Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib

Abstract

Overcoming the efflux mediated by ATP-binding cassette (ABC) transporters at the blood-brain barrier (BBB) remains a challenge for the delivery of small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib to the brain. Inhibition of ABCB1 and ABCG2 at the mouse BBB improved the BBB permeation of erlotinib but could not be achieved in humans. BBB disruption induced by focused ultrasound (FUS) was investigated as a strategy to overcome the efflux transport of erlotinib in vivo. In rats, FUS combined with microbubbles allowed for a large and spatially controlled disruption of the BBB in the left hemisphere. ABCB1/ABCG2 inhibition was performed using elacridar (10 mg/kg i.v). The brain kinetics of erlotinib was studied using 11 C-erlotinib Positron Emission Tomography (PET) imaging in 5 groups (n = 4-5 rats per group) including a baseline group, immediately after sonication (FUS), 48 h after FUS (FUS + 48 h), elacridar (ELA) and their combination (FUS + ELA). BBB integrity was assessed using the Evan's Blue (EB) extravasation test. Brain exposure to 11 C-erlotinib was measured as the area under the curve (AUC) of the brain kinetics (% injected dose (%ID) versus time (min)) in volumes corresponding to the disrupted (left) and the intact (right) hemispheres, respectively. EB extravasation highlighted BBB disruption in the left hemisphere of animals of the FUS and FUS + ELA groups but not in the control and ELA groups. EB extravasation was not observed 48 h after FUS suggesting recovery of BBB integrity. Compared with the control group (AUC Baseline = 1.4 ± 0.5%ID.min), physical BBB disruption did not impact the brain kinetics of 11 C-erlotinib in the left hemisphere (p > .05) either immediately (AUC FUS = 1.2 ± 0.1%ID.min) or 48 h after FUS (AUC FUS+48h = 1.1 ± 0.3%ID.min). Elacridar similarly increased 11 C-erlotinib brain exposure to the left hemisphere in the absence (AUC ELA = 2.2 ± 0.5%ID.min, p < .001) and in the presence of BBB disruption (AUC FUS+ELA = 2.1 ± 0.5%ID.min, p < .001). AUC left was never significantly different from AUC right (p > .05), in any of the tested conditions. BBB integrity is not the rate limiting step for erlotinib delivery to the brain which is mainly governed by ABCmediated efflux. Efflux transport of erlotinib persisted despite BBB disruption. challenge for cancer research [3]. Improving the knowledge regarding the physiology of the BBB and how it controls brain permeation of anticancer drugs remains a critical need [4]. The BBB is created by the endothelial cells that form the walls of the brain microvessels [5]. The "physical barrier" component of the BBB results from tight junctions between adjacent endothelial cells [5]. This key feature of the BBB considerably reduces paracellular flux of solutes between the blood and the brain and forces most molecular traffic to

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

“…Sonodynamic therapy using the 5-aminolevulinic acid (5-ALA) has been combined with transcranial MRI-guided focused ultrasound (MRgFUS) and real-time MRI thermometry to monitor and optimize the therapy in a rat brain tumor model, achieving an improved survival time [422]. Nevertheless, in a recent study, physical BBB disruption provoked by MB-enhanced FUS did not impact the brain kinetics of 11 C-erlotinib, while elacridar did increased its brain penetration (with or without FUS), indicating that erlotinib delivery into the brain is governed by ABC transporters efflux and not by the physical integrity of the brain and suggesting that the selection of the chemotherapeutic for FUS is critical, as this strategy may not overcome the ABC-mediated efflux [273].…”

“…PET was recently employed to validate the permeability and transporter function of a human iPSCs BBB model [172] and the evaluation of ABC transporter-humanized mice models [238,270]. Importantly, it has been used to evaluate drug delivery strategies, such as inhibition [250,251] or focused ultrasounds [273] (see Section 6.5 for details).…”

“…Their use to overcome the BBB has also been evaluated in animals and humans (further explained in [41,57]). For instance, higher brain accumulation of erlotinib was observed when it was coadministered with elacridar to rats [273] and in a rat xenograft model of glioma [331]. In a clinical study on healthy volunteers, the penetration of 11 C-verapamil was enhanced when coadministered with cyclosporine A [262].…”

The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid

“…IL IIE+L BCRP), which are responsible for the efflux of many drugs, including TKIs [20]. However, research has proven that TKIs, such as lapatinib, erlotinib, gefitinib, afatinib, crizotinib, and alectinib, in combination with cytotoxic drugs or alone, are potent in reducing the development of CNS tumors [21][22][23][24][25][26]. Lapatinib is a substrate for P-gp and BCRP, which are abundantly expressed in the intestine, liver, kidney and BBB [27].…”

“…The inhibited transporters affect the absorption of TKIs in the intestine, their hepatic and renal excretion and penetration through the BBB. The expression levels and activity of P-gp and BCRP are strongly associated with the limited distribution of most TKIs to the BT [22]. Research has shown that brain accumulation of axitinib, cediranib and crizotinib depends mainly on ABCB1 activity, whereas the brain disposition of sorafenib is predominantly influenced by the ABCG2 protein [23].…”