Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents
Inventors
Chen, Xiaoyuan • Jacobson Weiss, Orit
Assignees
US Department of Health and Human Services
Publication Number
US-10696631-B2
Publication Date
2020-06-30
Expiration Date
2037-05-09
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Abstract
The present invention is directed to a compound of Formula I or Formula III or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt: wherein the definitions R1-R13 and L1-L4 are provided in the disclosure, and wherein R14 is a peptide. The compounds of Formula I may be covalently bonded to a peptide via a linker to provide a compound of Formula III and thereby extend the half-life of the therapeutic compound. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use in the diagnosis or treatment of diseases.
Core Innovation
The present invention is directed to chemical conjugates of Evans Blue dye derivatives, specifically compounds of Formula I, Formula III, and related pharmaceutically acceptable esters, amides, solvates, or salts thereof, which may be covalently bonded to peptides via linkers. These conjugates incorporate an albumin-binding truncated Evans Blue domain, a chelating group for radionuclides, and may include therapeutic peptides or peptides capable of targeting specific cells or tissues, such as tumors.
The invention addresses the problem of short half-life and rapid clearance of therapeutic compounds in vivo, which limits their efficacy. Existing approaches such as PEGylation or fusion with large proteins like albumin or immunoglobulin G can increase half-life but often compromise biological activity or lack targeting specificity. Evans Blue dye has high affinity for serum albumin and can serve as a marker for albumin localization, but previous albumin-drug conjugates lack improved tissue targeting unless those tissues bind albumin inherently.
The invention provides compounds that utilize the Evans Blue domain to extend half-life by albumin binding, with the addition of chelators for radionuclides allowing for imaging or radiotherapy applications. By conjugating the Evans Blue derivative with peptides that can specifically bind target cells or tissues, such as tumors, these conjugates improve therapeutic or diagnostic targeting while maintaining or enhancing biological activity and controlling biodistribution. The compounds can be formulated into pharmaceutical compositions for treating diseases including cancer or diabetes through improved pharmacokinetics and targeted delivery.
Claims Coverage
The patent includes multiple independent claims focused on compounds of Formula I and Formula III, pharmaceutical compositions comprising these compounds, and methods of treating or diagnosing cancer using these compounds. Key inventive features relate to chemical structure, linker groups, peptide conjugation, chelators, and radionuclide incorporation.
Chemical conjugates of Evans Blue derivatives with defined linker and substituents
Claims include compounds of Formula I and II featuring Evans Blue derivatives substituted independently at multiple positions (R1-R12) with groups such as hydrogen, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy. Linkers L1-L3 are defined with specific repeating units including possible oxygen or amide replacements, provided no two adjacent CH2 groups are replaced. R13 is a chelating group selected from crown ether, cyclodextrin, porphyrin, or others.
Peptide conjugation to Evans Blue derivatives via selective linkers
Claims specify compounds of Formula III and IV where R14 is a peptide, including therapeutic peptides capable of binding target cells or tissues such as tumors. The peptides include known sequences such as cyclic Arg-Gly-Asp-Phe-Lys and others. Peptides may carry therapeutic or diagnostic functionality and may include radionuclides.
Incorporation of radionuclides for imaging and therapy
Claims cover compounds where the chelating group R13 and/or peptide R14 incorporates radionuclides including 64Cu, 67Cu, 90Y, 86Y, 111In, 186Re, 188Re, 89Zr, 99Tc, 153Sm, 213Bi, 225Ac, and 223Ra. These provide utility in radiotherapy or diagnostic imaging such as PET.
Pharmaceutical compositions and methods of use
Claims include pharmaceutical compositions comprising the claimed compounds with pharmaceutically acceptable carriers. Methods are claimed for treating or diagnosing cancer in mammals by administering therapeutically effective amounts of these compounds, optionally combined with additional active ingredients like doxorubicin, paclitaxel, and others.
The claims collectively cover novel Evans Blue derivative conjugates with specific substitutions, linkers, peptide conjugates, and radionuclide incorporation, along with related compositions and therapeutic or diagnostic methods, highlighting their utility in enhanced pharmacokinetics, targeting, imaging, and radiotherapy.
Stated Advantages
The compounds provide an efficient system for developing long-lasting and long-acting therapeutic and imaging agents with high efficacy by extending half-life via albumin binding.
Because of the strong binding of the Evans Blue moiety to albumin and its relatively small size, the biodistribution can be controlled with minimal interference with the biological function of the therapeutic or imaging agent.
Addition of chelators like NOTA or DOTA linked to the Evans Blue moiety enables facile incorporation of radionuclides for imaging or radiotherapy, enhancing versatility.
Documented Applications
Diagnosis or treatment of cancer in mammals including humans by administration of therapeutic or imaging agents comprising Evans Blue derivative conjugates.
Treatment of diabetes using compounds conjugated with therapeutic peptides such as GLP-1 or analogs, improving half-life and efficacy.
Use as imaging agents for PET or other radionuclide-based techniques in mapping tumor localization or blood volume.
Radiotherapy of tumors using radionuclide-labeled compounds to deliver targeted radiation doses.
Use in veterinary medicine for treatment of disease in companion animals and livestock.
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