University of Michigan

The Board of Regents Acting for and on Behalf of the University of

Raymond E Counsell

Jamey Paul Weichert

Marc A Longino

Susan W Schwendner

Karen L Meyer

Terushi Haradahira

Susan P Schwendner

Douglas A Bakan

Mark A Rampy

Anatoly N Pinchuk

Richard Neubig

Benedict R Lucchesi

Douglas Anthony Bakan

Marcian E Van Dort

Terry Ta-Jen Yu

Mohamed K Ruyan

Laura E Deforge

Laurie Strawn

A surface-modified lipoprotein-like oil-in-water emulsion useful as a blood-pool selective delivery vehicle for lipophilic imaging agents or lipophilic derivatives of water-soluble imaging agents. The blood-pool selective delivery vehicle remains in the blood for several hours, shows very little early hepatic sequestration, and is cleared from the blood within 24 hours. The mean diameter of the oil phase is less than 150 nm which minimizes sequestration by the reticuloendothelial system. The surface of the oil phase is modified with a polyethyl glycol-modified phospholipid to prevent normal interactions with the receptor sites of the hepatocytes. In radiographic imaging, radioactive or stable, synthetic or semi-synthetic polyhalogenated triglycerides, such as 2-oleoylglycerol-1,3-bis[7-(3-amino-2,4,6-triiodophenyl)heptanoate], or lipid soluble derivatives of traditional water-soluble contrast agents, such as aliphatic esters of iopanoic, diatrizoic, and acetrizoic acid, may be incorporated into the lipophilic core of a lipoprotein-like emulsion particle.

Blood-pool carrier for lipophilic imaging agents

A surface-modified lipoprotein-like oil-in-water emulsion useful as a blood-pool selective delivery vehicle for lipophilic imaging agents or lipophilic derivatives of water-soluble imaging agents. The blood-pool selective delivery vehicle remains in the blood for several hours, shows very little early hepatic sequestration, and is cleared from the blood within 24 hours. The mean diameter of the oil phase is less than 150 nm which minimizes sequestration by the reticuloendothelial system. The surface of the oil phase is modified with a polyethyl glycol-modified phospholipid to prevent normal interactions with the receptor sites of the hepatocytes. In radiographic imaging, radioactive or stable, synthetic or semi-synthetic polyhalogenated triglycerides, such as 2-oleoylglycerol-1,3-bis&lsqb;7-(3-amino-2,4,6-triiodophenyl)heptanoate&rsqb;, or lipid soluble derivatives of traditional water-soluble contrast agents, such as aliphatic esters of iopanoic, diatrizoic, and acetrizoic acid, may be incorporated into the lipophilic core of a lipoprotein-like emulsion particle.

Blood-pool selective carrier for lipophilic imaging agents

The present invention provides improved radioiodinated phospholipid ether analogs which demonstrate significant tumor avidity and longer plasma half-life than shorter-chain analogs. The radioiodinated phospholipid ether analogs of the present invention provide superior imaging and visualization of neoplastic lesions and tumor-specific cytotoxic cancer therapy.

Radioiodinated phospholipid ether analogs and methods of using the same

Improved radioiodinated phospholipid ether analogs are described which exhibit significant tumor avidity and longer plasma half-life relative to shorter chain analogs. Use of these compounds results in superior imaging and visualization of neoplastic lesions and tumor-specific cytotoxic cancer therapy.

A heat and shelf-stable oil-in-water emulsion useful as a tissue or cell-selective delivery vehicle. Radioactive or stable, synthetic or semi-synthetic polyhalogenated triglycerides, such as 2-oleoylglycerol-1,3-bis[7-(3-amino-2,4,6-triiodophenyl)heptanoate] or 2-oleoylglycerol-1,3-bis[.omega.-(3,5-bis-trifluoromethyl)hepatanoate] or phenyl acetate, can be incorporated into the lipophilic core of a lipoprotein-like emulsion particle. The lipophilic core is surrounded by a phospholipid membrane comprising cholesterol and apolipoproteins. For hepatocyte-selective delivery, the emulsion is chylomicron remnant-like by being in a size range of 50 to 200 nm as measured by number weighting analysis with a narrow size distribution (&lt;2% greater than 300 nm) and having a composition simulating naturally-occurring chylomicron remnants. Use of cholesterol in the emulsion formula facilitates association of apolipoproteins, especially Apo E which are recognized by liver cells and necessary for binding and uptake. Stability and size constraints can be achieved by using ultra high energy mixing equipment, such as such as the MicroFluidizer (Microfluidics Corp., Newton, Mass.) to form the emulsion. In preferred embodiments, osmolality of the emulsion is controlled by glycerol rather than normal saline.

