CONJUGATES OF LIPIDS AND ANTIMICROBIAL OR ANTINEOPLASTIC DRUGS

Abstract: This invention herein describes polar lipid conjugates and methods of achieving delivery to and accumulation of biologically active compounds including drugs into organs, tissues and cells, particularly at physiologically protected sites, at pharmicokinetically useful levels. These polar lipid conjugates of this invention permit drug concentrations to be achieved, especially in such physiologically protected sites, at levels at which such compounds are therapeutically effective after administration of systemic levels much lower than currently attainable otherwise. This technology is appropriate for use with antiproliferative, antineoplastic, antibiotic, antibacterial, antimycotic or antiviral drugs, agents and compounds, for rapid and efficient introduction of such agents, for example across the blood-brain barrier.

Description: CONJUGATES OF LIPIDS AND ANTIMICROBIAL OR ANTINEOPLASTIC DRUGS BACKGROUND OF THE INVENTION 1. Field of the Invention This invention is related to specific targeting of biologically-active compounds to specific cells, tissues and organs in vivo. The invention specifically provides polar lipid conjugates of biologically-active compounds, particularly antibacterial, antibiotic, antiviral, antimycotic, antiproliferative and antineoplastic compounds, drugs and agents, and methods of effecting the uptake and accumulation of biologically active compounds into organs, tissues and cells, particularly at physiologically protected sites, at pharmicokinetically useful levels. These polar lipid conjugates of this invention permit drug concentrations to be achieved, especially at physiologically protected sites, at levels at which such compounds are therapeutically effective after administration of systemic levels much lower than currently attainable otherwise. This technology is appropriate for rapid and efficient introduction of antiproliferative, antineoplastic, antibiotic, antibacterial, antimycotic or antiviral drugs, agents and compounds, for example across the blood-brain barrier. 2. Background of the Invention 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 organs, tissues and cells that would benefit from such treatment, and avoidance of the general physiological effects of the inappropriate delivery of such agents to other organs, tissues or cells in the body. One common example of the need for such specificity is for introducing or administering biologically-active compounds, particularly antimicrobial, antiviral and antiproliferative and antineoplastic compounds, drugs or agents, into physiologically-protected reservoirs in an animal. Examples of such protected sites include brain, central nervous system, eyes and testes, which are recognized as having physiological barriers (including endothelial cells and other structures) that inhibit transit of a variety of useful drugs into said reservoirs (for example, the blood-brain barrier) and into physiologically-restricted areas in vivo (such as lymph nodes). Avoiding general systemic side-effects is particularly important in administering biologically-active compounds targeted to such physiologically- protected sites, since achieving clinically useful concentrations of said compounds at these sites has frequently required administration of high systemic dosages which are associated with greater-than-acceptable levels of systemic toxicity. Drug Targeting It is desirable to increase the efficiency and specificity of administration of a therapeutic agent in a variety of pathological states to the cells of the relevant organs and tissues protected by physiological barriers (i.e., such as the blood-brain barrier) and in physiologically-restricted areas in vivo (such as lymph nodes). This is particularly important as relates to antibiotic, antibacterial, antimycotic, antiviral, antiproliferative and antineoplastic drugs. Such agents typically have systemic effects, including kidney and liver toxicity, hematopoietic suppression, teratogenic capacity, partitioning into breast milk and other pleiotropic cytotoxic effects that damage or otherwise deleteriously impact uninvolved organs, tissues and cells. This is particularly the case in delivering antibiotic, antibacterial, antimycotic, antiviral, antiproliferative and antineoplastic drugs to physiologically protected sites, since high systemic concentrations of such agents are required to promote partitioning of a sufficient amount of the antibiotic, antibacterial, antimycotic, antiviral, antiproliferative and antineoplastic drug into the protected sites to achieve a therapeutic result. Thus, an efficient delivery system which would enable the delivery of such drugs specifically to organs, tissues and cells in such physiologically protected sites 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. In addition, specific targeting of specific organs, tissues or cells wherein a biologically active compound preferentially accumulates in a specific organ, tissue or cell and does not generally or systemically accumulate in organs, tissues or cells in a body is desirable. An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality which could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site. Such a functionality would be especially valuable if it allowed differential rates of drug release, or specific release only at the appropriate drug target site comprising a specific organ, tissue or cell in a body. Numerous methods for enhancing the biological activity and the specificity of drug action have been proposed or attempted (see, for example, Kreeger, 1996, The Scientist, September 16, 1996, p. 6). To date, however, efficient or specific drug delivery remains to be predictably achieved. U.S. Patent No. 5,017,566, issued May 21, 1991 to Bodor disclose β- and γ-cyclodextrin derivatives comprising inclusion complexes of lipoidal forms of dihydropyridine redox targeting moieties. U.S. Patent No. 5,023,252, issued June 11, 1991 to Hseih disclose the use of pharmaceutical compositions comprising a neurologically active drug and a compound for facilitating transport of said drug across the blood-brain barrier including a macrocyclic ester, diester, amide, diamide, amidine. diamidine, thioester, dithioester, thioamide, ketone or lactone. U.S. Patent No. 5,024,998, issued June 18, 1991 to Bodor disclose parenteral solutions of aqueous-insoluble drugs with β- and γ-cyclodextrin derivatives. U.S. Patent No. 5,039,794, issued August 13, 1991 to Wier et al. disclose the use of a metastatic tumor-derived egress factor for facilitating the transport of compounds across the blood-brain barrier. U.S. Patent No. 5,112,863, issued May 12, 1992 to Hashimoto et al. disclose the use of N-acyl amino acid derivatives as antipsychotic drugs for delivery across the blood-brain barrier. U.S. Patent No. 5,124,146, issued June 23, 1992 to Neuwelt disclose a method for delivery of therapeutic agents across the blood-brain barrier at sites of increased permeability associated with brain lesions. U.S. Patent No. 5,149,794, issued September 22, 1992 to Yatvin et al. disclose lipid conjugates with antineoplastic and antiviral drugs. U.S. Patent No. 5,153,179, issued October 6, 1992 to Eibl disclose acylated glycerol and derivatives for use in a medicament for improved penetration of cell membranes. U.S. Patent No. 5,177,064, issued January 5, 1993 to Bodor disclose the use of lipoidal phosphonate derivatives of nucleoside antiviral agents for delivery across the blood-brain barrier. U.S. Patent 5,223,263, issued June 29, 1993 to Hostetler et al. disclose conjugates between antiviral nucleoside analogues and polar lipids, including phospholipids and ceramide. U.S. Patent No. 5,254,342, issued October 19, 1993 to Shen et al. disclose receptor-mediated transcytosis of the blood-brain barrier using the transferrin receptor in combination with pharmaceutical compounds that enhance or accelerate this process. U.S. Patent No. 5,256,641, issued October 26, 1993 to Yatvin et al. disclose lipid conjugates with antigenic peptides. U.S. Patent No. 5,258,402, issued November 2, 1993 to Maryanoff disclose treatment of epilepsy with imidate derivatives of anticonvulsive sulfamates. U.S. Patent No. 5,270,312, issued December 14, 1993 to Glase et al. disclose substituted piperazines as central nervous system agents. U.S. Patent No. 5,284,876, issued February 8, 1994 to Shashoua et al, disclose fatty acid conjugates of dopanergic drugs for tardive dyskinesia. U.S. Patent No. 5,389,623, issued February 14, 1995 to Bodor disclose the use of lipoidal dihydropyridine derivatives of antiinflammatory steroids or steroid sex hormones for delivery across the blood-brain barrier. U.S. Patent No. 5,405,834, issued April 11, 1995 to Bundgaard et al. disclose prodrug derivatives of thyrotropin releasing hormone. U.S. Patent No. 5,413,996, issued May 9, 1995 to Bodor disclose acyloxyalkyl phosphonate conjugates of neurologically-active drugs for anionic sequestration of such drugs in brain tissue. U.S. Patent No. 5,434,137, issued July 18, 1995 to Black disclose methods for the selective opening of abnormal brain tissue capillaries using bradykinin infused into the carotid artery. U.S. Patent No. 5,442,043, issued August 15, 1995 to Fukuta et al. disclose a peptide conjugate between a peptide having a biological activity and incapable of crossing the blood-brain barrier and a peptide which exhibits no biological activity and is capable of passing the blood-brain barrier by receptor-mediated endocytosis. U.S. Patent No. 5,466,683, issued November 14, 1995 to Sterling et al. disclose water soluble analogues of the anticonvulsant Tegretol ® (carbamazepine) for the treatment of epilepsy. U.S. Patent No. 5,484,809, issued January 16, 1996 to Hostetler et al. disclose taxol and taxol derivatives conjugated to phospholipids. U.S. Patent No. 5,484,911, issued January 16, 1996 to Hong et al. disclose nucleoside analogues conjugates to lipid moieties. U.S. Patent No. 5,512,671, issued April 30, 1996 to Piantadosi et al. disclose nucleoside analogues conjugates to lipid moieties. U.S. Patent No. 5,525,727, issued June 1 1, 1996 to Bodor disclose compositions for differential uptake and retention in brain tissue comprising a conjugate of a narcotic analgesic and agonists and antagonists thereof with a lipoidal form of dihydropyridine that forms a redox salt upon uptake across the blood-brain barrier that prevents partitioning back to the systemic circulation thereafter. U.S. Patent No. 5,543,389, issued August 6, 1996 to Yatvin et al. disclose salves and ointments for delivering antiproliferative compounds to skin. U.S. Patent No. 5,554,728, issued September 10, 1996 to Basava et al. disclose therapeutic peptides conjugated to lipid moieties. U.S. Patent No. 5,563,257, issued October 8, 1998 to Zilch et al. disclose nucleoside analogues conjugates to ether lipid moieties. U.S. Patent No. 5,580,571, issued December 3, 1996 to Hostetler et al. disclose nucleoside analogues conjugated to phospholipids. U.S. Patent No. 5,696,097, issued December 9, 1997 to Matsuda et al. disclose nucleoside analogues conjugates to lipid moieties. U.S. Patent No. 5,744,461, issued April 28, 1998 to Hostetler et al. disclose nucleoside analogues conjugated to phosphonoacetic acid lipid derivatives. U.S. Patent No. 5,744,592, issued April 28, 1998 to Hostetler et al. disclose nucleoside analogues conjugated to phospholipids. U.S. Patent No. 5,756,116, issued May 26, 1998 to Hostetler et al. disclose nucleoside analogues. U.S. Patent No. 5,756,711, issued