Title:  Ether lipid-containing pharmaceutical compositions and therapeutic uses thereof

United States Patent:  5,932,242

Inventors:  Franklin; J. Craig (East Windsor, NJ); Mayhew; Eric (Monmouth Junction, NJ); Perkins; Walter (Skillman, NJ); Janoff; Andrew (Yardley, PA)

Appl. No.:  720997

Pharmaceutical compositions are provided herein that contain, in addition to a pharmaceutically acceptable carrier, a lamellar lipid. The lipid is composed of an ether lipid and a lipid having a molecular shape that is complementary to the molecular shape of the glycerolipid. These compositions can be used therapeutically, for example, in the treatment of cancers and inflammatory conditions.

Summary of the Invention

Chemotherapeutic activity of ether lipids is believed to arise, at least in part, from their ability to accumulate in cancer cells, due to the lack in the cells of the alkyl cleavage enzymes necessary for hydrolysis, and hence, removal of these lipids. Exertion of detergent-like activity by ether lipids collected in cancer cell membranes can disturb the structure of the membranes, and hence, disrupt the cells. Most, but not all, normal cells possess the enzymes necessary for ether lipid hydrolysis and removal; however, red blood cells ("RBCs") do not possess these enzymes, and hence, are also susceptible to disruption due to intracellular ether lipid accumulation. Such hemolysis is a major dose-limiting toxicity of ether lipid therapeutic use. However, the red blood cell toxicity can be reduced by sequestering the ether lipid in a lipid based carrier such that the ether lipid and carriers are in a stable structure.

The ether lipid stably sequestered in the lipid carrier is unavailable for interaction with the membranes of normal cells, and therefore cannot disrupt the membranes' lipid structure. Nevertheless, when the ether lipid is released from the carrier, generally upon carrier breakdown in the body, it is then available for therapeutic action against cancer cells. Since tumors generally have a higher concentration of blood vessels than does the surrounding normal tissue, and as tumor vasculature tends to be more leaky to structures such as lipid-based carriers, the carriers will preferentially accumulate in tumors; hence, when broken down ether lipids will preferentially be released in the tumors.

This invention provides a composition containing, in addition to a pharmaceutically acceptable carrier, a lamellar lipid consisting essentially of an ether linkage-containing glycerolipid, i.e., an "ether lipid," and a "complementarily shaped lipid," i.e., a lipid having a shape that is complementary to the molecular of the ether lipid. The glycerolipid has the formula: 

wherein R¹ is preferably a group having the formula --(CH₂)_n1 CH₃, and more preferably is --(CH₂)₁₇ CH₃. Z is preferably oxygen. Most preferably, the glycerolipid is: 

 i.e., "ET-18-OCH₃."

The complementarily shaped lipid is preferably a neutral sterol, an anionic sterol derivative, cardiolipin, diarachidonoyl phosphatidylethanolamine ("DAPE") or a similar lipid. More preferably, the complementarily shaped lipid is cholesterol, cholesterol sulfate or a combination of cholesterol and cholesterol sulfate.

The pharmaceutical compositions of this invention can be used therapeutically, for example in the treatment of various cancers and inflammatory conditions, by administering to afflicted mammals an amount of a composition which comprises a therapeutically effective amount of the ether lipid.

Claim 1 of 21 Claims

1. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and,

(b) a lamella comprising a lipid which consists essentially of:

(i) a glycerolipid having the formula: 

(ii) a complementarily shaped lipid, wherein:

R¹ is a group having the formula Y₁ Y₂ ;

Y₁ is (CH₂)_n1 (CH=CH)_n2 (CH₂)_n3 (CH=CH)_n4 (CH₂)_n5 (CH=CH)_n6 (CH₂)_n7 (CH=CH)_n8 (CH₂)_n9 ;

the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 9 to 23;

n1 is zero or an integer of from 1 to 23, n3 is zero or an integer of from 1 to 20, n5 is zero or an integer of from 1 to 17, n7 is zero or an integer of from zero to 14 and n9 is zero or an integer of from 1 to 11;

each of n2, n4, n6 and n8 is independently zero or 1;

Y₂ is CH₃ or CO₂ H;

Z is oxygen or sulfur;

the glycerolipid comprises from about 30 mole percent to about 50 mole percent of the lipid;

the complementarily shaped lipid comprises from about 50 mole percent to about 70 mole percent of the lipid; and,

the MMAM_actual of the lipid is at least about 20% less than the MMAM_expected of the lipid.

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