Method and system for systemic delivery of growth arresting, lipid-derived bioactive compounds

Patent metadata

Field	Value
Publication number	US-9326953-B2
Application number	US-201213673180-A
Country	US
Kind code	B2
Filing date	Nov 9, 2012
Priority date	Apr 25, 2003
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

A system and method for optimizing the systemic delivery of growth-arresting lipid-derived bioactive drugs or gene therapy agents to an animal or human in need of such agents utilizing nanoscale assembly systems, such as liposomes, resorbable and non-aggregating nanoparticle dispersions, metal or semiconductor nanoparticles, or polymeric materials such as dendrimers or hydrogels, each of which exhibit improved lipid solubility, cell permeability, an increased circulation half life and pharmacokinetic profile with improved tumor or vascular targeting.

First claim

What is claimed is:

1. A system for delivering a therapeutic compound to an animal or human in need of such system comprising
liposomes that contain a hydrophobic chemotherapeutic agent and/or gene therapy agent,
wherein the lipid bilayer of the liposomes comprises cell-permeable pegylated C8 ceramide (PEG-C8) and pegylated distearoylphosphatidylethanolamine (PEG-DSPE) which both stabilize the lipid bilayer and have a molecular weight within the range of 2000-5000 g/mol,
wherein the lipid bilayer further comprises a free bioactive ceramide or ceramide analogue such that the free bioactive ceramide or ceramide analogue is independent of being conjugated to polyethylene glycol (PEG) and present at a concentration of at least 30 molar percent.

2. The system of claim 1 , wherein the ceramide analogue is a short-chain ceramide analogue.

3. The system of claim 1 , wherein the ceramide analogue comprises a ceramide derivative thereof that contains a 2-10 carbon short-chain fatty acid at SN-2 position.

4. The system of claim 1 , wherein the free bioactive ceramide or ceramide analogue comprises physiological ceramide or a derivative thereof containing a 12-24 carbon long-chain fatty acid at SN-2 position.

5. The system of claim 1 , wherein the gene therapy agent is present and is selected from the group consisting of oligonucleotides, ribozymes, DNA-zymes, plasmids, antisense and si-RNA.

6. The system of claim 1 , wherein said system is configured for the systemic delivery of the free bioactive ceramide or ceramide analogue and a hydrophobic chemotherapeutic agent and/or gene therapy agent to treat a pathology involving dysfunctional cell growth, and wherein the pathology is selected from the group consisting of cancer, neoplasm, arterial inflammatory disease, atherosclerosis, restenosis or vulnerable plaque and diabetes.

7. The system of claim 1 , wherein the lipid bilayer further comprises a cationic lipid.

8. The system of claim 7 , wherein the cationic lipid is diolcoyl-1,2-diacyl-3-trimethylammonium-propane.

9. The system of claim 1 , wherein the free bioactive ceramide is C6 ceramide.

10. The system of claim 9 , wherein the pegylated C8-ceramide is polyethylene glycol 750-C 8 ceramide.

11. The system of claim 9 , wherein the free ceramide or ceramide analogue is present at a concentration of at least 40 molar percent.

12. The system of claim 1 , wherein the lipid bilayer further comprises a fusogenic lipid.

13. The system of claim 12 , wherein the fusogenic lipid is a destabilizing lipid that forms a hexagonal conformation in aqueous solution, generating inverse micelles.

14. The system of claim 1 , wherein the liposomes do not comprise cholesterol.

15. The system of claim 1 , wherein the liposome lipid bilayer further comprises cholesterol.

Assignees

• Penn State Res Found

Inventors

• Kester Mark
• Stover Thomas
• Lowe Tao
• Adair James H
• Kim Young Shin

Classifications

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title

• A61K9/1272

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• A61K31/164 Primary

  of a carboxylic acid with an aminoalcohol, e.g. ceramides · CPC title

• Y10S977/783

  Organic host/matrix, e.g. lipid · CPC title

• A61P43/00

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