D and L etherlipid stereoisomers and liposomes

Details D and L etherlipid stereoisomers and liposomes D and L etherlipid stereoisomers and liposomes

2000-03-31

2003-12-23

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C428S402200

Reexamination Certificate

active

06667053

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a liposome comprising an ether lipid stereoisomer in the lipid bilayer of the liposome. The invention also encompasses pharmaceutical compositions comprising the liposome and methods of treating an animal with the liposome.
BACKGROUND OF THE INVENTION
Pharmaceutical therapeutics useful in the treatment of cancers or inflammatory conditions generally aim to slow the growth of, or destroy cancer cells or modulate the cells responsible for inflammatory responses. Optimal therapeutics, for instance cancer chemotherapy provides the decrease or eradication of cancer cell growth while avoiding or diminishing collateral damage to normal cells and tissues. The most effective anticancer agents are able to selectively target cancer cells while leaving normal cells relatively unaffected. Some etherlipids have been shown to be effective anticancer agents. However, the use of most etherlipids in vivo (to treat animals) has been accompanied by certain levels of toxicity to normal cells. Etherlipids are amphipathic lipids with ether linkages connecting their hydrocarbons with their molecular backbones. They are synthetic analogs of platelet activating factor (“PAF”; 1-O-2-acetyl-sn-glycero-3-phosphocholine). PAF is an effector believed to be involved in a variety of physiological processes, such as inflammation, immune responses and allergic reactions.
Ether lipids can accumulate in cell membranes, following which the lipids may affect the cells in a number of ways. Cell membrane accumulation can lead to disturbance of membrane lipid organization by a detergent-like activity of ether lipids; membrane structure, and hence, cell stability, can be disrupted by this activity. Phospholipid metabolism can also be disrupted, as the activities of several of the enzymes involved, e.g., CTP: phosphocholine cytidyl transferase, diacylglycerol kinase, sodium/potassium adenosine triphosphate phosphatase, acyl transferases, lysophospholipase, and phospholipases C and D, are inhibited in the presence of ether lipids. Ether lipids can also affect transmembrane signaling pathways, nutrient uptake, cellular differentiation and apoptosis.
Moreover, ether lipids are believed to be cytotoxic to cancer cells, and have been shown to be effective anticancer agents in animals (see, for example, Lohmeyer and Bittman, 1994; Lu et al. (1994a); Lu et al. (1994b); Dietzfelbinger et al. (1993); Zeisig et al. (1993); Berdel (1991); Workman (1991); Workman et al. (1991); Bazill and Dexter (1990); Berdel (1990); Guivisdalsky et al. (1990a); Guivisdalsky et al. (1990b); Powis et al. (1990); Layton et al. (1980); Great Britain Patent No. 1,583,661; U.S. Pat. No. 3,752,886). However, ether lipids are generally not toxic to most normal cells. Ether lipids' ability to act selectively on cancer cells is believed to be due to the cancer cells' lack of the alkyl cleavage enzymes necessary for hydrolysis of the lipids; the resulting intracellular lipid accumulation can disrupt the cell' functioning in a variety of ways. Normal cells typically possess these enzymes, and hence, are able to prevent the intracellular accumulation of ether lipids.
However, not all normal cells contain sufficient levels of alkyl cleavage enzymes to prevent intracellular ether lipid accumulation. Cells which do not possess the requisite levels of the enzymes can be subject to the same disruptive effects of ether lipid action as are cancer cells. Red blood cells, for example, lack the requisite alkyl cleavage enzymes, and hence, are also subject to a detergent-like activity of ether lipids. Hemolysis which results from exposure of these cells to ether lipids having detergent-like activity can be a major drawback to therapeutic use of the ether lipids (see, for example, Houlihan et al., 1995).
