Chemical conjugates of Evans Blue derivatives and their use as radiotherapy and imaging agents for targeting prostate cancer
Inventors
Chen, Xiaoyuan • Jacobson Weiss, Orit
Assignees
US Department of Health and Human Services
Publication Number
US-12161733-B2
Publication Date
2024-12-10
Expiration Date
2039-02-22
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Abstract
A compound of Formula I 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 of R1-R13 and L1-L4 are provided in the disclosure, and wherein R14 is a group capable of binding to prostate-specific membrane antigen (PSMA).
Core Innovation
The invention relates to functionalized derivatives of Evans Blue dye, particularly chemical conjugates that serve as radiotherapy and imaging agents targeting prostate cancer. These derivatives incorporate a group capable of binding to prostate-specific membrane antigen (PSMA), allowing for selective targeting of prostate cancer cells.
The problem addressed by the invention arises from limitations of prior PSMA-targeting agents used for prostate cancer treatment and imaging. Current anti-PSMA antibodies labeled with radionuclides exhibit bone marrow and hematology toxicity due to long blood half-life. Small molecule PSMA ligands, although having rapid clearance that reduces nonspecific background, suffer from limited tumor accumulation, restricting their efficacy.
The invention solves this problem by conjugating common PSMA-targeting ligands with an Evans Blue analog that reversibly binds to serum albumin. This modification leads to increased blood circulation half-life, enhanced tumor uptake, and improved retention in PSMA-positive tumors, which in turn results in more effective anti-tumor radiotherapy and higher imaging quality. The compounds are designed with a chelating group for radionuclide labeling, enabling both diagnostic imaging and therapeutic applications.
Claims Coverage
The patent contains one independent claim directed to a compound of Formula I and related pharmaceutical compositions and treatment methods. Four main inventive features are identified from the independent claim and its dependent claims.
Compound of Formula I with defined substitutions and linkers
A compound of Formula I or its pharmaceutically acceptable derivatives characterized by variable substituents R1-R13 and linking groups L1-L4, where R14 is a group capable of binding PSMA. This includes specific structural features such as alkyl, halo, hydroxyl, cyano substituents, polyethylene glycol segments in linkers, and defined spacing units.
Inclusion of a chelating group and radionuclide labeling
Compounds comprising a chelating group R13 which may be macrocyclic or linear moieties such as NOTA, DOTA, or others, that facilitate binding of radionuclides. Radionuclides specified include 64Cu, 67Cu, 86Y, 90Y, 111In, 177Lu, and others suitable for imaging or radiotherapy.
Pharmaceutical compositions comprising the compound
Pharmaceutical compositions including a compound of Formula I combined with pharmaceutically acceptable carriers such as binders, buffering agents, diluents, lubricants, preservatives, and other excipients, forming dosage forms suitable for administration.
Method of treating prostate cancer with the compound
A method of treating prostate cancer in a mammal by administering a therapeutically effective amount of said compound, optionally combined with other anticancer agents such as doxorubicin, paclitaxel, docetaxel, cisplatin, and others.
The independent claim and its dependent claims encompass compounds with defined chemical structures, their formulation into pharmaceutical compositions, radionuclide labeling for imaging and therapy, and methods of using these compounds for prostate cancer treatment, highlighting the invention's comprehensive approach to prostate cancer targeting using Evans Blue derivatives.
Stated Advantages
Increased blood half-life and tumor uptake leading to enhanced therapeutic efficacy and imaging quality compared to existing PSMA ligands.
Retention of high internalization rate by PSMA-expressing tumor cells, resulting in higher accumulation of the therapeutic agent.
Modifications that enable facile and high-yield conjugation with small molecules and biologics without interfering with their biological function.
The inclusion of a chelator allows simple labeling with radionuclides for dual diagnostic imaging and radiotherapy applications.
Documented Applications
Use as radiotherapy agents for treatment of prostate cancer, including metastatic castration-resistant prostate cancer.
Use as imaging agents for diagnostic procedures targeting PSMA-positive tumors, including positron emission tomography (PET) imaging.
Combination therapy with other anticancer compounds such as doxorubicin, paclitaxel, docetaxel, and cisplatin.
Use in veterinary applications for treatment of prostate cancer in non-human mammals.
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