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

被引：95

作者：

Che, Christian ^{[1
]}

Yang, Gaoqiang ^{[1
]}

Thiot, Carine ^{[1
]}

Lacoste, Marie-Claude ^{[1
]}

Currie, Jean-Christophe ^{[2
]}

Demeule, Michel ^{[1
]}

Regina, Anthony ^{[1
]}

Beliveau, Richard ^{[2
]}

Castaigne, Jean-Paul ^{[1
]}

机构：

[1] Angiochem, Montreal, PQ H2X 3Y7, Canada

[2] Univ Quebec, Mol Med Lab, Montreal, PQ H3C 3P8, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 07期

基金：

加拿大自然科学与工程研究理事会;

关键词：

GLYCOPROTEIN-DEFICIENT MICE; DELIVERY VECTOR ANGIOPEP-2; MULTIDRUG-RESISTANCE GENE; P-GLYCOPROTEIN; BREAST-CANCER; LUNG-CANCER; BARRIER; PROTEIN; TRANSPORTER; DISRUPTION;

D O I：

10.1021/jm9016637

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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 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 IC50 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.

引用

页码：2814 / 2824

页数：11

共 47 条

[11] Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector Angiopep-2 [J].