The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood-brain barrier cells

M. L. Pinzõn-Daza; R. Garzõn; P. O. Couraud; I. Romero; B. Weksler; D. Ghigo; A. Bosia; C. Riganti

doi:10.1111/j.1476-5381.2012.02103.x

The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood-brain barrier cells

Título traducido de la contribución: La asociación de estatinas más doxorrubicina encapsulada en liposomas dirigidos al receptor LDL aumenta la liberación in vitro del fármaco a través de las células de la barrera hematoencefálica

M. L. Pinzõn-Daza
, R. Garzõn
, P. O. Couraud
, I. Romero
, B. Weksler
, D. Ghigo
, A. Bosia
, C. Riganti

Escuela de Medicina y Ciencias de la Salud

Producción científica: Contribución a revista › Artículo de Investigación › revisión exhaustiva

84 Citas (Scopus)

Resumen

ANTECEDENTES Y OBJETIVO: El paso de fármacos a través de la barrera hematoencefálica (BHE) limita la eficacia de la quimioterapia en tumores cerebrales. Por ejemplo, el fármaco anticanceroso doxorrubicina, eficaz contra el glioblastoma in vitro, tiene escasa eficacia in vivo, porque es extruido por la glicoproteína P (Pgp/ABCB1), las proteínas relacionadas con la resistencia a múltiples fármacos y la proteína de resistencia al cáncer de mama (BCRP/ABCG2) en las células de la BBB. El objetivo de este estudio era convertir fármacos poco permeables como la doxorrubicina en fármacos capaces de atravesar la BBB.

MÉTODO EXPERIMENTAL: Los experimentos se realizaron en células endoteliales microvasculares cerebrales humanas primarias hCMEC/D3, solas y en co-cultivo con células tumorales epiteliales y cerebrales humanas.

RESULTADOS CLAVE: Las estatinas redujeron la actividad de eflujo de Pgp/ABCB1 y BCRP/ABCG2 en células hCMEC/D3 al aumentar la síntesis de NO, que provoca la nitración de residuos de tirosina críticos en estos transportadores. Las estatinas también aumentaron el número de receptores de lipoproteínas de baja densidad (LDL) expuestos en la superficie de las células BBB, así como en células tumorales como el glioblastoma humano. Demostramos que la asociación de estatinas y nanopartículas cargadas de fármacos diseñadas como LDL era eficaz como vehículo para que fármacos no permeantes como la doxorrubicina atravesaran la BBB, permitiendo su administración en células tumorales cerebrales primarias y metastásicas y logrando una citotoxicidad antitumoral significativa.

CONCLUSIONES E IMPLICACIONES: Sugerimos que nuestro enfoque de «caballo de Troya», basado en la administración de estatinas más un fármaco liposomal dirigido al receptor de LDL, podría tener aplicaciones potenciales en la terapia farmacológica de diferentes enfermedades cerebrales para las que la BBB representa un obstáculo.

Título traducido de la contribución	La asociación de estatinas más doxorrubicina encapsulada en liposomas dirigidos al receptor LDL aumenta la liberación in vitro del fármaco a través de las células de la barrera hematoencefálica
Idioma original	Inglés estadounidense
Páginas (desde-hasta)	1431-1447
Número de páginas	16
Publicación	British Journal of Pharmacology
Volumen	167
N.º	7
DOI	https://doi.org/10.1111/j.1476-5381.2012.02103.x
Estado	Publicada - jul. 12 2012

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

ODS 3: Salud y bienestar

Áreas temáticas de ASJC Scopus

Medicina General
Farmacología

Acceder al documento

10.1111/j.1476-5381.2012.02103.x

Huella

Profundice en los temas de investigación de 'La asociación de estatinas más doxorrubicina encapsulada en liposomas dirigidos al receptor LDL aumenta la liberación in vitro del fármaco a través de las células de la barrera hematoencefálica'. En conjunto forman una huella única.

Citar esto

Pinzõn-Daza, M. L., Garzõn, R., Couraud, P. O., Romero, I., Weksler, B., Ghigo, D., Bosia, A., & Riganti, C. (2012). The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood-brain barrier cells. British Journal of Pharmacology, 167(7), 1431-1447. https://doi.org/10.1111/j.1476-5381.2012.02103.x

@article{57105abb12864eab8ddd65a215667af3,

title = "The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood-brain barrier cells",

abstract = "BACKGROUND AND PURPOSE: The passage of drugs across the blood-brain barrier (BBB) limits the efficacy of chemotherapy in brain tumours. For instance, the anticancer drug doxorubicin, which is effective against glioblastoma in vitro, has poor efficacy in vivo, because it is extruded by P-glycoprotein (Pgp/ABCB1), multidrug resistance-related proteins and breast cancer resistance protein (BCRP/ABCG2) in BBB cells. The aim of this study was to convert poorly permeant drugs like doxorubicin into drugs able to cross the BBB.EXPERIMENTAL APPROACH: Experiments were performed on primary human cerebral microvascular endothelial hCMEC/D3 cells, alone and co-cultured with human brain and epithelial tumour cells.KEY RESULTS: Statins reduced the efflux activity of Pgp/ABCB1 and BCRP/ABCG2 in hCMEC/D3 cells by increasing the synthesis of NO, which elicits the nitration of critical tyrosine residues on these transporters. Statins also increased the number of low-density lipoprotein (LDL) receptors exposed on the surface of BBB cells, as well as on tumour cells like human glioblastoma. We showed that the association of statins plus drug-loaded nanoparticles engineered as LDLs was effective as a vehicle for non-permeant drugs like doxorubicin to cross the BBB, allowing its delivery into primary and metastatic brain tumour cells and to achieve significant anti-tumour cytotoxicity.CONCLUSIONS AND IMPLICATIONS: We suggest that our 'Trojan horse' approach, based on the administration of statins plus a LDL receptor-targeted liposomal drug, might have potential applications in the pharmacological therapy of different brain diseases for which the BBB represents an obstacle.",

