New Angiopep-Modified Doxorubicin (ANG1007) and EtoposDEe (ANG1009) Chemotherapeutics With Increased Brain Penetration

摘要

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 peptDEe 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 etoposDEe moieties are conjugated to Angiopep-2. Both agents killed cancer cell lines in vitro with similar IC50 values and with apparently similar cytotoxic mechanisms as unconjugated doxorubicin and etoposDEe. 2 and 3 exhibited dramatically higher BBB influx rate constants than unconjugated doxorubicin and etoposDEe and pooled within brain parenchymal tissue. Passage through the BBB was similar in Mdr1a (-/-) and wild type mice. These results provDEe further evDEence of the potential of this drug development platform in the isolation of novel therapeutics with increased brain penetration.