007
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

The present invention generally relates to nanoparticles with an amphiphilic component. One aspect of the invention is directed to a method of developing nanoparticles with desired properties. In one set of embodiments, the method includes producing libraries of nanoparticles having highly controlled properties, which can be formed by mixing together two or more macromolecules in different ratios. One or more of the macromolecules may be a polymeric conjugate of a moiety to a biocompatible polymer. In some cases, the nanoparticle may contain a drug. Other aspects of the invention are directed to methods using nanoparticle libraries.

First claim

The invention claimed is:

1. A nanoparticle comprising:
a first covalent conjugate having the following formula: lipid—hydrophilic polymer—targeting moiety;
a second covalent conjugate having the following formula: lipid—hydrophilic polymer;
wherein the hydrophilic polymer of the first and second conjugates is a poly(ethylene glycol) polymer;
a hydrophobic core comprising a polyester and an agent selected from the group consisting of a therapeutic agent, a diagnostic agent, and a prophylactic agent;
an amphiphilic layer around the hydrophobic core, the layer comprising at least three amphiphilic components,
wherein a first amphiphilic component of the layer is a phospholipid, and
wherein a second amphiphilic component and a third amphiphilic component of the layer are the lipid portions of the first and second covalent conjugates;
a hydrophilic outer layer comprising the hydrophilic polymer—targeting moiety portion of the first covalent conjugate and the hydrophilic polymer portion of the second covalent conjugate;
wherein the weight ratio of the amphiphilic components of the amphiphilic layer to the polyester is about 0.05 to 0.34; and
wherein the diameter of the nanoparticle is between about 40 and 500 nanometers.

2. The nanoparticle of claim 1 , wherein the thickness of the amphiphilic layer is about 1 to about 5 nanometers.

3. The nanoparticle of claim 1 , wherein the thickness of the amphiphilic layer is about 2.5 nanometers.

4. The nanoparticle of claim 1 , wherein the lipid of the first covalent conjugate is selected from the group consisting of a phosphatidylcholine, a phosphatidylinositol, a phosphatidylethanolamine, and a phosphatidic acid.

5. The nanoparticle of claim 1 , wherein the lipid of the first covalent conjugate is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine.

6. The nanoparticle of claim 1 , wherein the lipid of the second covalent conjugate is selected from the group consisting of a phosphatidylcholine, a phosphatidylinositol, a phosphatidylethanolamine, and a phosphatidic acid.

7. The nanoparticle of claim 1 , wherein the lipid of the second covalent conjugate is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine.

8. The nanoparticle of claim 1 , wherein the targeting moiety of the first covalent conjugate is selected from the group consisting of nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, p-glycoprotein receptors, and peptides.

9. The nanoparticle of claim 1 , wherein the targeting moiety is a peptide having a length of fewer than 8 amino acids.

10. The nanoparticle of claim 1 , wherein the targeting moiety comprises a peptide selected from the group consisting of AKERC (SEQ ID NO:1), CREKA (SEQ ID NO:2), ARYLQKLN (SEQ ID NO:3) and AXYLZZLN (SEQ ID NO:4); wherein X and Z are variable amino acids.

11. The nanoparticle of claim 1 , wherein the targeting moiety is an aptamer.

12. The nanoparticle of claim 1 , wherein the surface zeta potential of the nanoparticle is −80 mV to −30 mV.

13. The nanoparticle of claim 1 , wherein the hydrophobic core comprises a therapeutic agent selected from the group consisting of a chemotherapeutic agent, an antineoplastic agent, and a cytostatic agent.

14. The nanoparticle of claim 1 , wherein the hydrophobic core comprises a therapeutic agent selected from the group consisting of mitoxantrone and docetaxel.

15. The nanoparticle of claim 1 , wherein the hydrophobic core comprises a therapeutic agent selected from the group consisting of vascular endothelial growth factor (VEGF), fibroblast growth factors, monocyte chemoattractant protein 1 (MCP-1), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-beta), DEL-1, insulin like growth factors (IGF), placental growth factor (PLGF), hepatocyte growth factor (HGF), prostaglandin E1(PG-E1), prostaglandin E2(PG-E2), tumor necrosis factor alpha (TNF-alpha), granulocyte stimulating growth factor (G-CSF), granulocyte macrophage colony-stimulating growth factor (GM-CSF), angiogenin, follistatin, proliferin, PR39, PR11, nicotine, statins, niacin, bile acid resins, fibrates, and estradiol.

16. The nanoparticle of claim 1 , wherein the polyester is poly(lactic-co-glycolic acid).

17. The nanoparticle of claim 1 , wherein the first amphiphilic component is a lecithin.

18. A pharmaceutical composition comprising the nanoparticle of claim 1 .

19. A pharmaceutical composition comprising the nanoparticle of claim 3 .

Assignees

• Zhang Liangfang
• Radovic-Moreno Aleksandar F
• Gu Frank X
• Alexis Frank
• Langer Robert S
• Farokhzad Omid C
• Massachusetts Inst Technology
• Brigham & Womens Hospital

Inventors

• Zhang Liangfang
• Radovic-Moreno Aleksandar F
• Gu Frank X
• Alexis Frank
• Langer Robert S
• Farokhzad Omid C

Classifications

• A61K47/6937

  the polymer being PLGA, PLA or polyglycolic acid · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61K9/5123 Primary

  Organic compounds, e.g. fats, sugars · CPC title

• A61K47/6935

  the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol · CPC title