Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib

J Cereb Blood Flow Metab. 2021 Jul;41(7):1634-1646. doi: 10.1177/0271678X20965500. Epub 2020 Oct 20.

Abstract

P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict at the blood-brain barrier (BBB) the brain distribution of the majority of currently known molecularly targeted anticancer drugs. To improve brain delivery of dual ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution of the model ABCB1/ABCG2 substrate [11C]erlotinib in mice and rhesus macaques with PET. Tolerability of the erlotinib/tariquidar combination was assessed in human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline brain distribution of [11C]erlotinib was low (brain distribution volume, VT,brain < 0.3 mL/cm3). Co-infusion of erlotinib and tariquidar increased VT,brain in mice by 3.0-fold and in macaques by 3.4- to 5.0-fold, while infusion of erlotinib alone or tariquidar alone led to less pronounced VT,brain increases in both species. Treatment of cerebral organoids with erlotinib/tariquidar led to an induction of Caspase-3-dependent apoptosis. Co-infusion of erlotinib/tariquidar may potentially allow for complete ABCB1/ABCG2 inhibition at the BBB, while simultaneously achieving brain-targeted EGFR inhibition. Our protocol may be applicable to enhance brain delivery of molecularly targeted anticancer drugs for a more effective treatment of brain tumors.

Keywords: Blood–brain barrier; P-glycoprotein; brain delivery; breast cancer resistance protein; transporter inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Carbon Radioisotopes / metabolism*
  • Cell Membrane Permeability
  • Drug Delivery Systems
  • Drug Therapy, Combination
  • Erlotinib Hydrochloride / administration & dosage
  • Erlotinib Hydrochloride / pharmacology*
  • Female
  • Human Embryonic Stem Cells / drug effects
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Macaca mulatta
  • Male
  • Mice
  • Neoplasm Proteins / antagonists & inhibitors*
  • Quinolines / pharmacology*

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antineoplastic Agents
  • Carbon Radioisotopes
  • Neoplasm Proteins
  • Quinolines
  • Erlotinib Hydrochloride
  • tariquidar