May 26, 1998 to Zilch et al. disclose nucleoside analogues conjugates to lipid moieties. U.S. Patent No. 5,827,831, issued October 27, 1998 to Hostetler et al. disclose phospholipid-drug conjugates having enhanced gastrointestinal bioavailability. International Patent Application Publication Number WO85/02342, published 6 June 1985 for Max-Planck Institute disclose a drug composition comprising a glycerolipid or derivative thereof. International Patent Application Publication Number WO89/02733, published April 1989 to Vical disclose conjugates between antiviral nucleoside analogues and polar lipids, including phospholipids and ceramide. International Patent Application Publication Number WO89/1 1299, published 30 November 1989 for State of Oregon disclose a chemical conjugate of an antibody with an enzyme which is delivered specifically to a brain lesion site for activating a separately-administered neurologically-active prodrug. International Patent Application Publication Number WO91/04014, published 4 April 1991 for Synergen, Inc. disclose methods for delivering therapeutic and diagnostic agents across the blood-brain barrier by encapsulating said drugs in liposomes targeted to brain tissue using transport-specific receptor ligands or antibodies. International Patent Application Publication Number WO91/04745, published 18 April 1991 for Athena Neurosciences, Inc. disclose transport across the blood- brain barrier using cell adhesion molecules and fragments thereof to increase the permeability of tight junctions in vascular endothelium. International Patent Application Publication Number WO91/14438, published 3 October 1991 for Columbia University disclose the use of a modified, chimeric monoclonal antibody for facilitating transport of substances across the blood-brain barrier. International Patent Application Publication Number WO94/01131, published 20 January 1994 for Eukarion, Inc. disclose lipidized proteins, including antibodies. International Patent Application Publication Number WO94/01138, published 20 January 1994 for State of Oregon disclose lipid conjugates with antigenic peptides and antineoplastic and antiviral drugs. International Patent Application Publication Number WO94/03424, published 17 February 1994 for Ishikura et al. disclose the use of amino acid derivatives as drug conjugates for facilitating transport across the blood-brain barrier. International Patent Application Publication Number WO94/06450, published 31 March 1994 for the University of Florida disclose conjugates of neurologically- active drugs with a dihydropyridine-type redox targeting moiety and comprising an amino acid linkage and an aliphatic residue. International Patent Application Publication Number WO94/02178, published 3 February 1994 for the U.S. Government, Department of Health and Human Services disclose antibody-targeted liposomes for delivery across the blood-brain barrier. International Patent Application Publication Number WO95/07092, published 16 March 1995 for the University of Medicine and Dentistry of New Jersey disclose the use of drug-growth factor conjugates for delivering drugs across the blood-brain barrier. International Patent Application Publication Number WO96/00537, published 1 1 January 1996 for Southern Research Institute disclose polymeric microspheres as injectable drug-delivery vehicles for delivering bioactive agents to sites within the central nervous system. International Patent Application Publication Number WO96/04001 , published 15 February 1996 for Molecular/Structural Biotechnologies, Inc. disclose omega-3- fatty acid conjugates of neurologically-active drugs for brain tissue delivery. International Patent Application Publication Number WO96/22303, published 25 July 1996 for the Commonwealth Scientific and Industrial Research Organization disclose fatty acid and glycerolipid conjugates of neurologically-active drugs for brain tissue delivery. International Patent Application Publication Number WO98/03204, published 29 January 1998 for State of Oregon disclose salves and ointments for delivering antiproliferative compounds to skin. International Patent Application Publication Number WO98/17325, published 30 April 1998 for Oregon Health Sciences University disclose lipid conjugates with neurologically-active drugs. There remains a need in the art for an effective means for the specific delivery of biologically-active compounds, particularly antibiotic, antibacterial, antimycotic, antiviral, antiproliferative and antineoplastic drugs and agents, to physiologically restricted or protected sites. Advantageous embodiments of such delivery means are formulated to efficiently deliver the biologically-active compound to such a physiologically-protected site, including the brain and central nervous system, while minimizing hepatic and renal uptake of the agent or hematopoietic insult resulting therefrom. SUMMARY OF THE INVENTION The present invention is directed to improved methods for delivering biologically-active compounds, particularly drugs including preferably antibiotic, antibacterial, antimycotic, antiviral, antiproliferative and antineoplastic drugs, to specific organs, tissues and cells, most preferably comprising physiologically protected sites, in an animal in vivo. This delivery system achieves specific delivery of biologically-active compounds by conjugating the compounds with a polar lipid carrier. This invention has the specific advantage of effecting the delivery and accumulation of such compounds into particular organs, tissues and cells, most preferably wherein said organs, tissues and cells are protected by physiological barriers such as the blood-brain barrier, using a polar lipid carrier and thereby achieving effective concentration of such compounds more efficiently and with more specificity than conventional delivery systems. The invention provides compositions of matter comprising a biologically- active compound covalently linked to a polar lipid carrier molecule. Preferred embodiments also comprise a spacer molecule having two linker functional groups, wherein the spacer has a first end and a second end each comprising a functional linker group, wherein the polar lipid is attached to the first end of the spacer through a first linker functional group and the biologically-active compound is attached to the second end of the spacer through a second linker functional group. In preferred embodiments, the biologically-active compound is a drug, most preferably an antibiotic, antibacterial, antimycotic, antiviral, antiproliferative and antineoplastic drug or agent. Preferred polar lipids include but are not limited to acyl- and acylated carnitine, sphingosine, ceramide, cardiolipin, and more preferably, phospholipids including phosphatidyl choline, phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, and phosphatidic acid, more particularly wherein said phospholipids have been deacylated at one of the two fatty acid-conjugated glycerol hydroxyl groups to produce a /yso-phospholipid having an unesterified glycerol hydroxyl for conjugation via a spacer moiety to a biologically active compound as provided by the invention. Preferred biologically-active compounds include antibiotic, antibacterial, antimycotic, antiviral, antiproliferative and antineoplastic drugs. In particularly-preferred embodiments, the antiproliferative, antibiotic, antibacterial, antimycotic, antiviral or antineoplastic drug is covalently linked, either directly or via a spacer as disclosed herein, to a glycerol hydroxyl of a phospholipid, preferably phosphatidyl choline, phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, or phosphatidic acid. The invention also provides pharmaceutical compositions comprising a biologically active compound conjugated with or without a spacer moiety to a polar lipid, preferably a phospholipid and most preferably to a /y-rophospholipid via a glycerol hydroxyl group, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. The invention also provides compositions of matter comprising a biologically-active compound covalently linked to a lipid carrier molecule, most preferably a polar lipid via a spacer molecule wherein the spacer allows the biologically-active compound to act without being released in an organ, tissue or cell. In these embodiments of the invention, the first linker functional group attached to the first end of the spacer is characterized as "strong" and the second linker functional group attached to the second end of the spacer is characterized as "weak", with reference to the propensity of the covalent bonds between each end of the spacer molecule to be broken. In other embodiments of the compositions of matter of the invention, the spacer allows the specific hydrolytic or enzymatic release of the biologically- active compound at a particular organ, tissue or cellular site. One non-limiting example of such enzymatic release is mediated by a cellular phospholipase, preferably phospholipase A, or A 2 , wherein drug-acyl chain conjugates are cleaved at the ester bond between an acyl moiety comprising the spacer and the glycerol hydroxyl. In preferred embodiments, the spacer functional group is hydrolyzed by an enzymatic activity found in a specific organ, tissue or cell type, more preferably in an organ or tissue comprising a physiologically protected site including brain, central nervous system, eyes, testes and lymph nodes. In particularly preferred embodiments, the spacer functional group is hydrolyzed by an enzymatic activity found in brain tissue, including neuronal, glial and other brain cell types, preferably an esterase or lipase and most preferably an esterase or lipase having a differential expression and activity profile in the appropriate target cell type. In additional preferred embodiments, specific release of biologically-active compounds is achieved by enzymatic or chemical release of the biologically-active compound by extracellular cleavage of a cleavable linker moiety via an enzymatic activity specific for a particular organ, tissue or cell type, more preferably in an organ or tissue comprising a physiologically protected site, and most preferably brain tissue, with resulting specific uptake of the released antiproliferative, antibiotic, antibacterial, antimycotic, antiviral or antineoplastic drug or agent by the appropriate cell in said tissue. In another embodiment of this aspect of the invention, the spacer molecule is a peptide of formula (amino acid),,, wherein n is an integer between 2 and 25, preferably wherein the peptide comprises a polymer of one or more amino acids. In other embodiments of the compositions of matter of the invention, the biologically-active compound of the invention has a first functional linker group, and a polar lipid carrier, most preferably a phospholipid carrier, has a second functional linker group, preferably a hydroxyl group and most preferably a glycerol hydroxyl group of a phospholipid, wherein the compound is covalently linked directly to the lipid carrier by a chemical bond between the first and second functional linker groups. In preferred embodiments, each of the first and second functional linker groups is a hydroxyl group, a primary or secondary amino group, a phosphate group or substituted derivatives thereof or a carboxylic acid group. In another aspect of the invention is provided compositions of matter comprising a drug, most preferably an antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug or agent, covalently linked to a polar lipid carrier molecule. In still further embodiments of the compositions of