title: Translocation of LRP1 targeted carbon nanotubes of different diameters across the blood-brain barrier in vitro and in vivo.
abstract: Brain glioblastoma and neurodegenerative diseases are still largely untreated due to the inability of most drugs to cross the blood-brain barrier (BBB). Nanoparticles have emerged as promising tools for drug delivery applications to the brain; in particular carbon nanotubes (CNTs) that have shown an intrinsic ability to cross the BBB in vitro and in vivo. Angiopep-2 (ANG), a ligand for the low-density lipoprotein receptor-related protein-1 (LRP1), has also shown promising results as a targeting ligand for brain delivery using nanoparticles (NPs). Here, we investigate the ability of ANG-targeted chemically-functionalised multi-walled carbon nanotubes (f-MWNTs) to cross the BBB in vitro and in vivo. ANG was conjugated to wide and thin f-MWNTs creating w-MWNT-ANG and t-MWNT-ANG, respectively. All f-MWNTs were radiolabelled to facilitate quantitative analyses by γ-scintigraphy. ANG conjugation to f-MWNTs enhanced BBB transport of w- and t-MWNTs-ANG compared to their non-targeted equivalents using an in vitro co-cultured BBB model consisting of primary porcine brain endothelial cells (PBEC) and primary rat astrocytes. Additionally, following intravenous administration w-MWNTs-ANG showed significantly higher whole brain uptake than the non-targeted w-MWNT in vivo reaching ~2% injected dose per g of brain (%ID/g) within the first hour post-injection. Furthermore, using a syngeneic glioma model, w-MWNT-ANG showed enhanced uptake in glioma brain compared to normal brain at 24h post-injection. t-MWNTs-ANG, on the other hand, showed higher brain accumulation than w-MWNTs. However, no significant differences were observed between t-MWNT and t-MWNT-ANG indicating the importance of f-MWNTs diameter towards their brain accumulation. The inherent brain accumulation ability of f-MWNTs coupled with improved brain-targeting by ANG favours the future clinical applications of f-MWNT-ANG to deliver active therapeutics for brain glioma therapy.
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Houmam
authors.initials: H
authors.lastname: Kafa
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Julie Tzu-Wen
authors.initials: JT
authors.lastname: Wang
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Noelia
authors.initials: N
authors.lastname: Rubio
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klippstein
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Costa
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Hatem A F M
authors.initials: HA
authors.lastname: Hassan
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Jane K
authors.initials: JK
authors.lastname: Sosabowski
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Sukhvinder S
authors.initials: SS
authors.lastname: Bansal
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Preston
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: N Joan
authors.initials: NJ
authors.lastname: Abbott
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. Electronic address: khuloud.al-jamal@kcl.ac.uk.
authors.forename: Khuloud T
authors.initials: KT
authors.lastname: Al-Jamal
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008810:Mice, Inbred C57BL; D037742:Nanotubes, Carbon / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000378:metabolism*; D013552:Swine; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C531860:Angiopep-2; D004337:Drug Carriers; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D037742:Nanotubes, Carbon; D010455:Peptides; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins
keywords: Angiopep-2; Brain delivery; Carbon nanotube; Nanomedicine; Targeting; Transcytosis
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