Phospholipid ether analogs as cancer-targeting drug vehicles
Inventors
Weichert, Jamey P. • PINCHUK, Anatoly • Kozak, Kevin • LONGINO, Marc • Grudzinski, Joseph • Titz, Benjamin • Pak, Chorom • Stehle, Nathan
Assignees
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Publication Number
US-9345718-B1
Publication Date
2016-05-24
Expiration Date
Abstract
The present invention is directed to therapeutic compounds capable of targeting cancer cells and cancer stem cells. The present invention is further directed to compositions comprising these therapeutic compounds and methods of treating cancer comprising administering these therapeutic compounds.
Core Innovation
The invention relates to a phospholipid ether (PLE) analog therapeutic platform adapted from CLR1404 for delivering anti-cancer agents to cancer cells and cancer stem cells. The platform is described as a core A–B–D conjugate scaffold where A is a PLE moiety and B is a linker, and the therapeutic conjugates are presented as CLR1404-based PLE drug-delivery conjugates.
The described subject matter includes multiple antibody-drug-conjugate-like small-molecule conjugates in which therapeutic agents are linked to the CLR1404 (CLR1404/CLR1401) core. The therapeutic agents explicitly include paclitaxel, geldanamycin, and mertansine, with linkage chemistries including amide bonds, ester bonds, carbonate bonds, and carbamate bonds, and examples including glutaramic-acid, dicarboxylic-acid, carbamic-acid, carbonic–carboxylic acid, non-hydrolyzable phenyl ether, carbonyl, and short amino-acid or aminobutyramide linkers.
The partial content also describes selective delivery and retention of anti-cancer agents in cancer cells and cancer stem cells, including performance across the blood-brain barrier for brain cancers. Supporting discussion includes tumor/cell sequestration/retention studies, uptake studies and imaging in rat glioma and xenografts, as well as clinical imaging in NSCLC with radiolabeled CLR1404 (e.g., 124I-CLR1404 and 131I-CLR1404).
Additional CLR1404-linked conjugates, including CLR1608, are synthesized and characterized. In vitro cytotoxicity and viability-related evaluations are described for paclitaxel–CLR conjugates including CLR1601/1603 using IC50 data, and for CLR conjugates including CLR1606/1607 using flow-cytometry viability/apoptosis outcomes, including Annexin V and propidium iodide.
Claims Coverage
The provided claim text covers one independent inventive feature and one dependent refinement.
Therapeutic compound of Formula (V)
A therapeutic compound of Formula (V).
Pharmaceutical composition including pharmaceutically acceptable carriers
The therapeutic compound of Formula (V) is formulated as a pharmaceutical composition that includes one or more pharmaceutically acceptable carriers.
The provided claims cover a therapeutic compound defined by Formula (V), with a dependent formulation as a pharmaceutical composition including one or more pharmaceutically acceptable carriers.
Stated Advantages
Preferential uptake via lipid rafts.
Selective retention up to about 20 days.
Ability to target recurrent cancer and cancer stem cells.
Support for delivery across the blood-brain barrier for brain cancers.
Documented Applications
Treatment of recurrent cancer.
Targeting cancer stem cells (CSCs).
Delivery for brain cancers, including through the blood-brain barrier.
Tumor/cell sequestration/retention studies, including uptake studies.
Imaging in rat glioma and xenografts.
Clinical imaging in NSCLC.
In vitro cytotoxicity evaluation using IC50 data for paclitaxel–CLR conjugates (CLR1601/1603).
Flow-cytometry viability/apoptosis outcomes for CLR conjugates (CLR1606/1607), including Annexin V and propidium iodide readouts.
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