A number of different approaches are potentially available for decreasing or eliminating such drug-induced toxicity. One such approach is to incorporate the drugs into lipid-based carriers, e.g., liposomes. Such carriers can buffer drug toxicity, for example, by sequestering the drug in the carrier such that the drug is unavailable for inducing toxicity. Lipid carriers can also buffer drug-induced toxicity by interacting with the drug such that the drug is then itself unable to interact with the cellular targets through which it exerts its cytotoxic effects. The carriers also maintain the ability of the drugs to be therapeutically effective when released therefrom, e.g., when the carriers are broken down in the vicinity of tumors.
U.S. Pat. No. 5,762,958, incorporated herein by reference, describes a liposome having an ether lipid as a component of the liposome's lipid bilayer. Such liposomes reduce the toxicity of the ether lipids without inhibiting their anti-cancer efficacy. Nevertheless, there is no suggestion in U.S. Pat. No. 5,762,958 that the chirality of the ether lipid would have any effect on the toxicity of the liposomal formulation.
SUMMARY OF THE INVENTION
This invention provides a liposome having a lipid bilayer which comprises: an ether lipid having either a D or L chirality. Preferably, the lipid bilayer of the liposome comprises at least one lipid in addition to the D or L etherlipid. Most preferably, the liposome comprises (a) an underivatized phosphatidylcholine; (b) a sterol; (c) about 5-20 mole % of a phosphatidylethanolamine linked to a dicarboxylic acid at the ethanolamine group of the phosphatidylethanolamine (also referred to herein as the “headgroup-derivatized lipid”), and (d) greater than about 10 mole % to less than about 30 mole % of either the L or D stereoisomer of an ether lipid. Preferably, the ether lipid has the following formula:
wherein Y
1
is (CH
2
)
n1
(CH═CH)
n2
(CH
2
)
n3
(CH═CH)
n4
(CH
2
)
n5
(CH═CH)
n6
(CH
2
)
n
7
(CH═CH)
n8
(CH
2
)
n9
. The sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 3 to 23, n1 is zero or an integer of from 1 to 22, n3 is zero or an integer of from 1 to 19, n5 is zero or an integer of from 1 to 16, n7 is zero or an integer of from zero to 16, n9 is zero or an integer of from 1 to 10, and each of n2, n4, n6 and 8 is independently zero or 1. Y
2
is CH
3
or CO
2
H.
Z is oxygen or sulfur. Preferably, Z is O; accordingly, this invention's glycerol-based etherlipids preferably have a methoxy group at the sn-2 position of their glycerol backbone.
Most preferably, the etherlipid is a D or L stereoisomer of the formula
also known as “ET-18-OCH
3
,” or “edelfosine”).
Preferably, the liposome is a unilamellar liposome having a diameter of from greater than about 50 nm to less than about 200 nm, the underivatized phosphatidylcholine is an unsaturated or partially unsaturated phosphatidylcholine, more preferably, dioleoyl phosphatidylcholine, and the sterol is cholesterol. The headgroup derivatized lipid preferably comprises a phosphatidylethanolamine (“PE”) selected from the group consisting of dipalmitoyl phosphatidylethanolamine, palmitoyloleoyl phosphatidylethanolamine and dioleoyl phosphatidylethanolamine, and a dicarboxylic acid selected from the group consisting of glutaric acid, sebacic acid, succinic acid and tartaric acid. More preferably, the PE is dioleoyl phosphatidylethanolamine and the dicarboxylic acid is glutaric acid.
Preferred embodiments of this invention's liposome have bilayers containing dioleoyl phosphatidylcholine as the underivatized PC, cholesterol as the sterol, dioleoyl phosphatidylethanolamine-glutaric acid as the headgroup-derivatized lipid and ET-18-OCH
3
as the ether lipid. Most preferably, presently, the liposome's bilayer comprises about 20 mole percent of the ether lipid, about 10 mole percent of the headgroup-derivatized lipid, about 30 mole percent cholesterol and about 40 mole percent dioleoyl phosphatidylethanolamine. The liposome can further comprise an additional bioactive agent, that is an agent in addition to the ether lipid.
Also provided herein is a pharmaceutical composition comprising a pharmaceutically acceptab

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