Hepatocyte-selective oil-in-water emulsion

Method of making hepatocyte-selective oil-in-water emulsion

A heat and shelf-stable oil-in-water emulsion useful as a tissue or cell-selective delivery vehicle. Radioactive or stable, synthetic or semi-synthetic polyhalogenated triglycerides, such as 2-oleoylglycerol-1,3-bis�7-(3-amino-2,4,6-triiodophenyl)heptanoate! or 2-oleoylglycerol-1,3-bis�.omega.-(3,5-bis-trifluoromethyl)heptanoate! or phenyl acetate, can be incorporated into the lipophilic core of a lipoprotein-like emulsion particle. The lipophilic core is surrounded by a phospholipid membrane comprising cholesterol and apolipoproteins. For hepatocyte-selective delivery, the emulsion is chylomicron remnant-like by being in a size range of 50 to 200 nm as measured by number weighting analysis with a narrow size distribution (&lt;2% greater than 300 nm) and having a composition simulating naturally-occurring chylomicron remnants. Use of cholesterol in the emulsion formula facilitates association of apolipoproteins, especially Apo E which are recognized by liver cells and necessary for binding and uptake. Stability and size constraints can be achieved by using ultra high energy mixing equipment, such as such as the MicroFluidizer (Microfluidics Corp., Newton, Mass.) to form the emulsion. In preferred embodiments, osmolality of the emulsion is controlled by glycerol rather than normal saline.

Novel radioiodinated analogues of naturally-occurring phospholipid ethers are tumor-specific and have a triglycerol backbone structure which, in certain embodiments, is substituted at the 3-position with an alkyl phosphocholine and include a monoiodinated benzoyl side chain substituted at the 2-position in accordance with the general formula: ##STR1## where n=1-15 ##STR2## M=0-15; Z=.sup.123 I, .sup.125 I, and .sup.131 I; Y=NH.sub.2, NR.sub.2, and NR.sub.3, and R=alkyl, aralkyl.

Radioiodinated phospholipid ether analogues

Novel radioiodinated analogues of naturally-occurring phospholipid ethers are tumor-specific and have a triglycerol backbone structure which, in certain embodiments, is substituted at the 3-position with an alkyl phosphocholine and include a monoiodinated benzoyl side chain substituted at the 2-position in accordance with the general formula: ##STR1## where n= 1-15 ##STR2## m= 0-15; Z=.sup.123 I, .sup.125 I, and .sup.131 I; Y=NH.sub.2, NR.sub.2, and NR.sub.3, and R=alkyl, aralkyl.

Radioiodinated phospholipid ether analogues and methods of using same

Novel iodinated arylaliphatic triglyceride analogs as radiologic agents are liver and hepatocyte site-specific. The triglyceride backbone structure is preferably 1,3-disubstituted or 1,2,3-trisubstituted with, in some embodiments, a 3-substituted-2,4,6-triiodophenyl aliphatic chain wherein the chain has a structure similar to naturally occurring fatty acids. In another embodiment, a monoiodophenyl aliphatic chain is utilized. Any position remaining on the triglyceride backbone is substituted with a saturated or unsaturated aliphatic hydrocarbon chain of the type found in naturally occurring fatty acids. The triglyceride analogs can be radioiodinated. In a preferred embodiment, a lipid emulsion is provided as the carrier vehicle.

Polyiodinated triglyceride analogs as radiologic agents

Novel radioiodinated analogues of naturally-occurring phospholipid ethers are tumor-specific and have a triglycerol backbone structure which is substituted at the 3-position with an alkyl phosphocholine and include a monoiodinated benzoyl side chain substituted at either the 1- or 2-position. In some embodiments of the invention, the monoiodinated aralkyl side chain may be substituted directly onto alkyl phosphocholine in accordance with general Formula: provided that one and only one of X or Y is a monoiodinated aralkyl ##STR1## where Y=NH.sub.2, NR.sub.2, NR.sub.3, NR.sub.2 R'

Radioiodinated phosphate esters

Novel radioiodinated analogues of naturally occurring phospholipid ethers are tumor-specific to enable selective visualization of neoplastic lesions by gamma-camera scintigraphy. The novel compounds enable a physician to differentiate neoplastic lesions from non-neoplastic lesions in a manner not heretofore available.

Novel iodinated arylaliphatic triglyceride analogs as radiologic agents are liver and hepatocyte site-specific. The triglyceride backbone structure is preferably 1,3-disubstituted or 1,2,3-trisubstituted with, in some embodiments, a 3-substituted-2,4,6-triiodophenyl aliphatic chain wherein the chain has a structure similar to naturally occuring fatty acids. In another embodiment, a monoiodophenyl aliphatic chain is utilized. Any position remaining on the triglyceride backbone is substituted with a saturated or unsaturated aliphatic hydrocarbon chain of the type found in naturally occurring fatty acids. The triglyceride analogs can be radioiodinated. In a preferred embodiment, a lipid emulsion is provided as the carrier vehicle.

Novel radioiodinated analogues of naturally-occurring cholestrol esters, arylaliphatic cholesteryl ethers, are selective for low density lipoproteins and have been shown to be successful imaging agents for adrenal glands. The arylaliphatic cholesteryl ethers have the general formula: ##STR1## where X is a radioactive isotope of iodine and n is an integer between 1 and 20. Two illustrative examples, m-iodobenzyl cholesteryl ether and 12-(m-iodophenyl) dodecyl cholesteryl ether, were radiolabeled with .sup.125 I by an isotope exchange reaction. Tissue distribution studies indicate significant accumulation of the cholesteryl ethers in the adrenal glands, and to a lesser extent in the liver. The cholesteryl ethers selectively incorporate into plasma lipoproteins as determined by polyacrylamide gel electrophoresis.

Growing community of inventors

Ann Arbor, MI, United States of America

Raymond E Counsell