Feasibility Study of the Permeability and Uptake of Mesoporous Silica Nanoparticles across the Blood-Brain Barrier

PLoS One. 2016 Aug 22;11(8):e0160705. doi: 10.1371/journal.pone.0160705. eCollection 2016.

Abstract

Drug delivery into the brain is impeded by the blood-brain-barrier (BBB) that filters out the vast majority of drugs after systemic administration. In this work, we assessed the transport, uptake and cytotoxicity of promising drug nanocarriers, mesoporous silica nanoparticles (MSNs), in in vitro models of the BBB. RBE4 rat brain endothelial cells and Madin-Darby canine kidney epithelial cells, strain II, were used as BBB models. We studied spherical and rod-shaped MSNs with the following modifications: bare MSNs and MSNs coated with a poly(ethylene glycol)-poly(ethylene imine) (PEG-PEI) block copolymer. In transport studies, MSNs showed low permeability, whereas the results of the cellular uptake studies suggest robust uptake of PEG-PEI-coated MSNs. None of the MSNs showed significant toxic effects in the cell viability studies. While the shape effect was detectable but small, especially in the real-time surface plasmon resonance measurements, coating with PEG-PEI copolymers clearly facilitated the uptake of MSNs. Finally, we evaluated the in vivo detectability of one of the best candidates, i.e. the copolymer-coated rod-shaped MSNs, by two-photon in vivo imaging in the brain vasculature. The particles were clearly detectable after intravenous injection and caused no damage to the BBB. Thus, when properly designed, the uptake of MSNs could potentially be utilized for the delivery of drugs into the brain via transcellular transport.

MeSH terms

  • Animals
  • Biological Transport
  • Blood-Brain Barrier / metabolism*
  • Brain / blood supply
  • Brain / metabolism
  • