Liposomal delivery system with photoactivatable triggered release

• US 5,277,913 A
• Filed: 09/09/1991
• Issued: 01/11/1994
• Est. Priority Date: 09/09/1991
• Status: Expired due to Fees

• Current Assignee: David H. Thompson
• Original Assignee: David H. Thompson
• Inventors: Thompson, David H., Anderson, Valerie C.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): KISHORE, GOLLAMUDI S
• Application Number:
  US07/756,504
• Time in Patent Office: 855 Days
• Field of Search: 424/450, 424/417, 436/829, 428/402.2
• US Class Current: 424/450
• CPC Class Codes: A61K 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: Y10S 436/829 Liposomes, e.g. encapsulation
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

A triggered release liposomal delivery system is disclosed that selectively releases its contents in response to illumination or reduction in pH. The liposomes contain an amphipathic lipid, such as a phospholipid, having two chains derived from fatty acid that allow the lipid to pack into a bilayer structure. One or both of the alkyl chains contains a vinyl ether functionality that is cleaved by reactive oxygen species (ROS) or acid. A photosensitizer is incorporated into the liposomal cavity or membrane, and produces ROS or acid when illuminated to cleave the vinyl ether functionality and disrupt the liposomal membrane to release the vesicle contents. The lipid is preferably a plasmalogen, for example ##STR1## wherein R₁ and R₂ are each long chain hydrocarbons containing 12-24 carbons.

Claims

1. A liposome comprising:

a liposomal membrane consisting essentially of plasmalogens having a phospholipid with a vinyl ether functional group sufficiently close to an interface between the membrane and its environment or core that, when the vinyl ether functional group is cleaved to produce a product that forms a micelle in the membrane, pores are formed in the membrane through which the contents of the liposome may leave the liposome; and

a lysogenic substance that, in response to photoillumination or pH reduction, produces reactive oxygen species or hydrogen ions which cleave the vinyl ether functional group of the plasmalogen in response to photoillumination or pH reduction and form the pores in the membrane.

2. The liposome of claim 1 wherein the lysogenic substance produces reactive oxygen species that cleave the vinyl ether functional group in response to photoillumination or pH reduction.

3. The liposome of claim 1 wherein the lysogenic substance absorbs light and produces reactive oxygen species, in response to illumination of the lysogenic substance with light, which reactive oxygen species cleave the vinyl ether functional group.

4. The liposome of claim 1 wherein the lysogenic substance produces reactive oxygen species in response to illumination of the lysogenic substance with light having a wavelength greater than about 630 nm.

5. The liposome of claim 1 wherein the lysogenic substance produces hydrogen ions in response to photoillumination to lower the pH and cleave the vinyl ether functional group.

6. The liposome of claim 5 wherein the lysogenic substance produces hydrogen ions in response to photoillumination of the lysogenic substance with light of a wavelength that is absorbed by the lysogenic substance.

7. The liposome of claim 6 wherein the lysogenic substance produces hydrogen ions in response to photoillumination with light having a wavelength of 540-827 nm.

8. The liposome of claim 1 wherein the phospholipid comprises the compound:

##STR9## wherein R₁ and R₂ each comprise (CH₂)_n where n is 12-24 and R₃ is selected from the group consisting of choline, ethanolamine, serine and inositol.

9. The liposome of claim 8 wherein n is 12-16.

10. The liposome of claim 8 wherein n is 16-18.

11. The liposome of claim 8 wherein n is 12-16 for R₁ and n is 16-24 for R₂.

12. The liposome of claim 1 wherein the phospholipid comprises a polar head group and two lipophilic chains, wherein only one of the lipophilic chains contains the vinyl ether functionality.

13. The liposome of claim 1 further comprising a therapeutic substance contained within the cavity or membrane of the liposome.

14. The liposome of claim 13 wherein the therapeutic substance is contained in the lipid bilayer.

15. The liposome of claim 13 wherein the therapeutic substance is contained in the cavity.

16. The liposome of claim 14 wherein the lysogenic substance is contained in the cavity.

17. The liposome of claim 15 wherein the lysogenic substance is contained in the membrane.

18. The liposome of claim 1 wherein the liposomal membrane also comprises a stabilizing lipid, selected from the group consisting of dihydrocholesterol and dipalmitoyl phosphatidylcholine, in an amount sufficient to enhance liposome stabilization.

19. The liposome of claim 1 wherein the lysogenic substance is a phthalocyanine.

23. The liposome of claim 1 wherein the membrane consists of plasmalogens having the vinyl ether functional group within 9 carbons of the interface.

24. The liposome of claim 1 wherein the membrane consists of plasmalogens having the vinyl ether functional group within 4 carbons of the interface.

25. The liposome of claim 24 wherein the membrane consists of plasmalogens in which the vinyl ether functional group is at the interface with no intervening carbons between the interface and functionality.

26. The liposome of claim 1 wherein the sensitizer is selected from the group consisting of a phenathiazinequinone, bis(2-ethyl-1,3'"'"'-dioxolane)kryptocyanine, purpurin, phthalocyanine, and a clorin.

27. The liposome of claim 26 wherein the sensitizer is a phthalocyanine selected from the group consisting of 2,6,16,23-tetrahydroxy phthalocyanines, sulfonated naphthalocyanines, and octaalkoxy phthalocyanines.

20. A liposome, comprising:

a liposomal membrane consisting essentially of a plasmalogen lipid that contains a vinyl ether functional group which, when cleaved, produces a micelle that forms a stable pore in the membrane;

a lysogenic substance that locally reduces the pH or produces reactive oxygen species in response to illumination with light absorbed by the substance to cleave the vinyl ether functionality; and

a therapeutic substance carried by the liposome and released from the liposome through the pore in the membrane after illumination.

21. The liposome of claim 20 wherein the liposomal membrane encloses a cavity in which the therapeutic substance is contained, and the lysogenic substance is contained in the membrane.

22. The liposome of claim 20 wherein the liposomal membrane encloses a cavity, and the therapeutic substance is contained within the membrane and not the cavity.