Convalent conjugates of biologically-active compounds with amino acids and amino acid derivatives for targeting to physiologically-protected sites

Abstract

This invention herein describes a method of facilitating the entry of drugs into cells and tissues at physiologically protected sites at pharmacokinetically useful levels and also a method of targeting drugs to physiologically protected sites in vivo. Also provided are drug conjugates with an amino acid or derivative thereof for facilitating such targeted drug delivery. The conjugates and methods of this invention provide an advance over other drug targeting methods known in the prior art, because the invention provides drug concentrations in such physiologically protected sites that can reach therapeutically-effective levels after administration of systemic levels much lower than are currently administered to achieve a therapeutic dose. This technology is appropriate for use with psychotropic, neurotropic, neurological, antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs, agents and conjugates, for rapid and efficient introduction of such agents across, e.g., the blood-brain barrier. Further, the invention provides means for retention and prolonged enzymatic release of such drugs, agents and conjugates comprising the conjugates of the invention, in the brain and central nervous system and other physiologically-protected sites.

Description

[0001] This application claims priority to U.S. Ser. No. 09 / 993,976, filed Nov. 5, 2001, now U.S. Pat. No. 7,045,543, granted May 16, 2006, which is incorporated by reference in its entirety.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention is related to specific targeting of biologically-active compounds to specific cells, tissues and organs in vivo. The invention specifically provides conjugates of biologically-active compounds and methods of effecting the uptake and accumulation of biologically active compounds into organs, tissues and cells, particularly at physiologically protected sites, at pharmacokinetically useful levels. The 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 effic...

AI Technical Summary

Benefits of technology

[0063] The present invention is directed to an improved method for delivering biologically-active compounds, particularly drugs including preferably antibacterial, antibiotic, antiviral, antimycotic, antiproliferative and antineoplastic drugs and agents, and neurotropic, psychotropic and anticonvulsant drugs and agents, to physiologically protected sites in an animal in vivo. This delivery system achieves specific delivery of such biologically-active compounds through conjugating the compounds with an amino acid or amino acid derivative that is specifically transported into said physiologically-protected sites. This invention has the specific advantage of facilitating the entry of such compounds into cells and tissues protected by such physiological barriers as the blood-brain barrier via an amino acid or amino acid derivative that is specifically transported into said physiologically-protected sites, achieving effective intracellular concentration of such compounds more efficiently and with more specificity than conventional delivery systems.

[0071] In other embodiments of the compositions of matter of the invention, the spacer allows the facilitated hydrolytic release of antibacterial, antibiotic, antiviral, antimycotic, antiproliferative or antineoplastic drug or agent, or a neurotropic, psychotropic or anticonvulsant drug or agent at an intracellular site. Other embodiments of the spacer facilitate the enzymatic release of the antibacterial, antibiotic, antiviral, antimycotic, antiproliferative or antineoplastic drug or agent, or a neurotropic, psychotropic or anticonvulsant drug or agent of the invention at an intracellular site. In particularly preferred embodiments, the spacer functional group is hydrolyzed by an enzymatic activity found in a physiologically-protected site, such as the brain and central nervous system and more particularly including neuronal, glial and other brain cell types, wherein said enzymatic activity is preferably an esterase and most preferably an esterase having a differential expression and activity profile in different tissue cell types. In additional preferred embodiments, specific release of the antibacterial, antibiotic, antiviral, antimycotic, antiproliferative or antineoplastic drug or agent, or a neurotropic, psychotropic or anticonvulsant drug or agent of the invention is achieved by enzymatic or chemical release of these drugs by extracellular cleavage of a cleavable linker moiety via an enzymatic activity specific for, for example, brain tissue, followed by specific uptake of the released antibacterial, antibiotic, antiviral, antimycotic, antiproliferative or antineoplastic drug or agent, or a neurotropic, psychotropic or anticonvulsant drug or agent by the appropriate cell in said tissue.

[0074] As disclosed herein, the invention comprehends conjugates wherein the amino acid or amino acid derivative is specifically and selectively transported across certain physiological barriers to protected tissue sites, thereby facilitating delivery of drugs and other pharmaceutical agents to such 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 amino acid or derivative at the target site; prevent the non-specific release from the drug from the amino acid or derivative in the systemic circulation or in hepatic, renal or other inappropriate cells, tissue 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.

[0075] This type of conjugate has numerous advantages. The conjugates of the invention provide delivery of a variety of antibacterial, antibiotic, antiviral, antimycotic, antiproliferative or antineoplastic drug or agent, or a neurotropic, psychotropic or anticonvulsant drug or agent to physiologically restricted or protected sites in vivo at concentrations and pharmacokinetic 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.

[0076] In particular, felicitous design of the psychotropic, neurotropic / neurological drug / spacer / amino acid conjugate can provide an in vivo reservoir of time-dependent drug release in the physiologically protected tissue, 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 antibacterial, antibiotic, antiviral, antimycotic, antiproliferative or antineoplastic drug or agent, or a neurotropic, psychotropic or anticonvulsant drug or agent can be modulated by release via cleavage, preferably hydrolytic cleavage, of the spacer moiety, most preferably by an enzymatic activity in the protected tissue (e.g., brain) that has a differential pattern of expression or activity in different cell types in said tissue. 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.

Problems solved by technology

In the pharmacological and neurologic arts, it is well-recognized that the inability to deliver effective amounts of neurotropic, psychotropic and anticonvulsant drugs and agents across the blood-brain barrier severely limits the therapeutic efficacy of such pharmaceutical compounds and can prevent treatment of neurologic disease.

In addition, the use of even effective neurologic agents is further limited by systemic toxicity resulting from the high systemic concentrations that must be administered to achieve a therapeutic concentration of such agents in the brain, central nervous system and other neurological structures.

An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality that could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site.

An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality that could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site.

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