Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-05-16
2002-01-15
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S450000, C435S176000, C435S178000, C435S179000, C435S180000, C435S325000, C435S366000, C530S300000, C530S329000, C530S331000, C530S811000, C530S813000, C530S814000, C530S815000
Reexamination Certificate
active
06339060
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods of facilitating the entry of biologically-active compounds into phagocytic cells and for targeting such compounds to specific organelles within the cell. The invention specifically provides compositions of matter and pharmaceutical embodiments of such compositions comprising conjugates of such biologically-active compounds covalently linked to particulate carriers generally termed microparticles. Particular embodiments of such compositions include compositions wherein the biologically-active compounds are antiviral and antimicrobial drugs. In such compositions the microparticle is coated with an antiviral or antimicrobial drug, and then further coated with organic coating material that is the target of a microorganism-specific protein having enzymatic activity. Thus, the invention provides cell targeting of drugs wherein the targeted drug is only released in cells infected with a particular microorganism. Alternative embodiments of such specific drug delivery compositions also contain polar lipid carrier molecules. Particular embodiments of such conjugates comprise a coated microparticle wherein an antiviral or antimicrobial drug is covalently linked to a polar lipid covalently linked to a polar lipid compound and the particle further coated with a coating material, to facilitate targeting of such drugs to particular subcellular organelles within the cell.
2. Background of the Related Art
A major goal in the pharmacological arts has been the development of methods and compositions to facilitate the specific delivery of therapeutic and other agents to the appropriate cells and tissues that would benefit from such treatment, and the avoidance of the general physiological effects of the inappropriate delivery of such agents to other cells or tissues of the body. The most common example of the need for such specificity is in the field of antibiotic therapy, in which the amount of a variety of antibiotic, antiviral and antimicrobial agents that can be safely administered to a patient is limited by their cytotoxic and immunogenic effects.
It is also recognized in the medical arts that certain cells and subcellular organelles are the sites of pharmacological action of certain drugs or are involved in the biological response to certain stimuli. In particular, it is now recognized that certain cell types and subcellular organelles within such cell types are reservoirs for occult infection that evades normal immune surveillance and permits the persistence of chronic infections. Specific delivery of diagnostic or therapeutic compounds to such intracellular organelles is thus desirable to increase the specificity and effectiveness of such clinical diagnostic or therapeutic techniques.
A. Drug Targeting
It is desirable to increase the efficiency and specificity of administration of a therapeutic agent to the cells of the relevant tissues in a variety of pathological states. This is particularly important as relates to antiviral and antimicrobial drugs. These drugs typically have pleiotropic antibiotic and cytotoxic effects that damage or destroy uninfected cells as well as infected cells. Thus, an efficient delivery system which would enable the delivery of such drugs specifically to infected cells would increase the efficacy of treatment and reduce the associated “side effects” of such drug treatments, and also serve to reduce morbidity and mortality associated with clinical administration of such drugs.
Numerous methods for enhancing the cytotoxic activity and the specificity of antibiotic drug action have been proposed. One method, receptor targeting, involves linking the therapeutic agent to a ligand which has an affinity for a receptor expressed on the desired target cell surface. Using this approach, an antimicrobial agent or drug is intended to adhere to the target cell following formation of a ligand-receptor complex on the cell surface. Entry into the cell could then follow as the result of internalization of ligand-receptor complexes. Following internalization, the antimicrobial drug may then exert its therapeutic effects directly on the cell.
One limitation of the receptor targeting approach lies in the fact that there are only a finite number of receptors on the surface of target cells. It has been estimated that the maximum number of receptors on a cell is approximately one million (Darnell et al., 1986,
Molecular Cell Biology,
2d ed., W. H. Freeman: New York, 1990). This estimate predicts that there may be a maximum one million drug-conjugated ligand-receptor complexes on any given cell. Since not all of the ligand-receptor complexes may be internalized, and any given ligand-receptor system may express many-fold fewer receptors on a given cell surface, the efficacy of intracellular drug delivery using this approach is uncertain. Other known intracellular ligand-receptor complexes (such as the steroid hormone receptor) express as few as ten thousand hormone molecules per cell. Id. Thus, the ligand-receptor approach is plagued by a number of biological limitations.
Other methods of delivering therapeutic agents at concentrations higher than those achievable through the receptor targeting process include the use of lipid conjugates that have selective affinities for specific biological membranes. These methods have met with little success. (see, for example, Remy et al., 1962,
J. Org. Chem.
27: 2491-2500; Mukhergee & Heidelberger, 1962,
Cancer Res.
22: 815-22; Brewster et al., 1985,
J. Pharm. Sci.
77: 981-985).
Liposomes have also been used to attempt cell targeting. Rahman et al., 1982, Life Sci. 31: 2061-71 found that liposomes which contained galactolipid as part of the lipid appeared to have a higher affinity for parenchymal cells than liposomes which lacked galactolipid. To date, however, efficient or specific drug delivery has not been predictably achieved using drug-encapsulated liposomes. There remains a need for the development of cell-specific and organelle-specific targeting drug delivery systems.
B. Phagocytic Cell-Specific Targeting
Cell-specific targeting is also an important goal of antimicrobial therapy, particularly in the event that a specific cell type is a target of acute or chronic infection. Targeting in the case of infection of a specific cell type would be advantageous because it would allow administration of biologically-toxic compounds to an animal suffering from infection with a microbial pathogen, without the risk of non-specific toxicity to uninfected cells that would exist with nontargeted administration of the toxic compound. An additional advantage of such targeted antimicrobial therapy would be improved pharmacokinetics that would result from specific concentration of the antimicrobial agent to the sites of infection, i.e., the infected cells.
Phagocytic cells such as monocytes and macrophages are known to be specific targets for infection of certain pathogenic microorganisms.
Sturgill-Koszycki et al., 1994,
Science
263: 678-681 disclose that the basis for lack of acidification of phagosomes in
M. avium
and
M. tuberculosis
-infected macrophages is exclusion of the vesicular proton-ATPase.
Sierra-Honigman et al., 1993,
J. Neuroimmunol.
45: 31-36 disclose Borna disease virus infection of monocytic cells in bone marrow.
Maciejewski et al., 1993,
Virol.
195: 327-336 disclose human cytomegalovirus infection of mononucleated phagocytes in vitro.
Alvarez-Dominguez et al., 1993,
Infect. Immun.
61: 3664-3672 disclose the involvement of complement factor Clq in phagocytosis of
Listeria monocytogenes
by macrophages.
Kanno et al., 1993,
J. Virol.
67: 2075-2082 disclose that Aleutian mink disease parvovirus replication depends on differentiation state of the infected macrophage.
Kanno et al., 1992,
J. Virol.
66: 5305-5312 disclose that Aleutian mink disease parvovirus infects peritoneal macrophages in mink.
Narayan et al., 1992,
J. Rheumatol.
32: 25-32 disclose arthritis in animals caused by infection of macrophage precursors with lentivirus, an
Gallicchio Vincent S.
Meredith Michael J.
Stowell Michael H B
Yatvin Milton B.
McDonnell & Boehnen Hulbert & Berghoff
Naff David M.
Oregon Health & Science University
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