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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Laboratoire de Médecine Moléculaire, Chemistry Department, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, Canada.
Y
Y
Bertrand
J-C
JC
Currie
J
J
Poirier
M
M
Demeule
A
A
Abulrob
D
D
Fatehi
D
D
Stanimirovic
H
H
Sartelet
J-P
JP
Castaigne
R
R
Béliveau
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004705:Endocytosis; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000031:analogs & derivatives; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology; D010641:Phenotype; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C531860:Angiopep-2; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010455:Peptides; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C531859:paclitaxel-Angiopep-2 conjugate; D017239:Paclitaxel