title: New Angiopep-modified doxorubicin (ANG1007) and etoposide (ANG1009) chemotherapeutics with increased brain penetration.
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.
authors.affiliation: Angiochem, 201 President Kennedy Avenue (PK-R220), Montreal, Quebec, Canada H2X 3Y7.
authors.forename: Christian
authors.initials: C
authors.lastname: Ché
authors.forename: Gaoqiang
authors.initials: G
authors.lastname: Yang
authors.forename: Carine
authors.initials: C
authors.lastname: Thiot
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Lacoste
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Currie
authors.forename: Michel
authors.initials: M
authors.lastname: Demeule
authors.forename: Anthony
authors.initials: A
authors.lastname: Régina
authors.forename: Richard
authors.initials: R
authors.lastname: Béliveau
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Castaigne
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D005047:Etoposide / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity
chemical_list: C549238:ANG 1007; C549239:ANG 1009; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D010455:Peptides; D005047:Etoposide; D004317:Doxorubicin; C095122:multidrug resistance protein 3