Linkable sialyl Lewis X analogs
View Patent ↗Disclosed herein is a class of linkable tetrasaccharide compounds that includes the amino phenyl glycoside of sialyl Lewis X (SLe X ) and related analogs. These compounds have conjugatable nucleophilic groups, making them useful in preparing multimeric SLe X compositions. In particular, the disclosed SLe X compounds can be used to prepare selectin binding ligand conjugates by linking them to a reporter moiety, such as a contrast agent, a radiodiagnostic agent, or a cytotoxic or chemotherapeutic agent. The SLe X compounds and conjugates of the invention exhibit binding to selectin that is similar to native Sialyl Le x , and are, therefore, useful for diagnosing and treating selectin-mediated disorders and related conditions.
1. A selectin binding ligand conjugate comprising:
(a) at least one sialyl Lexis X analog (SLewis x ) moiety of formula (2);
wherein,
R is a point of attachment for a linker;
R′ is hydrogen or acyl; and
R″ is hydrogen or methyl
or a pharmaceutically acceptable salt thereof:
(b) a phospholipid moiety; and
(c) at least one linker attaching each said SLewis x moiety to said phospholipid moiety.
2. The conjugate of claim 1 , wherein said phospholipid moiety comprises a phospholipid of formula (H):
3. The conjugate of claim 1 , wherein said phospholipid moiety comprises a phospholipid of formula (I):
4. The conjugate of claim 1 , wherein said SLewis x moiety comprises four sialyl Lewis X residues.
5. A pharmaceutical composition comprising the conjugate of claim 1 dissolved or dispersed in a pharmaceutically acceptable carrier.
6. An ultrasound contrast agent comprising the conjugate of claim 1 .
7. The ultrasound contrast agent of claim 6 , wherein the phospholipid moiety is in the form of a gas-filled microbubble or a gas filled liposome.
8. The ultrasound contrast agent of claim 7 , wherein the gas comprises SF 6 or a fluorocarbon.
9. The ultrasound contrast agent of any one of claims 8 or 7 , further comprising DSPC and/or DPPG.
10. The ultrasound contrast agent of claim 7 , wherein the gas comprises C 4 F 10 .
11. The ultrasound contrast agent of claim 7 , wherein the microbubble or gas-filled liposome further comprises one or more components selected from the group consisting of PEG-4000 and palmitic acid.
12. A method for imaging a region of a patient, said method comprising administering to a patient an effective amount of the contrast agent of claim 7 and imaging a region of the patient.
13. A method for imaging a region of a patient, said method comprising administering to a patient an effective amount of the conjugate of claim 1 .