Ligand directed toroidal nanoparticles for therapy and diagnostic imaging

Patent metadata

Field	Value
Publication number	US-9468607-B2
Application number	US-68209808-A
Country	US
Kind code	B2
Filing date	Oct 9, 2008
Priority date	Oct 9, 2007
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

The present invention provides nanoparticles, methods of making the nanoparticles, and methods of using the nanoparticles to deliver therapeutic agents and/or imaging agents.

First claim

What is claimed is:

1. A substantially bi-concaved disc shaped nanoparticle, the nanoparticle comprising an aqueous inner core and an outer shell, wherein the outer shell comprises an amphiphilic polymer that forms a bi-layer and at least one molecule conjugated within the hydrophilic region of the amphiphilic polymer; wherein (a) the at least one molecule conjugated within the hydrophilic region of the amphiphilic polymer is selected from the group consisting of a targeting moiety, a biologically active agent, an imaging agent, and a metal atom, and (b) the amphiphilic polymer is polyethyleneimine conjugated to an amphiphilic lipid selected from palmitic acid, 10,12-pentacosadiynoic acid, and linoleic acid, such that at least 40% of free reactive groups of the polyethyleneimine are conjugated to the amphiphilic lipid.

2. The nanoparticle of claim 1 , wherein the amphiphilic polymer is from about 1% to about 10% by weight of the nanoparticle.

3. The nanoparticle of claim 1 , wherein the amphiphilic polymer comprising the outer shell is cross-linked by a method selected from the group consisting of a chemical means and a photo-chemical means.

4. The nanoparticle of claim 3 , wherein at least 50% by weight of the available reactive groups of the amphiphilic polymer are cross-linked.

5. The nanoparticle of claim 1 , wherein the surface of the amphiphilic polymer comprising the outer shell is derivatized with PEG.

6. The nanoparticle of claim 1 , wherein average diameter of the nanoparticle is from about 50 nm to about 500 nm.

7. The nanoparticle of claim 1 , wherein the average diameter of the nanoparticle is from about 100 nm to about 250 nm.

8. The nanoparticle of claim 1 , wherein the average height of the nanoparticle is from about 30 nm to about 80 nm.

9. The nanoparticle of claim 1 , wherein the nanoparticle comprises a through-hole.

10. The nanoparticle of claim 1 , wherein the nanoparticle comprises a depression.

11. The nanoparticle of claim 1 , wherein in the biologically active agent is a therapeutic agent selected from the group consisting of camptothecin, doxorubicin, fumagillin, and methotrexate.

12. The nanoparticle of claim 1 , wherein in the imaging agent is selected from the group consisting of a contrast agent, a radionuclide, and a fluorescent molecule.

13. The nanoparticle of claim 1 , wherein in the metal atom selected from the group consisting of manganese, cobalt, iron, gadolinium, copper, gold, titanium, tantalum, and iodine.

14. The nanoparticle of claim 1 , wherein the nanoparticle further comprises a water soluble molecule that is contained within the aqueous inner core.

15. The nanoparticle of claim 1 , wherein the nanoparticle further comprises a molecule conjugated to the surface of the outer shell of the nanoparticle.

16. The nanoparticle of claim 1 , wherein the nanoparticle further comprises a molecule conjugated within the hydrophobic region of the amphiphilic polymer comprising the outer shell of the nanoparticle.

17. The nanoparticle of claim 1 , wherein at least 50% of free reactive groups of the polyethyleneimine are conjugated to the amphiphilic lipid.

18. The nanoparticle of claim 1 , wherein about 50% to about 60% of free reactive groups of the polyethyleneimine are conjugated to the amphiphilic lipid.

19. The nanoparticle of claim 1 , wherein at least 55% of free reactive groups of the polyethyleneimine are conjugated to the amphiphilic lipid.

20. A substantially bi-concaved shaped nanoparticle comprising an aqueous inner core and a hydrophilic outer shell, wherein the outer shell comprises an amphiphilic polymer that forms a bi-layer, and wherein the nanoparticle is prepared by a process comprising the steps of:
(a) providing the amphiphilic polymer, wherein the amphiphilic polymer comprises polyethyleneimine conjugated to an amphiphilic lipid, wherein at least 40% of the free reactive groups of the polyethyleneimine are conjugated to the amphiphilic lipid, and the amphiphilic lipid is selected from palmitic acid, linoleic acid, and 10,12-pentacosadiynoic acid;
(b) forming a plurality of inverted micelles by agitating the amphiphilic polymer in a non-polar solvent;
(c) mixing the product of step (b) with at least one molecule suspended in an aqueous medium until the at least one molecule is transferred from the aqueous phase to the organic phase and then separating the organic phase from the aqueous phase, wherein the at least one molecule is selected from the group consisting of a targeting moiety, a biologically active agent, an imaging agent, and a metal atom;
(d) mixing a polar solvent with the separated organic phase from step (c), and evaporating the non-polar solvent that was in the organic phase at a pressure of about 350 mbar to 1000 mbar, such that an inversion of the inverted micelles occurs; and
(e) agitating the product of step (d) while maintaining a temperature from about 30° C. to about 65° C. to produce a bi-concaved shaped nanoparticle that has an outer shell, wherein the outer shell comprises a bi-layer formed by the amphiphilic polymer.

Assignees

• Lanza Gregory M
• Wickline Samuel A
• Pan Dipanjan
• Univ Washington

Inventors

• Lanza Gregory M
• Wickline Samuel A
• Pan Dipanjan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• Y10T428/2985

  Solid-walled microcapsule from synthetic polymer · CPC title

• A61K9/5146 Primary

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title

• A61K49/1824

  coated or functionalised nanoparticles (liposomes A61K49/1812; nanoemulsions A61K49/1806; micelles A61K49/1809) · CPC title