The interaction of carbon nanotubes with an in vitro blood-brain barrier model and mouse brain in vivo

Houmam Kafa,Julie Tzu-Wen Wang,Noelia Rubio,Kerrie Venner,Glenn Anderson,Elzbieta Pach,Belén Ballesteros,Jane E Preston,N Joan Abbott,Khuloud T Al-Jamal

doi:10.1016/j.biomaterials.2015.02.083

Abstract

Carbon nanotubes (CNTs) are a novel nanocarriers with interesting physical and chemical properties. Here we investigate the ability of amino-functionalized multi-walled carbon nanotubes (MWNTs-NH3+) to cross the Blood-Brain Barrier (BBB) in vitro using a co-culture BBB model comprising primary porcine brain endothelial cells (PBEC) and primary rat astrocytes, and in vivo following a systemic administration of radiolabelled f-MWNTs. Transmission Electron microscopy (TEM) confirmed that MWNTs-NH3+ crossed the PBEC monolayer via energy-dependent transcytosis. MWNTs-NH3+ were observed within endocytic vesicles and multi-vesicular bodies after 4 and 24 h. A complete crossing of the in vitro BBB model was observed after 48 h, which was further confirmed by the presence of MWNTs-NH3+ within the astrocytes. MWNT-NH3+ that crossed the PBEC layer was quantitatively assessed using radioactive tracers. A maximum transport of 13.0 ± 1.1% after 72 h was achieved using the co-culture model. f-MWNT exhibited significant brain uptake (1.1 ± 0.3% injected dose/g) at 5 min after intravenous injection in mice, after whole body perfusion with heparinized saline. Capillary depletion confirmed presence of f-MWNT in both brain capillaries and parenchyma fractions. These results could pave the way for use of CNTs as nanocarriers for delivery of drugs and biologics to the brain, after systemic administration.

Highlights

Carbon nanotubes (CNT) are novel nanomaterial with attractive physical, chemical and electronic properties [1]
We investigate the ability of amino-functionalized multi-walled carbon nanotubes (MWNTs-NH3þ) to cross the Blood-Brain Barrier (BBB) in vitro using a co-culture BBB model comprising primary porcine brain endothelial cells (PBEC) and primary rat astrocytes, and in vivo following a systemic administration of radiolabelled f-MWNTs
MWNT-NH3þ started to decompose at a temperature lower than the decomposition temperature (750 C) of the pristine material, which indicated the conjugation of functional groups to the MWNTs

Summary

Introduction

Carbon nanotubes (CNT) are novel nanomaterial with attractive physical, chemical and electronic properties [1]. Nano-meshworks of single-walled carbon nanotubes (SWNTs) and MWNTs on glass slides have been shown to support neuronal growth and responsiveness of rat hippocampal neurones. CNTs have shown intrinsic therapeutic action in stroke prevention in vivo without carrying a. The data suggested that conjugating CpG to SWNTs significantly enhanced the delivery into tumour-associated inflammatory cells compared to the free CpG [6]. These studies highlight the importance of using CNTs with/without therapeutic cargo to reach targets in the brain and eradicate tumours. None of the mentioned studies used systemic administration where crossing the BBB may constitute a major obstacle to CNTs brain delivery

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