Uptake of ANG1005, A Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer

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