Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification – Introduction of a polynucleotide molecule into or...
Reexamination Certificate
2000-02-10
2003-12-09
Ketter, James (Department: 1636)
Chemistry: molecular biology and microbiology
Process of mutation, cell fusion, or genetic modification
Introduction of a polynucleotide molecule into or...
C435S375000, C424S450000, C530S402000, C530S403000
Reexamination Certificate
active
06660525
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a therapeutic composition and method that employs, as the delivery vehicle, liposomes having an affinity moiety on the outer liposome surfaces. The moiety is shielded by a surface coating of hydrophilic polymers, until the liposomes contact a releasing agent effective to remove the surface coating.
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BACKGROUND OF THE INVENTION
Liposomes are used for a variety of therapeutic purposes, in particular, for carrying therapeutic agents to target cells by systemic administration of liposomes.
When liposomes are administered systemically, it is desirable to coat the liposomes with a hydrophilic agent, for example, a coating of hydrophilic polymer chains such as polyethylene glycol, to extend the blood circulation lifetime of the liposomes. An extended circulation time is often needed for liposomes to reach the target region, cell or site from the site of injection.
The use of such long-circulating liposomes, that is, liposomes with a surface coating of hydrophilic polymer chains, such as polyethylene glycol (PEG) chains, for targeting has been proposed (Allen, et al., 1995; DeFrees, et al., 1996; Blume, et al., 1993; Klibanov, et al., 1992; Woodle, 1991; Zalipsky, 1993; Zalipsky, 1994; Zalipsky, 1995). In one approach, a ligand, such as an antibody, for targeting the liposomes is linked to the polar head group of lipids forming the liposome. The problem with this approach is that the ligand is covered by the PEG chains, interfering with the ligand's interaction with the target and reducing its effectiveness as a targeting agent.
In another approach, the targeting ligand is attached to the distal ends of the PEG chains forming the hydrophilic polymer coating (Klibanov, et al., 1992; Kirpotin, et al., 1992). While this approach improves targeting, since the targeting moiety is more exposed, the approach has drawbacks in that the PEG chains act to stabilize liposome, making release of the liposome's contents at the target site difficult and in that the attached moiety can compromise the extended blood circulation lifetime provided by the surface coating of hydrophilic polymer chains (Klibanov, et al., 1992).
For a variety of reasons, it may be desirable to shield all or at least a portion of the targeting moieties attached to the liposome until a desired biodistribution of the liposomes is achieved. If a high density of moieties is desired, and all of the targeting moieties in an exposed state on liposome surface, the presence of the moieties may limit the blood circulation time of the liposomes. Another problem with unshielded targeting moieties is that the moiety may direct liposomes to non-target surfaces or cells, before a desired biodistribution is reached.
Therefore, it is desirable to provide a therapeutic liposome composition including affinity moieties, e.g., targeting moieties, where all or at least a portion of the moieties are initially shielded from interaction with a target surface, but which can be unshielded when a desired biodistribution is reached.
SUMMARY OF THE INVENTION
In one aspect, the invention includes a method of liposome-based therapy for a mammalian subject which includes systemically administering to the subject, liposomes with outer surfaces that contain (i) an affinity moiety effective to bind specifically to a target surface at which the therapy is aimed, and (ii) a hydrophilic polymer coating effective to shield the affinity moiety from interaction with the target surface. The hydrophilic polymer coating is made up of polymer chains which are covalently linked to surface lipid components in the liposomes through releasable linkages. The administered liposomes are allowed to circulate systemically until a desired biodistribution of the liposomes is achieved, and a releasing agent is then administered to the subject in an amount effective to cause release of a substantial portion of the releasable linkages in the administered liposomes, thereby to expose the affinity agent to the target surface.
In one embodiment of the method, the releasable linkages are reducible chemical linkages such as disulfide, ester or peptide linkages. In a preferred embodiment, the releasable linkages are disulfide linkages and the releasing agent is cysteine, glutathione or ascorbate.
In another embodiment, the releasable linkages are pH sensitive linkages, heat sensitive linkages or light sensitive linkages.
The hydrophilic polymer forming the liposome surface coating is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, and polyaspartamide.
In a preferred embodiment, the hydrophilic polymer chains are polyethylene glycol chains having molecular weights in the range 500 to 10,000 daltons.
In one embodiment, where a therapeutic agent is to be administered to a target region, the affinity moiety is a ligand effective to bind specifically with a receptor at the target region, and the liposomes include the therapeutic agent in entrapped form.
An example of this embodiment is treatment of a solid tumor, where the affinity moiety is effective to bind specifically to a tumor-specific antigen, the liposomes have an average size between 30-400 nm and include an entrapped drug, and the releasing agent is administered to the subject after the liposomes have extravasated into the tumor.
In another embodiment, the method of the invention
Huang Shi Kun
Martin Francis J.
Zalipsky Samuel
Alza Corporation
Katcheves Konstantina
Ketter James
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