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
; 41(7): 1634-1646, 2021 07.
Article
en En
| MEDLINE
| ID: mdl-33081568
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Quinolinas
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Encéfalo
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Radioisótopos de Carbono
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Barrera Hematoencefálica
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Clorhidrato de Erlotinib
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2
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Proteínas de Neoplasias
Tipo de estudio:
Guideline
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Cereb Blood Flow Metab
Año:
2021
Tipo del documento:
Article
País de afiliación:
Francia