Etherlipid-containing multiple lipid liposomes

Details Etherlipid-containing multiple lipid liposomes Etherlipid-containing multiple lipid liposomes

1999-09-03

2001-01-30

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C428S402200

Reexamination Certificate

active

06180137

ABSTRACT:

Etherlipids are synthetic analogues of platelet activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), an effector generally believed to be involved in a variety of physiological processes, such as inflammation, the immune response, allergic reactions and reproduction. Etherlipids have been shown to be effective antitumor agents in animals, and are believed to be selectively cytotoxic to a broad variety of cancer cells (see, for example, Dietzfelbinger et al. (1993); Zeisig et al. (1993); Powis et al. (1990); Berdel (1991); Bhatia and Hadju (1991); Reed et al. (1991); Workman (1991); Workman et al. (1991); Bazill and Dexter (1990); Berdel (1990); Counsell et al. (1990); Tritton and Hickman (1990); Muschiol et al. (1990); Layton et al. (1980); Runge et al. (1980); Great Britain Patent No. 1,583,661; U.S. Pat. No. 3,752,886). Etherlipids have also been shown to be antimetastatic and anti-invasive, and to be capable of cell differentiation induction.
Mechanisms of etherlipid cytotoxicity, while not definitively established, appear to involve action at, and possible disruption of, the cell membrane. The selective cytotoxicity of etherlipids may involve intracellular accumulation and differential activity of alkyl cleavage enzymes. Etherlipids may also be selective inhibitors of phosphatidylinositol phospholipase C and protein kinase C activities, as well as of phosphatidylcholine biosynthesis. Hence, etherlipids are potentially quite useful as therapeutic agents. However, their administration can also lead to hemolysis, hepatic dysfunction and gastrointestinal disorders. Applicants have found that certain liposomal formulations of etherlipids can buffer these toxicities without inhibiting anticancer efficacy, and thereby can provide a more therapeutically useful basis for etherlipid administration.
SUMMARY OF THE INVENTION
This invention provides a liposome comprising a bilayer having a lipid component which comprises: (a) a phosphatidylcholine; (b) a sterol; (c) a headgroup derivatized lipid and, (d) an etherlipid. The headgroup-derivatized lipid, comprising a phosphatidylethanolamine linked to a moiety selected from the group consisting of dicarboxylic acids, polyethylene glycols, gangliosides and polyalkylethers, comprises from about 5 mole percent to about 20 mole percent of the bilayer's lipid component; the etherlipid comprises from about 10 mole percent to about 30 mole percent of the lipid component.
Preferably, the phosphatidylcholine is dioleoyl phosphatidylcholine (“DOPC”), the sterol is cholesterol (“chol”), the headgroup-derivatized lipid is dioleoyl phosphatidylethanolamine-glutaric acid (“DOPE-GA”) and the etherlipid is
also known as “EL-18,” “ET-18-OCH
3
,” or “edelfosine”). Most preferably, the liposome is a unilamellar liposome having a diameter of from greater than about 50 nm to less than about 200 nm, and the liposome's bilayer has a lipid component comprising about 20 mole percent of the etherlipid, about 10 mole percent of the headgroup-derivatized lipid, about 30 mole percent cholesterol and about 40 mole percent dioleoyl phosphatidylcholine.
Also provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and such liposomes. Further provided is a method of treating a mammal afflicted with a cancer, including, but not limited to: a lung, brain, colon, ovarian or breast cancers, the method comprising administering the pharmaceutical compositions of this invention to the mammal.


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