matter of the invention are provided antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs or agents having a first functional linker group, and a polar lipid carrier having a second functional linker group, wherein the drug is covalently linked directly to the polar lipid carrier by a chemical bond between the first and second functional linker groups. In preferred embodiments, each of the first and second functional linker groups is a hydroxyl group, most preferably a glycerol hydroxyl group, a primary or secondary amino group, a phosphate group or substituted derivatives thereof or a carboxylic acid group. Preferred polar lipids include but are not limited to acyl- and acylated carnitine, sphingosine, ceramide, cardiolipin, and more preferably, phospholipids including phosphatidyl choline, phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, and phosphatidic acid, more particularly wherein said phospholipids have been deacylated at one of the two fatty acid-conjugated glycerol hydroxyl groups to produce a /ysø-phospholipid having an unesterified glycerol hydroxyl for conjugation with a drug as provided by the invention. In particularly-preferred embodiments, the antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug is covalently linked directly to a phospholipid, more preferably to a glycerol hydroxyl of a phospholipid, most preferably wherein the phospholipid comprises a lyso form of phosphatidyl choline, phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, or phosphatidic acid. The invention also provides pharmaceutical compositions comprising said antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs conjugated with or without a spacer moiety to a polar lipid, most preferably a phospholipid, in a pharmaceutically acceptable carrier. The invention also provides compositions of matter comprising an antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug covalently linked directly to phospholipid and most preferably to a glycerol hydroxyl of said phospholipid, wherein the covalent linkage allows the drug to act without being released at an organ, tissue or cellular site. In other embodiments of the compositions of matter of the invention, the covalent linkage allows the specific hydrolytic or enzymatic release of an antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug or agent at a particular organ, tissue or cellular site. One non-limiting example of such enzymatic release is mediated by a cellular phospholipase, preferably phospholipase A, or A 2 , wherein the drug is cleaved at the ester bond between an acyl moiety comprising the drug and the glycerol hydroxyl. In particularly preferred embodiments, the cleavage is mediated by a hydrolytic or enzymatic activity found in a specific organ, tissue or cell type, more preferably in an organ or tissue comprising a physiologically protected site including brain, central nervous system, eyes, testes and lymph nodes. In particularly preferred embodiments, the spacer functional group is hydrolyzed by an enzymatic activity found in brain tissue, including neuronal, glial and other brain cell types, wherein said enzymatic activity is preferably an esterase or lipase and most preferably an esterase or lipase having a differential expression and activity profile in different tissue cell types. In additional preferred embodiments, specific release of the antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug or agent of the invention is achieved by enzymatic or chemical release of these drugs by extracellular cleavage of the drug-lipid covalent linkage, preferably via an enzymatic activity specific for, for example, brain tissue, followed by specific uptake of the released antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug by the appropriate cell in said tissue. As disclosed herein, the invention comprehends a polar lipid conjugate with a biologically active compound wherein the polar lipid selectively promotes delivery to or preferential accumulation in particular organs, tissues or cells in an animal in vivo. In preferred embodiments, the invention provides said polar lipid- drug conjugates that promote association with and transit across certain physiological barriers to organs, tissues or cells comprising physiologically protected sites. In other preferred embodiments, the biologically active compounds are drugs, more preferably antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs. The invention preferably provides specific delivery or accumulation of said polar lipid-drug conjugates to said physiologically restricted or protected sites. In embodiments comprising a spacer moiety, the spacer component of the conjugates of the invention will preferably act to specifically release the drug from the lipid at the target site; prevent the non-specific release from the drug from the lipid in the systemic circulation or in hematopoietic, hepatic, renal or other inappropriate cells, tissues or organs; target the conjugate to a specific cell or cell type within the protected tissue; prevent interaction and/or uptake of the drug by hematopoietic, ocular, hepatic or renal tissues; or perform other functions to maximize the effectiveness of the drug. This type of conjugate has numerous advantages. The polar lipid conjugates of the invention provide delivery or preferential accumulation of a variety of biologically active compounds, preferably antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs and agents, to organs, tissues or cells, most preferably physiologically restricted or protected sites in vivo at concentrations and pharmicokinetic rates not heretofore attainable. A benefit of this advantage is the achievement of therapeutic indices of agents in such protected sites whereby the agent is useful for achieving a desired therapeutic goal. Another benefit is decreased hepatic toxicity, hematopoietic suppression (such as thrombocytopenia, leukopenia, aplastic anemia, leukocytosis, eosinophilia, pancytopenia, agranulocytosis), reduced systemic metabolism, degradation and toxicity, reduced hepatic clearance, reduced systemic adverse drug interactions, and generally reduced side effects due to the achievement of a lower, therapeutically- effective dose as the result of surmounting the physiological barrier. These biological effects can also result in simplified dosage schedules, particularly for drugs with short systemic half-lives. In addition, in preferred embodiments the polar lipid conjugates of the invention incorporate a variable spacer region that may allow pharmacologically- relevant rates of drug release from polar lipid carrier molecules to be engineered into the compositions of the invention, thereby increasing their clinical efficacy and usefulness. Thus, time-dependent drug release and specific drug release in organs, tissues and cells expressing the appropriate degradative enzymes are a unique possibility using the polar lipid conjugates of the invention. In particular, felicitous design of the inventive conjugates of the invention, most preferably said antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug/spacer/polar lipid conjugates can provide an in vivo reservoir of time-dependent drug release in a specific organ, tissue or cell, preferably comprising a physiologically protected site, resulting in specific delivery of therapeutic amounts to such tissues using a reduced dosage regime to minimize non-specific, systemic and deleterious side effects. In such formulations, the amount and activity of the antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug can be modulated by release via cleavage, preferably hydrolytic cleavage, of the spacer moiety, most preferably by an enzymatic activity in the organ, tissue or cell, most preferably comprising a physiologically protected tissue (e.g., brain) that has a differential pattern of expression or activity in different cell types in said tissue or systemically. The conjugates of the invention can also be combined with other drug delivery approaches to further increase specificity and to take advantage of useful advances in the art. Specific preferred embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts the structure of the AE 6 PC compound of the invention. Figure 2 depicts the synthetic scheme for producing the AE 6 PC compound of the invention. Figure 3 depicts the structure of the AE 6 C compound of the invention. Figure 4 depicts the synthetic scheme for producing the AE 6 C compound of the invention. Figure 5A depicts a comparison of brain uptake of AZT and the AE 6 PC and AE 6 C compounds of the invention in fasted mice orally intubated and administered 0.5mL of 7.5mM AZT, AE 6 C or AE 6 PC in FBS. Figure 5B depicts a comparison of brain uptake of AZT and the AE 6 PC and AE 6 C compounds of the invention in mice intravenously injected with 0.5mL of 7.5mM AZT, AE 6 C or AE 6 PC in a pharmaceutically-acceptable carrier. Figure 6 depicts a comparison of testes uptake of AZT and the AE 6 PC and NE 6 C compounds of the invention in fasted mice orally intubated and administered 0.5mL of 7.5mM AZT, AE 6 C or AE 6 PC in FBS. Figures 7A through 7E depict a comparison of infection of NIH 3T3 cells in culture over a 24h period with a Mo-MuLN derived human growth hormone recombinant expression construct in the presence of 0.25mM AZT, AE 6 PC or AE 6 C, or ddl, IE 6 PC or IE 6 C Figures 8A through 8C depict methotrexate-polar lipid conjugates of the invention. Figures 9A and 9B illustrate synthetic schemes for producing Mtx salicylate esters conjugated to sphingosine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides compositions of matter, pharmaceutical compositions and methods for achieving specific delivery to and accumulation of biologically-active compounds into organs, tissues and cells, most preferably organs, tissues and cells comprising physiologically-protected sites in an animal. For the purposes of this invention, the term "biologically-active compound" is intended to encompass all naturally-occurring or synthetic compounds capable of eliciting a biological response or having an effect, either beneficial or cytotoxic, on biological systems, particularly cells and cellular organelles. These compounds are intended to include but are not limited to all varieties of drugs, particularly antiproliferative drugs and agents, antimicrobial drugs, including antibacterial, fungicidal, anti-protozoal and antiviral drugs, antineoplastic drugs, and cytotoxic and cytostatic compounds. In preferred embodiments, the invention provides polar lipid conjugates comprising antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs, agents and compounds. Specifically, the invention provides said antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs, agents and compounds wherein said drugs, agents and compounds are linked to a polar lipid compound via a cleavable linker moiety. As used herein the terms "antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs and agents" are intended to include any drug, agent or compound having an antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic effect in an animal, preferably a human. In particular, the term "antimicrobial drug" will be understood to encompass said antibiotic, antibacterial, antimycotic, and antiviral compounds, as well as other compounds that have an antimicrobial effect (such as anti-plasmodial drugs). For the purposes of this invention, the term "antimicrobial drug" is intended to encompass any pharmacological agent effective in inhibiting, attenuating, combating or overcoming infection of mammalian cells by a microbial pathogen