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Pharm Res. 2009 Nov;26(11):2486-94. doi: 10.1007/s11095-009-9964-5. Epub 2009 Sep 23.

Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer.

Author information

1
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.

Abstract

PURPOSE:

We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport.

METHODS:

The transfer coefficient (K(in)) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer.

RESULTS:

The BBB K(in) for (125)I-ANG1005 uptake (7.3 +/- 0.2 x 10(-3) mL/s/g) exceeded that for (3)H-paclitaxel (8.5 +/- 0.5 x 10(-5)) by 86-fold. Over 70% of (125)I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain (125)I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of (125)I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of (14)C-paclitaxel by 4-54-fold.

CONCLUSIONS:

The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel.

PMID:
19774344
PMCID:
PMC2896053
DOI:
10.1007/s11095-009-9964-5
[Indexed for MEDLINE]
Free PMC Article

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