author = "Pinz{\~o}n-Daza, \{M. L.\} and R. Garz{\~o}n and Couraud, \{P. O.\} and I. Romero and B. Weksler and D. Ghigo and A. Bosia and C. Riganti",

note = "{\textcopyright} 2012 The Authors. British Journal of Pharmacology {\textcopyright} 2012 The British Pharmacological Society.",

year = "2012",

month = jul,

day = "12",

doi = "10.1111/j.1476-5381.2012.02103.x",

language = "English (US)",

volume = "167",

pages = "1431--1447",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John Wiley and Sons Inc.",

number = "7",

}

Pinzõn-Daza, ML, Garzõn, R, Couraud, PO, Romero, I, Weksler, B, Ghigo, D, Bosia, A & Riganti, C 2012, 'The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood-brain barrier cells', British Journal of Pharmacology, vol. 167, n.º 7, pp. 1431-1447. https://doi.org/10.1111/j.1476-5381.2012.02103.x

The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood-brain barrier cells. / Pinzõn-Daza, M. L.; Garzõn, R.; Couraud, P. O. et al.
En: British Journal of Pharmacology, Vol. 167, N.º 7, 12.07.2012, p. 1431-1447.

Producción científica: Contribución a revista › Artículo de Investigación › revisión exhaustiva

TY - JOUR

T1 - The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood-brain barrier cells

AU - Pinzõn-Daza, M. L.

AU - Garzõn, R.

AU - Couraud, P. O.

AU - Romero, I.

AU - Weksler, B.

AU - Ghigo, D.

AU - Bosia, A.

AU - Riganti, C.

PY - 2012/7/12

Y1 - 2012/7/12

N2 - BACKGROUND AND PURPOSE: The passage of drugs across the blood-brain barrier (BBB) limits the efficacy of chemotherapy in brain tumours. For instance, the anticancer drug doxorubicin, which is effective against glioblastoma in vitro, has poor efficacy in vivo, because it is extruded by P-glycoprotein (Pgp/ABCB1), multidrug resistance-related proteins and breast cancer resistance protein (BCRP/ABCG2) in BBB cells. The aim of this study was to convert poorly permeant drugs like doxorubicin into drugs able to cross the BBB.EXPERIMENTAL APPROACH: Experiments were performed on primary human cerebral microvascular endothelial hCMEC/D3 cells, alone and co-cultured with human brain and epithelial tumour cells.KEY RESULTS: Statins reduced the efflux activity of Pgp/ABCB1 and BCRP/ABCG2 in hCMEC/D3 cells by increasing the synthesis of NO, which elicits the nitration of critical tyrosine residues on these transporters. Statins also increased the number of low-density lipoprotein (LDL) receptors exposed on the surface of BBB cells, as well as on tumour cells like human glioblastoma. We showed that the association of statins plus drug-loaded nanoparticles engineered as LDLs was effective as a vehicle for non-permeant drugs like doxorubicin to cross the BBB, allowing its delivery into primary and metastatic brain tumour cells and to achieve significant anti-tumour cytotoxicity.CONCLUSIONS AND IMPLICATIONS: We suggest that our 'Trojan horse' approach, based on the administration of statins plus a LDL receptor-targeted liposomal drug, might have potential applications in the pharmacological therapy of different brain diseases for which the BBB represents an obstacle.

AB - BACKGROUND AND PURPOSE: The passage of drugs across the blood-brain barrier (BBB) limits the efficacy of chemotherapy in brain tumours. For instance, the anticancer drug doxorubicin, which is effective against glioblastoma in vitro, has poor efficacy in vivo, because it is extruded by P-glycoprotein (Pgp/ABCB1), multidrug resistance-related proteins and breast cancer resistance protein (BCRP/ABCG2) in BBB cells. The aim of this study was to convert poorly permeant drugs like doxorubicin into drugs able to cross the BBB.EXPERIMENTAL APPROACH: Experiments were performed on primary human cerebral microvascular endothelial hCMEC/D3 cells, alone and co-cultured with human brain and epithelial tumour cells.KEY RESULTS: Statins reduced the efflux activity of Pgp/ABCB1 and BCRP/ABCG2 in hCMEC/D3 cells by increasing the synthesis of NO, which elicits the nitration of critical tyrosine residues on these transporters. Statins also increased the number of low-density lipoprotein (LDL) receptors exposed on the surface of BBB cells, as well as on tumour cells like human glioblastoma. We showed that the association of statins plus drug-loaded nanoparticles engineered as LDLs was effective as a vehicle for non-permeant drugs like doxorubicin to cross the BBB, allowing its delivery into primary and metastatic brain tumour cells and to achieve significant anti-tumour cytotoxicity.CONCLUSIONS AND IMPLICATIONS: We suggest that our 'Trojan horse' approach, based on the administration of statins plus a LDL receptor-targeted liposomal drug, might have potential applications in the pharmacological therapy of different brain diseases for which the BBB represents an obstacle.

U2 - 10.1111/j.1476-5381.2012.02103.x

DO - 10.1111/j.1476-5381.2012.02103.x

M3 - Research Article

C2 - 22788770

SN - 0007-1188

VL - 167

SP - 1431

EP - 1447

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 7

ER -