Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep‐2
A Regina, M Demeule, C Che, I Lavallee… - British journal of …, 2008 - Wiley Online Library
A Regina, M Demeule, C Che, I Lavallee, J Poirier, R Gabathuler, R Béliveau, JP Castaigne
British journal of pharmacology, 2008•Wiley Online LibraryBackground and purpose: Paclitaxel is highly efficacious in the treatment of breast, head
and neck, non‐small cell lung cancers and ovarian carcinoma. For malignant gliomas,
paclitaxel is prevented from reaching its target by the presence of the efflux pump P‐
glycoprotein (P‐gp) at the blood–brain barrier. We investigated the utilization of a new drug
delivery system to increase brain delivery of paclitaxel. Experimental approach: Paclitaxel
molecules were conjugated to a brain peptide vector, Angiopep‐2, to provide a paclitaxel …
and neck, non‐small cell lung cancers and ovarian carcinoma. For malignant gliomas,
paclitaxel is prevented from reaching its target by the presence of the efflux pump P‐
glycoprotein (P‐gp) at the blood–brain barrier. We investigated the utilization of a new drug
delivery system to increase brain delivery of paclitaxel. Experimental approach: Paclitaxel
molecules were conjugated to a brain peptide vector, Angiopep‐2, to provide a paclitaxel …
Background and purpose
Paclitaxel is highly efficacious in the treatment of breast, head and neck, non‐small cell lung cancers and ovarian carcinoma. For malignant gliomas, paclitaxel is prevented from reaching its target by the presence of the efflux pump P‐glycoprotein (P‐gp) at the blood–brain barrier. We investigated the utilization of a new drug delivery system to increase brain delivery of paclitaxel.
Experimental approach
Paclitaxel molecules were conjugated to a brain peptide vector, Angiopep‐2, to provide a paclitaxel–Angiopep‐2 conjugate named ANG1005. We determined the brain uptake capacity, intracellular effects and antitumour properties of ANG1005 in vitro against human tumour cell lines and in vivo in human xenografts. We then determined ANG1005 activity on brain tumours with intracerebral human tumour models in nude mice.
Key results
We show by in situ brain perfusion that ANG1005 enters the brain to a greater extent than paclitaxel and bypasses the P‐gp. ANG1005 has an antineoplastic potency similar to that of paclitaxel against human cancer cell lines. We also demonstrate that ANG1005 caused a more potent inhibition of human tumour xenografts than paclitaxel. Finally, ANG1005 administration led to a significant increase in the survival of mice with intracerebral implantation of U87 MG glioblastoma cells or NCI‐H460 lung carcinoma cells.
Conclusions and implications
These results demonstrate the antitumour potential of a new drug, ANG1005, and establish that conjugation of anticancer agents with the Angiopep‐2 peptide vector could increase their efficacy in the treatment of brain cancer.
British Journal of Pharmacology (2008) 155, 185–197; doi:fn1; published online 23 June 2008
Wiley Online Library