Amphiphilic compound assisted nanoparticles for targeted delivery

• US 9,333,179 B2
• Filed: 10/05/2009
• Issued: 05/10/2016
• Est. Priority Date: 04/04/2007
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Original Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Inventors: Zhang, Liangfang, Radovic-Moreno, Aleksandar F., Gu, Frank X., Alexis, Frank, Langer, Robert S., Farokhzad, Omid C.
• Primary Examiner(s): Blanchard, David J
• Assistant Examiner(s): Anthopolos, Peter
• Application Number:
  US12/573,591
• Publication Number:
  US 20100203142A1
• Time in Patent Office: 2,409 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

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.

Claims

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.