Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1

Laboratoire de Médecine Moléculaire, Chemistry Department, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, Canada.
British Journal of Cancer (Impact Factor: 4.84). 11/2011; 105(11):1697-707. DOI: 10.1038/bjc.2011.427
Source: PubMed


ANG1005 consists of three molecules of paclitaxel conjugated via ester bonds to the 19-amino-acid peptide Angiopep-2. The new chemical agent has been shown to cross the blood-brain barrier (BBB) by receptor-mediated transcytosis via low-density lipoprotein receptor-related protein 1 (LRP1). The experiments here examined the role of LRP1 in the subsequent endocytosis of drug into cancer cells.
Localisation of ANG1005 and Angiopep-2 was examined by immunohistochemistry and in-vivo near-infrared fluorescence imaging in mice carrying orthotopic glioma tumours. Transport of ANG1005 and Angiopep-2 was examined in U87 glioblastoma cell lines.
Systemically administered ANG1005 and Cy5.5Angiopep-2 localised to orthotopic glioma tumours in mice. The glioma transplants correlated with high expression levels of LRP1. Decreasing LRP1 activity, by RNA silencing or LRP1 competitors, decreased uptake of ANG1005 and Angiopep-2 into U87 glioblastoma cells. Conversely, LRP1 expression and endocytosis rates for ANG1005 and Angiopep-2 increased in U87 cells under conditions that mimicked the microenvironment near aggressive tumours, that is, hypoxic and acidic conditions.
ANG1005 might be a particularly effective chemotherapeutic agent for the wide array of known LRP1-expressing brain and non-brain cancers, in particular those with an aggressive phenotype.

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Available from: Danica Stanimirovic
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    • "uice for chemotherapeutic agents into the brain as BBB penetration is currently the Achilles ' heel in brain cancer therapies ( Jovčevska et al . , 2013 ) . Uptake of paclitaxel through the BBB followed by endocytosis into tumor cells was shown to be increased after conjugating the taxane paclitaxel to a 19 amino acid sequence named angiopep - 2 ( Bertrand et al . , 2011 ) . This peptide was derived from the Kunitz domain , a known ligand of LRP1 . A phase I clinical study showed that this conjugate ( GRN1005 ) is well tolerated ( Kurzrock et al . , 2012 ; Drappatz et al . , 2013 ) . Therapeutic concentrations could be reached in the tumor and three patients where prior taxane therapy was unsuccessful s"
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