in vivo or in vitro. Antimicrobial drugs as provided as components of the antimicrobial agents of the invention include but are not limited to penicillin and drugs of the penicillin family of antimicrobial drugs, including but not limited to penicillin-G, penicillin-N, phenethicillin, ampicillin, amoxacillin, cyclacillin, bacampicillin, hetacillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticaricillin, and imipenim; cephalosporin and drugs of the cephalosporin family, including but not limited to cefadroxil, cefazolin, caphalexn, cephalothin, cephapirin, cephradine, cefaclor, cefamandole, cefonicid, cefoxin, cefuroxime, ceforanide, cefotetan, cefmetazole, cefoperazone, cefotaxime, ceftizoxime, ceftizone, moxalactam, ceftazidime, and cefixime; aminoglycoside drugs and drugs of the aminoglycoside family, including but not limited to streptomycin, neomycin, kanamycin, gentamycin, tobramycin, amikacin, and netilmicin; macrolide and drugs of the macrolide family, exemplified by azithromycin, clarithromycin, roxithromycin, erythromycin, lincomycin, and clindamycin; tetracyclin and drugs of the tetracyclin family, for example, tetracyclin, oxytetracyclin, democlocyclin, methacyclin, doxycyclin, and minocyclin; quinoline and quinoline-like drugs, such as, for example, naladixic acid, cinoxacin, norfloxacin, ciprofloxacin, ofloxicin, enoxacin, and pefloxacin; antimicrobial peptides, including but not limited to polymixin B, colistin, and bacatracin, as well as other antimicrobial peptides such as defensins (Lehrer et al., 1991, Cell 64: 229-230), magainins (Zasloff, 1987, Proc. Nat/. Acad. Sci. USA 84: 5449- 5453), cecropins (Lee et a/., 1989, Proc. Natl. Acad. Sci. USA 86: 9159-9162 and Boman et al., 1990, Eur. J. Biochem. 201 : 23-31), and others, provided as naturally-occurring, chemically synthesized in vitro or produced as the result of engineering to make such peptides resistant to the action of pathogen-specific proteases and other deactivating enzymes; other antimicrobial drugs, including chloramphenicol, vancomycin, rifampicin, metronidazole, ethambutol, pyrazinamide, sulfonamides, isoniazid, and erythromycin. Antiviral drugs, including but not limited to reverse transcriptase inhibitors, protease inhibitors, antiherpetics such as acyclovir and gancyclovir, azidothymidine (3'azido, 3'-deoxythymidine, Zidovudine, AZT), dideoxyinosine (Didanosine, ddl), dideoxycytidine (Zalcitabine, ddC), cytidine arabinoside, ribavirin, amantadine, iododeoxyuridine, foscarnet, trifluoridine, methizazone, vidarabine and levanisole are also encompassed by this definition and are expressly included therein. Antimycotic drugs provided by the invention and comprising the pharmaceutical compositions thereof include but are not limited to clotrimazole, nystatin, econazole and myconixole, ketoconazole, grisefulvin, ciclopixox, naftitine and other imidizole antimycotics. Antiproliferative and antineoplastic agents provided by the invention and comprising the pharmaceutical compositions thereof include but are not limited to methotrexate, doxarubicin, daunarubicin, epipodophyllotoxins. 5-fluorouracil, tamoxifen, actinomycin D, vinblastine, vincristine, colchicine and taxol. The invention also provides antibiotic drugs and agents wherein an antimicrobial agent is a toxin capable of specific cytotoxicity against the microbe, its host cell or both. The term "toxin" is intended to encompass any pharmacological agent capable of such toxicity, including for example ricin from jack bean, diphtheria toxin, and other naturally-occurring and man-made toxins. Appropriate formulations and pharmaceutical compositions of the antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug/ polar lipid conjugates of the invention will be apparent and within the skill of one of ordinary skill in this art to advantageously prepare in view of the instant disclosure. In preferred embodiments, said pharmaceutical compositions are provided for topical application, comprising appropriately chosen salves, ointments and emollients. In particularly preferred embodiments, said topical application is specifically adapted for administration to ocular tissues, comprising electrolytically balanced solutions for topical and direct administration to vertebrate, preferably mammalian and most preferably human eyes. In alternative formulations, the pharmaceutical composition comprises complexes formed for example with serum albumin, polyvinylpyrrolidone and other pharmaceutically acceptable carriers and excipients for parenteral administration, including but not limited to intravenous, intramuscular, and subcutaneous routes of administration. In yet alternative embodiments, the pharmaceutical compositions of the invention are provided to be orally bioavailable by administration in tablets, capsules, elixirs, gums, and other formulations comprising excipients adapted for transit of the conjugates of the invention through the gastrointestinal tract. Oral and parenteral routes of administration are preferred. In preferred embodiments, the polar lipid conjugates are provided wherein the biologically active compound is in a form having reduced, inhibited, or essentially no biological activity and wherein this form of the compound is capable of being converted by chemical or enzymatic means, most preferably in vivo, into a form having a desired biological activity; when the biologically active compound is a drug, this form of the drug is commonly termed a "prodrug." Embodiments of such prodrugs useful in the present invention include prodrugs that can be converted by chemical or enzymatic means in a targeted organ, tissue or cell in an animal. In preferred embodiments, said prodrugs are converted into a form having a desired biological activity in an organ or tissue extracellularly, i.e. within the physical and anatomically-recognized province of the organ or tissue but not within any particular cell in the organ or tissue. In such embodiments, the activated prodrug is then capable of having the desired biological activity without entry into any particular cell comprising said organ or tissue. In alternative embodiments, the activated prodrug is then capable of entering a cell comprising said organ or tissue and having the desired biological activity thereof. In additional preferred embodiments, the prodrug is only converted into the active form after entry into a particular cell or cell type comprising said organ or tissue. 00/33884 . the terms "chemic-. PCT/US99/163 1 encompass chemical conditions (including but not limited to salt or other electrolyte concentration, metabolite concentration. pH. osmolality. osmolarity. dielectric constant, temperature, pressure, or chemical catalyst concentration) or presence of enzymatic activity (including but not limited to esterases. amidases. peptidases, nucleases, peroxidases, lipases. or redox proteins) in an organ, tissue or cell, most preferably in a physiologically-protected site in an animal, most preferably a human. It will be understood that the choice of spacer moiety comprising any particular embodiment of the pharmaceutical compositions or compositions of matter of the invention, and particularly the choice of said linker functional groups comprising said spacer moieties, is chosen to match the chemical or enzymatic means present in the organ, tissue or cell targeted by said composition. The compositions of matter and pharmaceutical compositions provided by the invention comprise biologically-active compounds covalently linked to a polar lipid carrier. A polar lipid carrier, as defined herein is intended to mean any polar lipid that is delivered to. or preferentially accumulates in. an organ, tissue or cell in an animal. In particularly preferred embodiments, the polar lipid conjugates have an affinity for, or are capable of crossing, a biological membrane and in particular a physiological barrier protecting certain cells, tissues and organs in an animal body. Polar lipid carriers encompassed by this invention include but are not limited to sphingosine. sphingomyelin and other sphingolipids. ceramide and cardiolipin, and more preferably, phospholipids. most preferably phosphatidyl choline. phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl inositol. phosphatidyl serine, and phosphatidic acid, and more particularly wherein said phospholipids have been deacylated at one of the two fatty acid-conjugated glycerol hydroxyl groups to produce a /Ysσ-phospholipid having an unesterified glycerol hydroxyl for conjugation with a biologically active compound as provided by the invention, as these terms are understood in the art (see. Lehninger, Biochemistry. 2d ed.. Chapters 1 1 & 24, Worth Publishers: New York. 1975). Additionally, certain other lipids, such as acylated carnitine. comprise the conjugates of the invention (see Small. 1986, "From alkanes to phospholipids," Handbook of Lipid Research: Physical Chemistry of Lipids, Volume 4, Chapters 4 and 12. Plenum Press: New York). For the purposes of this iin ention. the term "polar lipid" is not intended to encompass "lipoid " -type compounds, such as. for example, aliphatic phosphonates (see. for example. U.S. Patent No. 5.413.996). The compositions of matter and pharmaceutical compositions of the invention may further comprise a spacer moiety comprising a first end and a second end. each end of the spacer having a functional linking group. For the purposes of this invention, the term "spacer" or "spacer moiety" is intended to encompass any chemical entity that links a biologically-active compound and a polar lipid compound according to the invention. Such spacer moieties may be designed to promote or effect the delivery to or accumulation at specific organs, tissues or cells, or to promote, influence, modulate or regulate the release of the biologically-active compound at the desired target site. Such spacers may facilitate enzymatic release at specific organs, tissues and cell, preferably at extracellular sites therein: more preferably, said spacers inhibit enzymatic. hydroljtic or other release systemically in an animal. Spacer groups, as described herein, include, but are not limited to aminohexanoic acid, adipic acid, and other bifunctional organic acids; peptides including homopolymers such as polyglycine: substituted fatty acids; carbohydrate moieties including mono-, di- and other saccharides: oligonucleotides; polyamides, polyethylenes. and short functionalized polymers having a carbon backbone which is from one to about twelve carbon molecules in length. Particularly preferred embodiments of such spacer moieties comprise peptides of formula (amino acid) n . wherein n is an integer between 2 and 25 and the peptide is a polymer of one or more amino acids, and ω- or otherwise functionalized substituted and unsubstituted fatty acyl chains. The term "linker functional group" is defined herein as any functional group for covalently binding the polar lipid carrier or biologically-active agent to the spacer group. These groups can be designated either "weak" or "strong" based on the stability of the covalent bond which the linker functional group will form between the spacer and either the polar lipid carrier or the biologically- active compound. The weak functionalities include, but are not limited to phosphoramide, phosphoester. carbonate, amide, carboxyl-phosphoryl anhydride, thioester and most preferably ester. The strong functionalities include, but are not limited to ether, thioether, amine, amide and most preferably ester. The use of a strong linker functional group between the spacer group and the