Methods and compositions for X-ray induced release from pH sensitive liposomes

Patent metadata

Field	Value
Publication number	US-9849087-B2
Application number	US-201214357038-A
Country	US
Kind code	B2
Filing date	Nov 8, 2012
Priority date	Nov 8, 2011
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

Compositions including pH sensitive lipid vesicles comprised of a lipid layer, an agent, and an organic halogen such that the agent is released from the vesicles after exposure to ionizing radiation. Methods of delivering the agent to a target in a subject using the compositions provided herein are also described. The methods allow for controlled release of the agent. The timing of release of the agent from the lipid vesicle may be controlled as well as the location of release by timing and localizing the exposure to ionizing radiation exposure.

First claim

We claim:

1. A pH sensitive lipid vesicle composition comprising a lipid layer surrounding an aqueous medium configured for the controlled release of an agent upon exposure to ionizing radiation, the aqueous medium comprising the agent and an organic halogen and the lipid layer comprising a pH sensitive lipid,
wherein the organic halogen is chloral hydrate and has a concentration of between 0.1M and 1.0M in the aqueous medium within the vesicle and
wherein exposure of the aqueous medium to ionizing radiation increases the acidity of the aqueous medium and allows the agent to be released from the lipid vesicle.

2. The composition of claim 1 , wherein the agent is a cancer therapeutic agent, a polypeptide, a toxin, a radiotherapeutic agent, a radiosensitizing agent, an angiogenesis inhibitor, an imaging agent or combinations thereof.

3. The composition of claim 1 , wherein the lipid layer comprises pH sensitive lipid selected from phosphatidylethanolamine, palmitoylhomocysteine, diacylsuccinylglycerols, and dioleoylphosphatidylethanolamine.

4. The composition of claim 1 , wherein the lipid layer further comprises a lipid anchored polyethylene glycol, cholesterol or at least one polypeptide capable of localizing in the lipid layer.

5. The composition of claim 1 , further comprising a targeting molecule.

6. The composition of claim 5 , wherein the targeting molecule is selected from a targeting polypeptide, a folate receptor, an antibody or combinations thereof.

7. The composition of claim 1 , wherein exposure to ionizing radiation releases at least 25% of the agent within 4 hours after exposure or wherein exposure to ionizing radiation releases at least 50% of the agent within 8 hours after exposure.

8. The composition of claim 1 , wherein the ionizing radiation source is X-rays or gamma rays.

9. The composition of claim 1 , wherein the pH sensitive lipid vesicle is a liposome.

10. A pharmaceutical composition comprising the pH sensitive lipid vesicle composition of claim 1 and a pharmaceutically acceptable carrier.

11. A method of for the controlled release of an agent, the method comprising:
a. providing the composition of claim 1 ;
b. exposing the composition to ionizing radiation to increase the free protons in the aqueous medium inside the lipid layer;
c. destabilizing the lipid layer with the free protons to increase the permeability of the lipid layer to the agent; and
d. releasing the agent from the pH sensitive lipid vesicle.

12. The method of claim 11 , wherein exposure to ionizing radiation releases at least 25% of the agent within 4 hours after exposure.

13. The method of claim 11 , wherein exposure to ionizing radiation releases at least 50% of the agent within 8 hours after exposure.

14. The method of claim 11 , wherein the agent is not released from the pH sensitive lipid vesicle until ionizing radiation triggers the agent's release.

15. The composition of claim 1 , wherein the pH sensitive lipid is dioleoylphosphatidylethanolamine.

16. The composition of claim 1 , wherein the agent is not released from the pH sensitive lipid vesicle until ionizing radiation triggers the agent's release.

Assignees

• Univ Arkansas

Inventors

• Fologea Daniel
• Henry Ralph
• Salamo Greg
• Mazur Yuriy
• Borrelli Michael J

Classifications

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61N5/10

  X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence) · CPC title

• A61K9/0009

  involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K9/1271 Primary

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title