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

Background and PurposeThe 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 (...

Full description

Autores:
Tipo de recurso:
Fecha de publicación:
2012
Institución:
Universidad del Rosario
Repositorio:
Repositorio EdocUR - U. Rosario
Idioma:
eng
OAI Identifier:
oai:repository.urosario.edu.co:10336/23615
Acceso en línea:
https://doi.org/10.1111/j.1476-5381.2012.02103.x
https://repository.urosario.edu.co/handle/10336/23615
Palabra clave:
Breast cancer resistance protein
Compactin
Doxorubicin
Immunoglobulin enhancer binding protein
Low density lipoprotein receptor
Multidrug resistance protein
Nanoparticle
Nitric oxide
Rho kinase
Rhoa guanine nucleotide binding protein
Rhoa kinase
Simvastatin
Unclassified drug
Article
Blood brain barrier
Brain cell
Controlled study
Drug cytotoxicity
Drug dosage form comparison
Drug efficacy
Drug mechanism
Drug penetration
Drug potentiation
Drug receptor binding
Drug transport
Enzyme activity
Glioblastoma
Human
Human cell
In vitro study
Liposomal delivery
Microvascular endothelial cell
Priority journal
Protein expression
Tumor cell line
Atp-binding cassette transporters
Blood-brain barrier
Cell line
Doxorubicin
Humans
Hydroxymethylglutaryl-coa reductase inhibitors
Liposomes
Lovastatin
Nf-kappa b
Nitric oxide synthase
Nitrites
Rho-associated kinases
Rhoa gtp-binding protein
Simvastatin
Atp-binding cassette transporters
Blood-brain barrier
Central nervous system tumours
Doxorubicin
Liposomes
Low-density lipoproteins receptor
Nitric oxide
Statins
ldl
tumor
Cell line
Receptors
Rights
License
Abierto (Texto Completo)
Description
Summary:Background and PurposeThe 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 ApproachExperiments were performed on primary human cerebral microvascular endothelial hCMEC/D3 cells, alone and co-cultured with human brain and epithelial tumour cells. Key ResultsStatins 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 ImplicationsWe 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. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.