biologically- active compound will tend to decrease the rate at which the compound will be released at the target site, whereas the use of a weak linker functional group between the spacer group and the compound may act to increase the release rate of the compound at the target site. Enzymatic release is, of course, also possible, but such enzyme-mediated modes of release will not necessarily be correlated with bond strength in such embodiments of the invention. Spacer moieties comprising enzyme active site recognition groups, such as spacer groups comprising peptides having proteolytic cleavage sites therein, are envisioned as being within the scope of the present invention. Specifically, such specifically- cleavable peptides are preferably prepared so as to be recognized by enzymes present in particular organs or tissues such as brain and other physiologically restricted or protected sites in vivo, so that the drug is preferentially liberated from the polar lipid conjugate at appropriate drug delivery sites. An illustrative example of such a specifically-cleavable peptide is a portion of the proopiomelanocortin family of peptides, which are cleaved in mammalian brain tissue to release a variety of peptides hormones and effector molecules, such as the enkephalins. Other beneficial and advantageous specifically-cleavable peptides will be recognized by those of ordinary skill in the art. The linker functional groups are selected to inhibit or prevent cleavage of the covalent linkage between the spacer and the biologically active compound, or between the spacer and the polar lipid carrier, at a site other than the specific site to which the conjugate is targeted. The polar lipid conjugates of the invention are also preferably provided comprised of spacer moieties that impart differential release properties on the conjugates related to differential expression or activity of enzymatic activities in specific organs, tissues or cells in comparison with such activities in systemic circulation or in inappropriate targets, such as hepatic, renal or hematopoietic tissues. In preferred embodiments, said organs, tissue and cells comprise physiologically restricted or protected sites in vivo. Differential release is also provided in certain embodiments in specific cell types comprising such physiologically protected tissues, for example, in different cell types (neuronal, glial, etc.) in brain tissue. The polar lipid conjugates of the invention are provided for targeting said conjugates to specific organs, tissues and cells in an animal. In preferred embodiments, the conjugates are targeted to eye, spleen, lung, testes and the central nervous system, most preferably the brain. In particularly preferred embodiments of the present invention are provided antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug/polar lipid conjugates for specific delivery to or accumulation in specific organs, tissues and cells in an animal. In particularly preferred embodiments, the polar lipid/drug conjugates are targeted to the central nervous system, most preferably brain tissue, for the alleviation or amelioration of pathological disease states therein. In such embodiments of the invention are provided methods and polar lipid/drug conjugates for facilitating the transit of the polar lipid conjugates of antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs, agents and compounds across the blood-brain barrier and into targeted regions of the brain, for the treatment of animal, preferably human, diseases and pathological conditions. Among the most common such diseases and conditions are acquired immune deficiency syndrome, neuroblastoma, glioma, astrocytoma, meningioma, sarcoma, metastatic melanoma, metastatic adenocarcinoma, syphilis, encephalitis, meningitis, nocardiosis, abscess, coccidiodomycosis, cryptococcosis, subdural empyema, extrapulmonary tuberculosis, leptospirosis, toxoplasmosis, trichinosis, trypanosomiasis, mycoplasma infection, herpetic encephalitis, and schistosomiasis. In additional embodiments of the invention are provided polar lipid/drug conjugates of polar lipids and antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs, agents and compounds for delivery to or accumulation in lung tissue or spleen tissue, wherein said conjugates particularly comprise salicylic acid esters between the polar lipid and the drug. In one preferred embodiment, the compound is the ceramide N-(methotrexate)-N- (6aminocaproyl(salicylate) sphingosine ester. In such embodiments of the invention are provided methods and conjugates for treating animal, preferably human, diseases and pathological conditions. Among the most common such diseases and conditions are acquired immune deficiency syndrome; lung tumors such as adenocarcinoma, small cell carcinoma, and other tumors of the lung; tuberculosis; bronchitis; emphysema; pneumonia; cystic fibrosis; Gaucher's disease; and other diseases and disorders of lung or spleen tissue. The invention specifically provides methods for preparing and administering biologically active compounds, most preferably antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs, agents and compounds for use in treating pathological conditions in vivo. Said methods include but are not limited to parenteral methods, such as intravenous, intramuscular and subcutaneous injection; oral methods, including administration of pills, tablets, elixirs, capsules and other formulations; topical administration, including ointments, salves, poultices and the like, particularly including solutions specifically adapted for topical administration to the eye; and rectal administration, including suppositories, enemas and other appropriate formulations. Oral and parenteral routes of administration are preferred. Animals to be treated with the polar lipid conjugates of biologically active compounds according to the invention using the methods disclosed herein are intended to include all vertebrate animals, preferably domesticated animals, such as cattle, horses, goats, sheep, fowl, fish, household pets, and others, as well as wild animals, and most preferably humans. The following Examples illustrate certain aspects of the above-described method and advantageous results. The following examples are shown by way of illustration and not by way of limitation. EXAMPLE 1 A polar lipid conjugate with azidothymidine was prepared by conjugating an adipic acid linker moiety to a polar lipid via an ester linkage, as follows. The structure of this conjugate is shown in Figure 1, and the synthetic scheme is shown in Figure 2. A polar lipid (lysophosphatidylcholine) comprising unesterified hydroxyl groups was reacted with an activated adipic acid monomethylester (AMME) in the presence of 1.0 equivalent of dicyclohexyl carbodiimide (DCCD) overnight at 40-50°C at pH 6.5-7.5. The derivatized lysophosphatidylcholine was then reacted with 0.1N methanolic potassium hydroxide at room temperature, and optionally then treated with 2.0 equivalents of tert-butyl dimethyl silyl imidazole (TBDMS) overnight at 40-50°C. This lysophosphatidylethanolamine species, derivatized by an ester linkage between the glycerol hydroxyl group of lysophosphatidylethanolamine and the 1- carboxylate group of adipic acid, was then esterified at the 7-carboxylate group of the adipic acid spacer with azidothymidine and DCCD overnight at 40-50°C. The azidothymidine-phosphatidylethanolamine conjugate was then deprotected, if appropriate, by treatment with 4.0 equivalents of t-butylammonium fluoride at 0°C for 10 minutes. Side products of the synthetic reaction are removed using conventional chemical purification techniques. Synthesis of conjugates comprising ester linkages advantageously permits control of rates of drug release based on differences in amount and rates of esterase enzymatic activity in the brain. EXAMPLE 2 A polar lipid conjugate of azidothymidine comprising an ester linkage is prepared by conjugating a linker moiety to a polar lipid via an amide linkage, as follows. The structure of this conjugate is shown in Figure 3, and the synthetic scheme is shown in Figure 4. A polar lipid (sphingosine) comprising unconjugated amino groups was reacted with a activated adipic acid monomethyl ester (AMME) in the presence of 1.0 equivalent of dicyclohexyl carbodiimide (DCCD) overnight at 40-50°C. The derivatized sphingosine was then reacted with 0.1N methanolic potassium hydroxide at room temperature, and then treated with 2.0 equivalents of tert-butyl dimethyl silyl imidazole (TBDMS) overnight at 40-50°C. This sphingosine species, derivatized by an amide linkage between the amino group of sphingosine and the 1 -carboxylate group of AMME was then esterified at the 7-carboxylate group of unprotected adipic acid with azidothymidine and DCCD overnight at 40-50°C. The azidothymidine- sphingosine conjugate was then deprotected by treatment with 4.0 equivalents of t-butylammonium fluoride at 0°C for 10 minutes. Side products of the synthetic reaction were removed using conventional chemical purification techniques. EXAMPLE 3 The ability of the polar lipid/drug conjugates described in Examples 1 and 2 to specifically target physiologically-protected sites in vivo was determined in comparison with azidothymidine (AZT) itself as follows. Thirty-six fasted Swiss mice were orally intubated and administered AZT, AE 6 C or AE 6 PC at a concentration of about 7.5mM in 0.5mL fetal bovine serum. At intervals of 2, 4, 8 and 24 hr after administration, the amount of each compound localized in brain, testes, thymus and spleen was determined by radioimmunassay as follows. Tissues were removed from sacrificed mice, frozen and kept at -20°C until use. Frozen tissues were weighed, thawed and then homogenized at 0-4°C in a volume (in mL) of 0.5% sodium ascorbate equal to three times the weight of the tissue in grams. The homogenate was then centrifuged at 16,000g for 15min. The resulting supernatant was boiled for 5 min in a DB-1 Dry Block Heater, and the pellet was resuspended in lmL of 0.5% sodium ascorbate. After these treatments, both the pellet fraction and the supernatant fraction were centrifuged at 16,000g for 15 min. A small pellet was recovered from the centrifuged supernatant. The supernatant from the boiled supernatant fraction was decanted from the pellet into a fresh test tube, and the volume noted. The supernatant from the centrifuged pellet fraction was decanted from the pellet and added to the fresh test tube containing the supernatant fraction, and the two supernatant fractions mixed by vortexing. The volume of the mixed supernatant was reduced to the original volume of the supernatant fraction supernatant by bubbling nitrogen gas therethrough at 37°C. The reduced supernatant fraction was then stored at -20°C. The pellet fractions were mixed and extracted three times with lmL anhydrous methanol. A volume of 0.5% sodium ascorbate equal to the original volume of 0.5% sodium ascorbate used for homogenation was added to a fresh test tube, the volume noted and the methanol extracts of the pellet added. This volume was then reduced to the original volume of 0.5% sodium ascorbate used for homogenation by bubbling nitrogen gas therethrough at 37°C. The reduced pellet fraction, which contains the lipid-associated fraction of the prodrug, was then stored at -20°C. These protocols were also used in experiments assaying drug and prodrug uptake and accumulation, both in vivo and in vitro, with other drug/prodrug conjugates, specifically ddl and IE 6 C. In the present example, all samples were analyzed for AZT by radioimmunassay using a