Lipophilic nanoparticles for drug delivery

• US 10,568,898 B2
• Filed: 08/13/2014
• Issued: 02/25/2020
• Est. Priority Date: 08/13/2013
• Status: Active Grant

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Thaxton, C. Shad, Gordon, Leo I., Mutharasan, Raja Kannan, Grun, Casey N., Foit, Linda
• Primary Examiner(s): Worsham, Jessica
• Application Number:
  US14/911,957
• Publication Number:
  US 20160193361A1
• Time in Patent Office: 2,022 Days
• Field of Search: None
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 47/6917 the form being a lipoprotein vesicle, e.g. HDL or LDL proteins
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5169 Proteins, e.g. albumin, gelatin

Abstract

Nanostructures having a core, a lipid layer and a lipoprotein which are useful for delivering therapeutic agents are provided herein. Methods of treating disease using the nanostructures are also provided, including methods of treating cancer, infectious disease, vascular disease etc.

Claims

1. A structure comprising:

a nanostructure core comprising an inorganic material;

a shell comprising a lipid layer surrounding and attached to the nanostructure core, the shell having an inner surface and an outer surface, wherein the shell has a therapeutic profile for a therapeutic agent, wherein the therapeutic agent is attached to the shell,

wherein the therapeutic profile is modified to regulate the binding capacity and/or the binding affinity between the therapeutic agent and the nanostructure;

a protein bound to at least the outer surface of the shell,

wherein at least 80% of the lipids in the outer surface of the shell have negatively charged head groups, and wherein 20-400 therapeutic agents are associated per structure; and

wherein the inner surface of the shell comprises PDP PE 16;

0 or PDP PE 18;

1.

2. The structure of claim 1 wherein the lipid layer is a lipid bilayer.

3. The structure of claim 2 wherein the protein is an apolipoprotein.

4. The structure of claim 2 wherein the therapeutic profile is associated with the outer surface of the shell.

5. The structure of claim 1, wherein the therapeutic profile is lipids in the outer surface of the shell having negative head groups.

6. The structure of claim 5, wherein at least 95% of the lipids in the outer surface of the shell have negatively charged head groups.

7. The structure of claim 5, wherein the lipids in the outer surface of the shell are selected from the group consisting of 18:

0 PG (1,2-Distearoyl-sn-glycero-3-phosphoglycerol), 16;

0 PG (1,2-dipalmitoyl-sn-glycero-3-phospho-(1′

-rac-glycerol)), 18;

1 delta9-Cis PG, 18;

3 PG (1,2-dilinolenoyl-sn-glycero-3-phospho-(1′

-rac-glycerol)), 18;

0 PA (1,2-Distearoyl-sn-glycero-3-phosphate), cardiolipin, brain PI (phosphatidylinositol), 16;

0 PA (1,2-Dipalmitoyl-sn-glycero-3-phosphate), and 18;

2 PG (1,2-dilinoleoyl-sn-glycero-3-phospho-(1′

-rac-glycerol)).

8. The structure of claim 1, wherein the therapeutic profile is lipids in the outer surface of the shell having mixtures of negative and neutral head groups.

9. The structure of claim 1, wherein the therapeutic profile is lipids in the outer surface of the shell having mixtures of positive and neutral head groups.

10. The structure of claim 1, wherein the therapeutic profile is lipids in the outer surface of the shell having mixtures of negative and positive head groups.

11. The structure of claim 1, wherein the therapeutic profile is lipids in the outer surface of the shell having mixtures of negative, positive and neutral head groups.

12. The structure of claim 1, wherein the shell comprises lipids and the lipids in the shell are selected from the group consisting of phospholipids, unsaturated lipids, saturated lipids, and therapeutic lipids.

13. The structure of claim 1, wherein the therapeutic agent is selected from the group consisting of an anti-infectious disease agent, a chemotherapeutic agent, another type of anti-cancer agent, an anti-immunological disease agent, an anti-vascular disease agent, and an anti-rheumatologic disease agent.

16. The structure of claim 13, wherein the chemotherapeutic agent is doxorubicin, andrographolide, or vincristine.

17. The structure of claim 1, wherein the inner surface of the shell comprises PDP PE 16:

0 and the outer surface of the shell comprises a lipid selected from a group consisting of 18;

0 PG (1,2-Distearoyl-sn-glycero-3-phosphoglycerol), 16;

0 PG (1,2-dipalmitoyl-sn-glycero-3-phospho-(1′

-rac-glycerol)), 18;

1 delta9-Cis PG, 18;

3 PG (1,2-dilinolenoyl-sn-glycero-3-phospho-(1′

-rac-glycerol)), 18;

0 PA (1,2-Distearoyl-sn-glycero-3-phosphate), cardiolipin, brain PI (phosphatidylinositol), 16;

0 PA (1,2-Dipalmitoyl-sn-glycero-3-phosphate), and 18;

2 PG (1,2-dilinoleoyl-sn-glycero-3-phospho-(1′

-rac-glycerol)).

18. The structure of claim 1, wherein the inner surface of the shell comprises PDP PE 18:

1 and cardiolipin.

19. The structure of claim 1, wherein the inner surface of the shell comprises PDP PE 18:

1 and wherein the shell comprises;

(i) sphingomyelin;

or

(ii) cardiolipin, 16;

0 PA (1,2-Dipalmitoyl-sn-glycero-3-phosphate), and 18;

2 PG (1,2-dilinoleoyl-sn-glycero-3-phospho-(1′

-rac-glycerol)).

14. A structure comprising:

a nanostructure core comprising an inorganic material;

a shell comprising a lipid layer surrounding and attached to the nanostructure core, the shell having an inner surface and an outer surface;

an apolipoprotein bound to at least the outer surface of the shell; and

a therapeutic agent adsorbed on the outer shell and/or incorporated between the inner surface and outer surface of the shell, wherein the therapeutic agent is selected from the group consisting of andrographolide and vincristine,

wherein at least 80% of the lipids in the outer surface of the shell have negatively charged head groups.

15. A method of treating a disease with reduced toxicity, comprising

administering to a subject having a disease a nanostructure comprising a core, a shell comprising a lipid layer surrounding and attached to the core, the shell having an inner surface and an outer surface;

an apolipoprotein associated with the shell and a therapeutic agent having toxic properties in order to treat the disease, while causing less toxicity than the toxicity caused by treatment of a subject having the disease with the therapeutic agent alone,

wherein the disease is a cancer that expresses scavenger receptor type B-,

wherein toxicity is cardiotoxicity,

wherein 20-400 therapeutic agents are associated per structure, and

wherein the inner surface of the shell comprises PDP PE 16;

0 or PDP PE 18;

1.