Abstract
This report describes the synthesis and preliminary biological characterization of 2 (ANG1007) and 3 (ANG1009), two new chemical entities under development for the treatment of primary and secondary brain cancers. 2 consists of three doxorubicin molecules conjugated to Angiopep-2, a 19-mer peptide that crosses the blood-brain barrier (BBB) by an LRP-1 receptor-mediated transcytosis mechanism. 3 has a similar structure, with the exception that three etoposide moieties are conjugated to Angiopep-2. Both agents killed cancer cell lines in vitro with similar IC(50) values and with apparently similar cytotoxic mechanisms as unconjugated doxorubicin and etoposide. 2 and 3 exhibited dramatically higher BBB influx rate constants than unconjugated doxorubicin and etoposide and pooled within brain parenchymal tissue. Passage through the BBB was similar in Mdr1a (-/-) and wild type mice. These results provide further evidence of the potential of this drug development platform in the isolation of novel therapeutics with increased brain penetration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / deficiency
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Amino Acid Sequence
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / metabolism*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Biological Transport
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism
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Brain / cytology
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Brain / metabolism*
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Brain / pathology
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Brain Neoplasms / drug therapy
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Cycle / drug effects
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Cell Line, Tumor
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Doxorubicin / analogs & derivatives*
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Doxorubicin / chemistry*
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Doxorubicin / metabolism*
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Doxorubicin / pharmacology
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Doxorubicin / therapeutic use
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Etoposide / analogs & derivatives*
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Etoposide / chemistry*
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Etoposide / metabolism*
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Etoposide / pharmacology
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Etoposide / therapeutic use
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Etoposide / toxicity
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Female
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Humans
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Inhibitory Concentration 50
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Kinetics
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Male
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Mice
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Peptides / chemistry*
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Peptides / metabolism*
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Peptides / pharmacology
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Peptides / therapeutic use
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Peptides / toxicity
Substances
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ANG 1007
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ANG 1009
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ATP Binding Cassette Transporter, Subfamily B
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Antineoplastic Agents
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Peptides
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Etoposide
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Doxorubicin
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multidrug resistance protein 3