Abstract 3578: New Angiochem-modified doxorubicin with increased brain penetration and efficacy against brain tumors

The blood-brain barrier (BBB) is mainly formed by brain capillary endothelial cells which are closely sealed by tight junctions and express high levels of active efflux transport proteins, including P-glycoprotein (Pgp). As a result, the overwhelming majority of small molecules, proteins and peptides do not cross the BBB. Angiochem's engineered peptide compounds (EPiC) provides a non-invasive and flexible platform for small and large molecules to treat brain diseases. Based on these properties, we have created a portfolio of new drug entities composed of siRNA, peptides and mAbs, the most advanced of which is ANG1005 formed by chemical conjugation of our peptide to three molecules of paclitaxel. ANG1005 demonstrated safety and efficacy in two phase ½ clinical trials for the treatment of primary and secondary brain tumors in humans. In the present study, we have investigated the brain uptake of a new chemical entity formed by conjugation of the peptide Angiopep-2 (An2) with 3 molecules of the anti-cancer drug doxorubicin. Despite the clinical effectiveness of doxorubicin in the treatment of many malignant tumors, clinical trials involving systemic administration have demonstrated very limited efficacy in the treatment of gliomas. This limited efficacy can be explained by the poor penetration of the drug thru the BBB and by the effect of the multidrug resistance pump, P-gp. Here, we show by mice in-situ brain perfusion that the ANG-doxorubicin (ANG1007) is transported very efficiently across the BBB. The transport rate is higher than that of unconjugated doxorubicin by at least 10-fold. In vitro, ANG1007 inhibits cancer cell proliferation, with highly cytotoxic activities against various tumor cell lines. In addition, brain perfusion studies performed with P-gp knock-out mice showed that ANG1007 bypasses the drug efflux pump P-gp at the BBB. Furthermore, ANG1007 inhibits growth of glioblastoma s.c. tumors and increases survival of mice implanted with brain tumors. In conclusion, these data confirm that conjugation of chemotherapeutic drugs such as doxorubicin to the peptide Angiopep-2 significantly enhances their entry into the brain and further validate the use of Angiochem's technology for new brain tumor therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract