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

Patent metadata

Field	Value
Publication number	US-10220000-B2
Application number	US-201715847350-A
Country	US
Kind code	B2
Filing date	Dec 19, 2017
Priority date	Nov 8, 2011
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

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 configured for the controlled release of an agent upon exposure to ionizing radiation, the composition comprising:
a lipid layer, the lipid layer comprising a pH sensitive phospholipid selected from the group consisting of a phosphatidylethanolamine, a phosphatidylcholine, and a combination thereof, and
an aqueous medium, the aqueous medium comprises the agent and an organic halogen capable of interacting with ionizing radiation to increase the acidity of the aqueous medium,
wherein the organic halogen is selected from chloral hydrate and bromal hydrate and has a concentration between 0.01 M and 2 M in the aqueous medium within the vesicle.

2. The composition of claim 1 , wherein the pH sensitive phospholipid is selected from the combination of the phosphatidylethanolamine and the phosphatidylcholine.

3. The composition of claim 1 , wherein the lipid layer further comprises a member selected from a lipid anchored polyethylene glycol, cholesterol, a targeting molecule, a pH sensitive polymer, a polypeptide capable of localizing in the lipid layer, and any combination thereof.

4. The composition of claim 3 , wherein the lipid layer comprises the lipid anchored polyethylene glycol, cholesterol, or both the lipid anchored polyethylene glycol and cholesterol.

5. The composition of claim 3 , wherein the targeting molecule is selected from a targeting polypeptide, a folate receptor, an antibody, and any combination thereof.

6. The composition of claim 3 , wherein the pH sensitive polymer comprises a pH sensitive moiety selected from the group consisting of methylacrylic acid, ethylacrylic acid, propylacrylic acid, butylacrylic acid, and any combination thereof.

7. The composition of claim 1 , wherein the agent is selected from a group consisting of a cancer therapeutic agent, a polypeptide, a toxin, a radiotherapeutic agent, a radiosensitizing agent, an angiogenesis inhibitor, an imaging agent, and any combination thereof.

8. The composition of claim 3 , wherein the molar ratio of the pH sensitive lipid, the lipid anchored polyethylene glycol, cholesterol, the targeting molecule, the pH sensitive polymer, and the polypeptide capable of localizing in the lipid layer is configured to initiate sustained release of the agent following exposure to ionizing radiation while sealing the lipid layer prior to exposure to ionizing radiation at an initial pH.

9. The composition of claim 1 , wherein the aqueous medium has a concentration of organic halogen configured to initiate sustained release of the agent following exposure to ionizing radiation while sealing the lipid layer prior to exposure to ionizing radiation at an initial pH.

10. The composition of claim 1 , wherein the composition is configured release at least 25% of the agent within 4 hours of interacting with ionizing radiation.

11. The composition of claim 1 , wherein the composition is configured to release at least 50% of the agent within 8 hours of interacting with ionizing radiation.

12. A pH sensitive lipid vesicle composition configured for the controlled release of an agent upon exposure to ionizing radiation, the composition comprising:
a lipid layer, the lipid layer comprising a pH sensitive phospholipid selected from the group consisting of a phosphatidylethanolamine, a phosphatidylcholine, and a combination thereof, a lipid anchored polyethylene glycol, and cholesterol, and an aqueous medium, the aqueous medium comprises the agent and an organic halogen capable of interacting with ionizing radiation to increase the acidity of the aqueous medium,
wherein the organic halogen is selected from chloral hydrate and bromal hydrate and has a concentration between 0.01 M and 2 M in the aqueous medium within the vesicle.

13. The composition of claim 12 , wherein the pH sensitive phospholipid is selected from the combination of the phosphatidylethanolamine and the phosphatidylcholine.

14. The composition of claim 12 , wherein the molar ratio of the pH sensitive lipid, the lipid anchored polyethylene glycol, and cholesterol in the lipid layer is configured to initiate sustained release of the agent following exposure to ionizing radiation while sealing the lipid layer prior to exposure to ionizing radiation at an initial pH.

15. The composition of claim 12 , wherein the aqueous medium has a concentration of organic halogen configured to initiate sustained release of the agent following exposure to ionizing radiation while sealing the lipid layer prior to exposure to ionizing radiation at an initial pH.

16. A method for the localized release of an agent within a subject, the method comprising:
administering a pH sensitive lipid vesicle composition as in claim 1 to a subject and exposing a portion of the subject to ionizing radiation whereby interaction of the composition to the ionizing radiation within the exposed portion of the subject initiates the release of agent from the composition.

17. The method of claim 16 , wherein the molar ratio of the pH sensitive lipid in the lipid layer is configured to initiate sustained release of the agent following exposure to ionizing radiation while sealing the lipid layer prior to exposure to ionizing radiation within the subject.

18. The method of claim 16 , wherein the aqueous medium has a concentration of organic halogen configured to initiate sustained release of the agent following exposure to ionizing radiation while sealing the lipid layer prior to exposure to ionizing radiation within the subject.

19. The method of claim 16 , wherein the lipid layer further comprises a lipid anchored polyethylene glycol and cholesterol.

Assignees

• Univ Arkansas
• Bioventures Llc

Inventors

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

Classifications

• A61K9/0009

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

• A61N5/10

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

• A61K47/10

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

• A61K45/06

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