kit (ZDN-Trac 125 I RIA kit, obtained from DiaSorin Inc., Stillwater, MΝ) according to the manufacturer's instructions. These results were expressed as pmol of each compound per gram of wet weight and are shown in Table IA. The ratio of the amount of each conjugate to free AZT (i.e., AE 6 C/AZT and AE 6 PC/AZT) was calculated and is shown in Table IA. These results demonstrated that both AE 6 C and AE 6 PC conjugates were delivered to physiologically-protected sites at amounts from 3- to 129-fold higher than free AZT. The greatest differential delivery of the conjugated compounds compared with free AZT was found for brain and testes. Both compounds showed essentially equivalent preferential delivery to each of these tissues when compared with unconjugated AZT. The absolute amount of each compound peaked in all tissues within 2 hr (within the margins of experimental error); however, within 4-8 hr the amount of free AZT in each tissue dropped to about 10%) of the value detected at 2 hr. In contrast, for AE 6 C the amount detected after 24 hr remained at about 53% of the peak value detected at 4hr in spleen (32-fold higher than unconjugated AZT), at about 37% of the peak value detected at 2hr in brain (129-fold higher than unconjugated AZT), at about 20% of the peak value detected at 2hr in thymus (48-fold higher than unconjugated AZT), and at about 4% of the peak value detected at 2hr in testes (34-fold higher than unconjugated AZT). For AE 6 PC, the amount detected after 24 hr remained at about 21%) of the value detected at 2hr in spleen (34-fold higher than unconjugated AZT), at about 32% of the value detected at 2hr in brain (109-fold higher than unconjugated AZT), at about 14% of the value detected at 2hr in thymus (33-fold higher than unconjugated AZT), and at about 5% of the value detected at 2hr in testes (21 -fold higher than unconjugated AZT). Table IB compares the results of testicular uptake of AZT, AE 6 C and AE 6 PC in fasted mice where the drug was administered by oral intubation as above, or by intravenous (IN) injection of fed mice with 0.5mL of a 7.5mM solution of each of the drugs or drug conjugated in a acceptable injection vehicle. The results obtained with IN injection are consistent with the results obtained TABLE IA Uptake of AZT, AEβC or AEβPC by Fasted Mice Time After AEfiC ΔEfiEC AZT Saliflflf Intubation pmol/g wet wt AEtOAZT A-EfcPC/AZT Brain 2 hr *801.9 ± 15.2 783.6 ± 55.0 ± 3.1 15 14 hr 545.6 ± 41.5 495.9 ± 12.2 12.6 ± 4.3 43 39 θ hr 353.1 ± 473 304.9 ± 21.4 5.9 ± 0.4 60 52 24 hr 296.8 ± 41.6 251.4 ± 0.1 2.3 ± 1.0 129 109 Testes 2 hr 5718.7 ± 461.4 69573 ± 760.4 1532.5 ± 289.4 4 5 4 hr 4122.8 ± 497.8 5385.8 ± 662.1 495.3 ± 123.8 8 11 8 hr 769.8 137.8 469.6 1 56.1 22.4 ± 4.4 34 21 !\- 24 hr 227.9 ± 16.2 371.2 ± 54.2 L Thymus 2 hr 3246.0 ± 262.9 2959.5 ± 332.5 1016.5 ± 140.6 3 3 4 hr 3194.2 ± 319.5 2318.4 ± 93.8 431.3 ± 91.9 7 5 θ hr 787.5 ± 0.7 549.9 ± 44.1 16.5 ± 7.4 48 33 24 hr 635.3 ± 9.8 403.6 ± 84.6 L Spleen 2 hr 1861.5 ± 177.6 3081.7 ± 352.7 372.0 ± 98.6 5 8 4 hr 2025.4 ± 145.4 2298.1 ± 205.4 249.1 ± 53.4 8 9 8 hr 1090.5 ± 76.8 1148.7 ± 70.7 33.9 ± 17.8 32 34 24 hr 1076.8 ± 61.4 660.4 ± 127.4 L Oral Intubation of Fasted Mice with 0.5 ml of 7.48 mM of AZT, AE^C < or AEβPC i in FBS. 'Mean±SE; L: Too low to be measure by RIA. - with oral intubation administration. However, although initial concentrations of both the conjugates are greater initially, the drugs are also more rapidly cleared, presumably as a consequence of the more rapid "bolus" effect achieved by IN injection. TABLE IB Testes Uptake of AZT. AE and AE C PC bv Mice ' = time after administration of drug 2 = pmol/g wet weight X = too low to be measured R, = Ratio of (AE 6 C)/(AZT) R 2 = Ratio of (AE 6 PC)/(AZT) The results shown in Table IA are represented graphically in Figures 5A and 5B (for brain) and 6 (for testes). Figure 5A graphically represents the data presented in Table IA, and demonstrates that both AE 6 C and AE 6 PC reach higher concentrations and persist longer in brain tissue that AZT alone when administered by oral intubation. Of special interest is the fact that AE 6 PC is eliminated very slowly in brain. Twenty-four hours after drug administration, the concentration of this drug conjugate remains more than 100-fold higher than AZT itself. An additional advantage of AE 6 PC over AE 6 C in these studies is its higher solubility in water-based solutions, which may be important for clinical use. Figure 5B shows the results of brain uptake and accumulation experiments performed by intravenous administration of AZT, AE 6 PC and AE 6 C, as described above regarding testes-specific uptake and accumulation of these drugs. These results show enhanced accumulation of the polar lipid drug conjugates in brain tissue, and at higher absolute amounts of the compounds (compare the units on the y axes of Figures 5A and 5B). These graphic representations also illustrate that both conjugated compounds are found at essentially equivalent and much higher levels in brain that unconjugated AZT, and that much more of all three compounds are found in testes than in brain (compare the scale of the ordinate). In addition, all three compounds are cleared from testes between 4 and 8 hr, with levels of all three compounds remaining essentially the same between 8 and 24 hr in testes. Uptake and retention experiments using ddl and IE 6 C were performed substantially as described above for AZT drugs and prodrugs. ddl and IE 6 C were administered by oral intubation of 0.5mL containing 3.75mM drug or prodrug in 100% fetal bovine serum. The results of these experiments are shown in Table IC. These results demonstrate an increase in brain content of IE ( ,C between 2 hrs and 24 hrs of oral administration. Between 24 hrs and 48 hours, there is a marked reduction in the amount of this compound in the brain. At all times, the amount of prodrug conjugate in brain was more than 100-fold higher than free ddl. In the testes, no change in IE 6 C was observed between 2 hrs and 24 hrs. In both brain and testes, however, there was a marked reduction in the amount of IE 6 C between 24 hrs and 48 hrs. These results suggest that IE 6 C is relatively stable in serum, and this stability probably accounts for the maintenance of prodrug levels in brain and testes between 2 hrs and 24 hrs. This maintenance persists despite the fact that the prodrug is being eliminated from these two organs, as evidenced by the marked decrease in prodrug concentration between 24 and 48 hrs, presumably after the serum prodrug concentration has decreased. TABLE IC Uptake and Retention of ddl and IE 6 C in Mouse Tissues = time after oral administration 2 = pmoles/gram wet weight In another series of experiments, production of HgH by 3T3 cells resulting from infection with a recombinant Moloney murine leukemia virus (Mo-MuLV) construct was used to measure the intensity of viral infection after treatment with drug and prodrug embodiments of antiviral compounds. In these experiments, cells were incubated with each drug or prodrug for 12, 24 or 48 hours prior to infection with the HgH recombinant expression construct. The level of recombinant HgH production in control cells was assigned a value of 100% . Any decrease (or increase) in HgH production indicates a drug-mediated effect. Drug and prodrug embodiments of AZT and ddl were tested. Both prodrugs were able to block virus infection for longer periods after the removal of the drugs following an acute exposure for 2 hours. The results of these experiments are shown in Figures 7A through 7E. In Figure 7A, NIH 3T3 cells were exposed to lμM AZT or AE 6 C for two hours and then infected with the HgH-encoding recombinant viral construct 6h, 12h or 24h after removal of the drug. AE 6 C was shown to suppress viral growth better than AZT at 12 and 24 hours after drug removal. It is important to note that viral growth was suppressed even 24 hours after removal of AE 6 C. This suggested that this prodrug had saturated the cellular lipid phase, releasing active drug many hours after removal. Moreover, AZT-treated cultures showed greater viral infection levels than controls. Figure 7B shows results of a comparison between ddl and the ddl prodrug, IE 6 C. This prodrug was made using synthetic chemistries similar to those disclosed in Example 2 for AZT conjugates. Cells were incubated for 2 hours in 0.375μM ddl or IE 6 C, the drug removed and the cells infected with the recombinant viral construct Oh, 12h, 24h, and 48h thereafter. The results presented in Figure 7B show that the ddl prodrug was most efficient at inhibiting recombinant virus expression 12 hours following the removal of the drug. The prodrug continued to suppress viral infection even 24 hr after removal of the prodrug. Free ddl was not able to prevent reinfection. Similar effects were obtained when NIH 3T3 cells were chronically exposed to prodrugs for four days. Figure 7C shows the results of studies in which cells were grown in medium containing 0.25μM AZT, AE 6 C or AE 6 PC for four days. The drug containing medium was then removed either 12, 24 or 48 hours prior to virus infection. The drug and virus treatments were staggered to ensure that all cells were simultaneously infected with the same batch of virus. Following a two-hour exposure to virus, cells were reincubated for 20 hour in medium free of both drugs and virus. Cells were then assayed for HgH content by RIA. Prodrug was found to inhibit recombinant virus infection even 48h after removal of the prodrug from the cell culture medium. AZT, on the other hand, was associated with an increase in virus infection 48h after removal of the drug. The prolonged antiviral action of the prodrugs was not unexpected because the prodrugs readily entered the cells, were retained for prolonged periods of time, maintaining stable intracellular drug pools, although the effect of AZT was unexpected. In similar experiments, cells pretreated with 0.375 / uM ddl or IE 6 C were not able to block viral infection at 24 and 48 hours after drug removal (shown in Figure 7D), although prodrug-treated cells were slightly more resistant to infection. Interestingly, these results show that not only were ddl and AZT not able to prevent viral infection, but both ddl- and AZT-treated cells were more sensitive to infection than control cells. Cells pretreated with prodrug were better protected against infection for longer periods of time after drug removal from the culture media than cells pretreated with ddl. In fact, ddl was unable to prevent infection at any of the times studied, and ddl-treated cells were more prone to infection than untreated control cells when exposed to virus either 24 or 48 hours after drug removal. Even more striking were the increased levels of infection in AZT-treated cells when they were exposed to virus at either 24 or 48 hours following drug removal. These results are consistent with the idea that prolonged treatment with free drug blocks cell division. When the drug is removed, blocked cells can then proceed in their mitotic cycle, resulting in a burst of dividing cells greater than that in control cells not treated with AZT or ddl. Because cell division is a prerequisite for productive infection to occur (insertion of the viral genome into the DNA of the cell), a release of a mitotic cell division block during the two hour exposure to virus could readily account for the increased level of infection following removal of free drug. The prodrug IE 6 C, which probably releases lower amounts of active drug, apparently does not block division to the same