Conjugate having a cleavable linkage for use in a liposome
AssigneeAlza Corporation
InventorsSamuel Zalipsky, Alberto A. Gabizon
Life of this patent
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Abstract
Conjugates of a hydrophobic moiety, such as a lipid, linked through a cleavable dithiobenzyl linkage to a therapeutic agent are described. The dithiobenzyl linkage is susceptible to cleavage by mild thiolysis, resulting in release of the therapeutic agent in its original form. The linkage is stable under nonreducing conditions. The conjugate can be incorporated into liposomes for administration in vivo and release of the therapeutic agent in response to endogeneous in vivo reducing conditions or in response to administration of an exogeneous reducing agent.
Claims42
A conjugate for use in a liposomal drug-delivery vehicle, the conjugate having the general structural formula:
- wherein L is a hydrophobic moiety suitable for incorporation into a liposomal lipid bilayer, R1 represents a therapeutic drug covalently attached to the dithiobenzyl moiety, and where orientation of the CH2R1 group is selected from the ortho position and the para position.
A liposome composition, comprising liposomes comprised of vesicle-forming lipids including from about 1 to about 30 mole percent of a conjugate having the general structural formula:
- wherein L is a hydrophobic moiety suitable for incorporation into a liposomal lipid bilayer, R1 represents a therapeutic drug covalently attached to the dithiobenzyl moiety, and where orientation of the CH2R1 group is selected from the ortho position and the para position,
- wherein said therapeutic drug is released from the conjugate in vivo in response to a physiologic condition or an artificially induced condition.
A method for retaining a drug in a liposome, comprising preparing liposomes comprised of a vesicle-forming lipid and of between about 1 to about 30 mole percent of a conjugate having the general form:
- wherein L is a hydrophobic moiety suitable for incorporation into a liposomal lipid bilayer, R1 represents a therapeutic drug covalently attached to the dithiobenzyl moiety, and where orientation of the CH2R1 group is selected from the ortho position and the para position,
- whereby said preparing is effective to retain the drug in the liposomes until release from the conjugate in response to a physiologic condition or an artificially induced condition.
Dependencies are inferred from the claim text.