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.
Highlights
The blood–brain barrier (BBB) is a major obstacle for drug delivery to the brain, limiting the number of drugs reaching the market to tackle brain disorders [1]
The in vitro BBB model consists of primary porcine brain endothelial cells (PBEC) co-cultured with rat astrocytes. functionalised multi-walled carbon nanotubes (f-MWNTs) were visualised within endocytic vesicles of PBECs and crossed the monolayer within 24 h
Studies have shown that ANG exhibited significantly greater transcytosis capacity across bovine brain endothelial cells compared to transferrin, lactoferrin and avidin [11]
Summary
The blood–brain barrier (BBB) is a major obstacle for drug delivery to the brain, limiting the number of drugs reaching the market to tackle brain disorders [1]. Nanoparticles (NPs), providing a flexible platform for conjugating drugs and targeting ligands, have been extensively researched to facilitate BBB crossing and effective delivery to the brain [2]. F-MWNTs injected directly into the brain led to a significant reduction in neuronal damage in rats [4], and led to improved motor function recovery in an Endothelin-1 rat stroke model via the successful delivery of caspase-3 siRNA to neurons in mouse brain cortex [5]. We demonstrated the ability of f-MWNTs to cross the BBB in vitro and in vivo [7]. The in vitro BBB model consists of primary porcine brain endothelial cells (PBEC) co-cultured with rat astrocytes. Following intravenous (i.v.) administration, radiolabelled f-MWNT was found to reach mouse brain without the use of a targeting ligand
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