extent. When NIH 3T3 cells were continuously exposed to equal molar concentrations of AZT, AE 6 C and AE 6 PC, the prodrugs blocked infection better than did free AZT (Figure 7E). Figure 7E illustrates the results of experiments wherein NIH 3T3 cells were treated with free AZT, AE 6 C and AE 6 PC conjugates and then infected with the HgH-encoding recombinant Mo-MuLV construct. In these experiments, NIH 3T3 cells were infected with the recombinant construct for 24 hr without added drug or in the presence of 0.25mM unconjugated AZT, AE 6 C or AE 6 PC. Infection rate was determined as the amount of recombinant hGH that was detected in infected cells; this is expressed in Figure 7E as percent of control (cells infected without unconjugated AZT, AE 6 C or AE 6 PC in the culture media). These results show that all three compounds reduced the rate of infection in these cells to less than about 10% of the infection rate observed in the absence of these compounds. EXAMPLE 4 In another series of experiments, the antifolate drug methotrexate was conjugated with a variety of polar lipid carriers via organic spacer moieties having specific reactive functional groups. A representative sample of such compounds is shown in Figures 8A through 8C, wherein MC represents Mtx linked to sphingosine via an amide bond to a 6-aminohexanoic acid spacer; ME 6 C represents Mtx linked to sphingosine via an ester linkage to a 6-hydroxyhexanoic acid spacer; and MSC represents Mtx linked to sphingosine via a salicylic acid ester linkage to a 6-aminohexanoic acid spacer. Also studied was a conjugate of azidothymidine linked to sphingosine via an ester linkage to a 6-hydroxyhexanoic acid spacer (AE 6 C, shown in Figure 3). The compounds were tested for their growth inhibitory effects on murine NIH 3T3 cells growing in cell culture. About one million such cells per PI 00 tissue culture plate were grown in DMEM media supplemented with 10% fetal calf serum (GIBCO, Grand Island, NY) in the presence or absence of a growth-inhibitory equivalent of each prodrug. Cell numbers were determined after 70 hours growth in the presence or absence of the prodrug. In a second set of experiments, an amount of a brain homogenate containing an enzymatically-active esterase was included in the growth media. The results from these experiments are shown in Table II. As can be seen from these data, the MC prodrug had no effect on the growth and survival of the cells. This result did not change upon co-incubation with the esterase-containing brain extract, which was expected due to the nature of the drug/spacer linkage (an amide bond). A different result was obtained with the ME 6 C conjugate. The prodrug was ineffective in inhibiting cell growth or survival in the absence of brain extract. Upon addition of the brain extract, however, a significant increase in Mtx cytotoxicity was observed. This is consistent with cleavage of the ester linkage by the brain extract-derived esterase. A similar result was obtained with the MCS conjugate, indicating that the brain extract esterase activity was capable of cleaving the salicylic acid ester as well. These results indicate that for Mtx-containing conjugates, the free drug must be released from the prodrug for biological activity. These results suggest that specific release of this drug, and perhaps others, can be achieved using cleavable linker moieties that are specifically cleaved only in pathogen-infected cells. Table III shows the results of a comparison of drug uptake and retention studies performed with AZT and the prodrug AE 6 C and with ddl and the prodrug IE 6 C. Antiviral amounts (l μM AZT, AE 6 C, ddl or IE 6 C) of these compounds were added to NIH 3T3 cell cultures and incubated for 2 hr. Cells were then transferred to media (DMEM, GIBCO) without drug and incubated for an additional 24 hr. Cell samples were analyzed by radioimmunassay (RJA) at 0, 6, 12 and 24 hr after removal of drug or prodrug. As shown in the Table, both prodrugs (AE 6 C and IE 6 C) were retained in the cells to a much greater extent than free drug (for AZT, up to 35-fold higher at 12 hr and for ddl, up to 23-fold higher at 12 hours; the ratios could not be calculated for the 24 hr time point, but is estimated to be at least 64-fold and 41 -fold, respectively). These results indicate that prodrug-polar lipid conjugates are both taken up and retained to a greater extent that free AZT or ddl in mammalian cells. AZT and ddl prodrugs were also found to be significantly less toxic to hematopoietic cells than free drug. For example, the prodrug AE 6 C was much less toxic to NIH/3T3 cells in vitro and also to bone marrow erythroid (BFU-E) and myeloid (CFU-GM) hemopoietic progenitor cells of both murine and human origin. In mice, AE 6 C was found to be appreciably less toxic than AZT to the marrow cells in culture (BFU-E) . This was confirmed in studies of human bone marrow toxicity. BFU-E toxicity data with human bone marrow cells demonstrated that AZT was found to be significantly more toxic than AE 6 C in culture. Studies of murine and human myeloid precursor cells in vitro upheld these conclusions. Evaluating the effects of AE 6 C and AZT on mouse and human hematopoietic progenitor cells confirmed that AE 6 C was less hemotoxic than AZT. These observations indicated that AE 6 C is significantly lower in bone marrow toxicity when compared to AZT and could, therefore, overcome one of the recognized drawbacks of AZT therapy. TABLE II Sample 1 # Sample 3 # cells/plate 2 cells/plate 4 Control/FBS 7.8 x 10 6 Control/FBS 13 x 10 6 ME 6 C/FBS 6.5 x 10 6 MSC/FBS 2.1 x 10 6 ME 6 C/brain 2.7 x 10 6 MSC/brain 0.51 x 10 6 Mtx/FBS 0.16 x 10 6 Mtx/FBS 0.13 x 10 6 Mtx/brain 0.09 x 10 6 Mtx/brain 0.06 x 10 6 Control/brain N.D. Control/brain 6.2 x 10 6 1 _ cells incubated with drug/FBS or drug/brain extract for 1 hour at 37°C 2 _-. cell growth and survival determined 70 hours after drug addition 3 --_ cells incubated with drug/FBS or drug/brain extract for 2 hours at 37°C cell growth and survival determined 72 hours after drug addition TABLE III too low to be measured by RIA EXAMPLE 5 The ability of the polar lipid/drug conjugates as described in Examples 1, 2, 3 and 4 to specifically target organs or tissues in vivo was further determined in comparison with methotrexate (Mtx) itself as follows. The ceramide N-(methotrexate)-(N-6-salicylate(aminocaproyl))-sphingosine (a salicylic acid ester of methotrexate conjugated to sphingosine via a 6-amino hexanoic acid spacer, termed MSC herein and illustrated in Figure 8C) was synthesized according to one of the following equivalent protocols, shown in Figures 9A and 9B. In the first protocol, shown in Figure 9A, D-erythro- sphingosine was reacted at room temperature with two equivalents of tert-butyl dimethyl silyl imidazole (TBDMS) in tetrahydrofuran (THF) to yield the sphingosine derivative protected at both head group hydroxy Is with TBDMS. The protected sphingosine product of this reaction was then conjugated at room temperature with one equivalent of aminocaproyl salicylate in dry chloroform (CHC1 3 ) containing dimethylaminopyridine (DMAP) and carbonyl diimidazole (CDI), resulting in amide bond formation between the amino head group of sphingosine and the carboxyl group of the 6-amino group of the caproate spacer. The sphingosine-salicylate conjugate produced in this reaction was then treated with sodium methoxide (NaOMe) at room temperature to remove the acetate protecting group on the salicylate phenol oxygen atom. Activated methotrexate was then covalently linked to this salicylate phenol group by reaction with the sphingosine-salicylate conjugate at room temperature in the presence of DMAP and CDI, forming an salicylate ester with Mtx. In the final step, the sphingosine head group hydroxyls were deprotected by treatment with hydrochloric acid (HCl). In an alterative reaction scheme, shown in Figure 9B, D-erythro-sphingosine was reacted at room temperature with three equivalents of aminocaproyl salicylate in dry chloroform containing DMAP and CDI. In this reaction scheme, the resulting sphingosine-salicylate conjugate was conjugated to 6-aminocaproyl salicylate at the head group amino group as well as the two head group hydroxyls. The head group hydroxyls and the protected salicylate phenol oxygen were then deprotected by treatment with NaOMe at room temperature. The product of this reaction was sphingosine conjugated to a single 6-aminocaproyl salicylate at the sphingosine amino group, and having a deprotected phenol group on the salicylate moiety. The sphingosine hydroxyl groups were then protected by reaction with 2,2-dimethoxypropane at room temperature in acetone and para-toluene sulfonic acid (pTsOH). Activated Mtx was then conjugated in an ester linkage to the phenol group of the salicylate moiety with DMAP and CDI at 40°C. In the final step, the sphingosine hydroxyl groups were deprotected using trifluoroacetic acid. In vivo drug distribution studies were performed using MSC as follows. Forty-eight fasted Swiss mice were administered Mtx or MSC intravenously by tail vein injection at a concentration of about 0.336mM in 0.5mL fetal bovine serum or saline. At two hours after administration, the amount of each compound localized in lung, kidney, thymus and spleen was determined by radioimmunassay; tissue samples were prepared as described above in Example 3. All tissue samples were analyzed for Mtx by radioimmunassay as follows. Appropriate serial dilutions of a Mtx-ceramide standard and a tritiated Mtx standard were prepared in Buffer A (comprising 0.05M sodium phosphate, pH 7.4/ 0.1M sodium chloride/ 0.1%) gelatin). A stock solution of tritiated Mtx was prepared by mixing 50μL l .OmCi/mL 3 H-Mtx (obtained from DuPont, Boston, MA) with 4.95mL Buffer B (comprising 0.05M sodium phosphate, pH 7.0 and 0.2M 2-mercaptoethanol), aliquotted in lmL aliquots, and stored at 4°C in the dark until use. Standard Mtx-ceramide solution was prepared by dissolving 7.3mg Mtx (98%o purity) into 7.152mL Buffer A (to a final concentration of l OOng/μL) and stored at 4°C in the dark until use. Serial dilutions of Mtx-ceramide stock solution were prepared at concentrations of 1.0, 0.8. 0.6, 0.4, 0.2, 0.1 , 0.05, 0.025, and 0.0125 ng/lOOμL. Immediately prior to performing the assay, anti-Mtx antibody (obtained from American Qualex Int'l. Corp., San Clemente, CA) was diluted 1 :5500 in Buffer A from a 1 :50 antibody stock solution (prepared using Buffer A), and 3 H-Mtx was diluted by the addition of 200μL stock solution (l μCi/l OOμL) to 5mL Buffer A. The assay was performed by mixing lOOμL 3 H- Mtx, lOOμL antibody, lOOμL Mtx-ceramide standard or sample, and Buffer A to a final volume of 500μL. Controls contained Buffer A in place of antibody, Mtx- ceramide standard, or sample. The mixtures were incubated at room temperature for 50min after mixing, and then at 4°C for lOmin. 