Ultrasound-induced delivery of erlotinib to the brain is not enough to counter efflux pumps

摘要

The tyrosine kinase inhibitor (TKI) erlotinib (Tarceva©) is an efficient therapy for patients with mutated epidermal growth factor receptor non-small-cell lung cancer. Unfortunately, the brain is a common site of progression and 40% of patients develop brain metastases. This may be explained by the low brain disposition of erlotinib, due to poor permeability across the blood-brain barrier (BBB). ATP-binding cassette efflux transporters at the BBB, the P-glycoprotein (ABCB1) and the Breast Cancer Resistance Protein (ABCG2), were shown to work in concert to restrict brain distribution of most TKIs, including erlotinib. Focused ultrasound (FUS) and microbubbles is a reliable technical approach to safely and temporarily overcome the “physical” properties of the BBB by loosening the tight junctions. Here, we hypothesized that opening the paracellular route using FUS may overcome the ABCB1/ABCG2-mediated efflux of erlotinib at the BBB.