200μL dextran-coated charcoal (prepared by dissolving 5g Norit A charcoal and 0.5g dextran T-70 in 400mL water) was then added to each assay mixture, vortexed or otherwise thoroughly mixed, incubated at 4°C for lOmin, and then centrifuged 4°C for 15min at 2500rpm in a Beckman J-6B centrifuge (Beckman Coulter Instruments, Palo Alto, CA). lOOμL of the supernatant was removed and added to 7mL scintillation fluid (Ecolume) in a scintillation vial, and the amount of radioactivity determined by liquid scintillation using a liquid scintillation counter (Beckman). The results obtained in these assays are shown in Table IN and are expressed as pmol of each compound per gram of wet weight and are the mean ± standard error for three animals assayed. The ratio of the amount of each conjugate to free MTX (i.e., MSC/MTX) was calculated and is shown in Table IN. These results demonstrated that MSC conjugates were delivered to lung and spleen at amounts from 1 1- to 163-fold higher than free MTX. The greatest differential delivery of the conjugated compounds compared with free MTX was found for lung. Although delivery using saline and fetal bovine serum (FBS) was essentially the same in spleen, FBS produced more than a tenfold increase in delivery to lung tissue. Delivery to kidney was slightly greater for MSC (2-3 fold), while free MTX was delivered three- to tenfold more efficiently than MSC in thymus. These experiments were repeated in a series that included assay of 2-hour uptake in liver tissue. In these experiments, MTX or MSC was administered either in FBS or dimethylsulfoxide (DMSO). At two hours after administration, the amount of each compound localized in liver, lung, kidney, thymus and spleen was determined by radioimmunassay as described above. These results are shown in Table N and are expressed as pmol of each compound per gram of wet weight and are the mean ± standard error for four animals assayed. The ratio of the amount of each conjugate to free MTX (i.e., MSC/MTX) was calculated and is shown in Table N. Preferential localization of MSC over MTX was again observed in lung and spleen tissue, ranging from 12-33 fold (although in these experiments higher levels were detected in spleen than in lung). In particular, the absolute amount of MSC detected was highest in lung and spleen tissue in animals administered MSC in DMSO. As previously observed, MSC and MTX were found at relatively equivalent levels in kidney, and MTX was present at about 10-fold excess over MSC in thymus. The results from liver were similar to kidney; however, the absolute levels of MTX and MSC were much higher in liver. In fact, liver showed the highest absolute levels of MTX observed, while the absolute amount of MSC detected in liver was similar to the levels observed in spleen. In contrast to lung and spleen tissue, however, more MSC was detected in liver tissue from animals administered with the compound in FBS than in DMSO. These results demonstrate that salicylate ester-containing conjugates can be used to specifically target lung and spleen tissues with the biologically active compounds of the invention. TABLE IV Ratio Tissue MTX * MSC (MSC/MTX) FBS | Saline FBS Saline FBS j Saline Lung | 137 ±7.1 | 1 16 ±22 1528 ±126 | 18829 ±955 j 1 1 | 163 Spleen | 139 ±3.2 | 134 ±19 2891 ±388 | 2568 ± 414 j 21 1 19 Thymus | 200 ±9.3 | 192 ±20 67.7 ±24.4 j 25.9 ± 5.9 | 0.3 ! 0- 1 Kidney j 515 ± 47 j 452 ±99 1437 ±184 j 1053 ±58.5 j 3 i 2 Values in pmol per gram wet weight ± standard error TABLE V Values in pmol per gram wet weight ± standard error The results of a two-hour uptake study in mouse brain using Mtx, MC, MSC and ME 6 C are shown in Table VI. In these studies, fed or fasted mice were administered drug or prodrug conjugates by oral intubation or intravenous injection, as described above. These results show a five- to greater than three hundred-fold increase in uptake and accumulation in mouse brain of prodrug over methotrexate alone, further demonstrating the efficacy of drug delivery to the brain using the prodrugs of the invention. TABLE VI Two-Hour Uptake into Mouse Brain of Mtx and Prodrugs Thereof ' = drugs/prodrugs administered by oral intubation 2 = drugs/prodrugs administered by tail vein (intravenous) injection It should be understood that the foregoing disclosure emphasizes certain specific embodiments of the invention and that all modifications or alternatives equivalent thereto are within the spirit and scope of the invention as set forth in the appended claims.

Claims: What is claimed is: 1. A composition of matter comprising a biologically active compound and a polar lipid carrier, wherein the biologically active compound comprises a first linker functional group and the polar lipid carrier comprises a second linker functional group, wherein the first linker functional group is covalently linked to the second linker functional group, and wherein the composition specifically accumulates in an organ or tissue selected from the group consisting of lung, spleen and organs or tissues comprising physiologically protected sites, when the composition is administered orally or parenterally to an animal. 2. The composition of matter of claim 1 , further comprising a spacer, wherein the spacer has a first end and a second end, each end comprising a linker functional group wherein the linker functional group of the first end of the spacer is covalently linked to the polar lipid carrier and the linker functional group of the second end of the spacer is covalently linked to the biologically active compound. 3. A composition of matter according to Claims 1 or 2 wherein the biologically active compound is an antiproliferative, antineoplastic, antibiotic, antibacterial, antimycotic or antiviral drug. 4. A composition of matter according to Claim 3 wherein the polar lipid carrier is sphingosine and the first end of the biologically active compound or the first end of the spacer is covalently linked to the sphingosine amino group. 5. A composition of matter according to Claim 3 wherein the polar lipid carrier is a phospholipid and the first end of the biologically active compound or the first end of the spacer is covalently linked to a glycerol hydroxyl group of the phospholipid. 6. A composition of matter according to claim 3 wherein the biologically active compound is methotrexate, azidothymidine, dideoxyinosine, dideoxycytosine, acyclovir, or gancyclovir. 7. A composition of matter according to Claim 3 wherein the biologically active compound has biological activity in an organ or tissue without being released from the polar lipid carrier or the spacer. 8. A composition of matter according to Claim 3 wherein the polar lipid carrier or spacer allows specific hydrolytic release of the biologically active compound in a particular organ or tissue. 9. A composition of matter according to Claim 3 wherein the polar lipid carrier or spacer allows specific enzymatic release of the biologically active compound in a particular organ or tissue. 10. A composition of matter according to Claim 3 wherein the first functional linker group is a hydroxyl group, a primary or secondary amino group, a carboxylic acid group, a phosphate group or substituted derivatives thereof. 1 1. A composition of matter according to Claim 3 wherein the second functional linker group is a hydroxyl group, a primary or secondary amino group, a carboxylic acid group, a phosphate group or substituted derivatives thereof. 12. The composition of matter of Claim 3 wherein the polar lipid is acyl carnitine, acylated carnitine, sphingosine, ceramide, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, cardiolipin or phosphatidic acid. 13. A composition of matter according to Claim 3 wherein the biologically active compound is a prodrug wherein the biological activity of the prodrug is specifically produced in a particular organ or tissue. 14. A composition of matter according to Claim 3, wherein the spacer comprises salicylic acid and the covalent linkage between the polar lipid carrier and the spacer or the biologically active compound is an ester linkage, wherein the composition specifically accumulates in lung tissue or spleen tissue when administered to an animal. 15. A composition of matter that is N-(methotrexate)-N-(6- aminocaproyl)salicylate))-sphingosine. 16. A composition of matter that is 1 -azidothymidine, 6- lysophosphatidylethanolamine adipic acid diester. 17. A composition of matter that is 1 -sphingosine adipic acid amide, 6- azidothymidine adipic acid ester. 18. A pharmaceutical composition comprising a composition of matter according to claims 1 through 17. 19. A pharmaceutical composition according to claim 18 wherein the biologically active compound is orally bioavailable. 20. A pharmaceutical composition according to claim 18 wherein the composition is topically applied. 21. Use of the composition of matter of claims 1 through 17 for preparing a medicament for treating a pathological condition or disease state in cells, tissues or organs in an animal, wherein the medicament is administered to the animal in an amount sufficient to alleviate the pathological condition or disease state in the animal. 22. A use according to claim 21 wherein the pathological condition or disease state is present in a physiologically restricted or protected site in the animal. 23. A use according to claim 22 wherein the disease state is present in brain tissue. 24. A use according to claim 23 wherein the disease is AIDS, encephalitis, meningitis, neuroblastoma, glioblastoma, astrocytoma or neurosyphilis. 25. A use according to claim 22 wherein the disease state is present in testes. 26. A use according to claim 21 wherein the disease state is present in spleen. 27. A use according to claim 21 wherein the disease state is present in an eye. 28. A use of the composition of matter of claims 1 through 17 for preparing a medicament for delivering a biologically active compound to a tissue or organ in an animal, wherein the medicament is administered to the animal in an amount sufficient for the biologically active compound to specifically accumulate in the tissue or organ in the animal. 29. A use according to claim 28 wherein the tissue or organ in which the biologically active compound specifically accumulates comprises a physiologically restricted or protected site in the animal. 30 A method for treating a pathological condition or disease state in cells, tissues or organs in an animal, the method comprising the step of administering to the animal a pharmaceutical composition of Claim 18 in an acceptable carrier or formulation and in an amount sufficient to alleviate the pathological condition or disease state in the animal. 31. A method for treating a pathological condition or disease state in an animal, wherein the pathological condition or disease state is present in a physiologically restricted or protected site in the animal, the method comprising the step of administering to the animal a pharmaceutical composition according to Claim 18 in an acceptable carrier or formulation and in an amount sufficient to alleviate the pathological condition or disease state in the animal. 32. A composition of matter that is 2',3' dideoxyinosine, 6- lysophosphatidylethanolamine adipic acid diester. 33. A composition of matter that is 2', 3' dideoxyinosine, 6- lysophosphatidylcholine adipic acid diester. 34. A composition of matter that is 1 -sphingosine adipic acid amide, 2'3' dideoxyinosine adipic acid ester. 35. A composition of matter that is 1 -sphingosine adipic acid amide, 2'3' dideoxycytidine adipic acid ester. 36. A composition of matter that is 2', 3' dideoxycytidine, 6- lysophosphatidylethanolamine adipic acid diester. 37. A composition of matter that is 2',3' dideoxycytidine, 6- lysophosphatidylcholine adipic acid diester. 38. A composition of matter that is 1 -azidothymidine, 6- lysophosphatidylcholine adipic acid diester.

Inventors: MEREDITH MICHAEL J, STOWELL MICHAEL B, YATVIN MILTON B, MEREDITH, MICHAEL, J., STOWELL, MICHAEL, ., B., YATVIN, MILTON, B.
Applicants: MEREDITH MICHAEL J, STOWELL MICHAEL B, UNIV OREGON HEALTH SCIENCES, YATVIN MILTON B, MEREDITH, MICHAEL, J., OREGON HEALTH SCIENCES UNIVERSITY, STOWELL, MICHAEL, ., B., YATVIN, MILTON, B.
Application year: 1999
Main classification: A61K47
IPC codes: A61K47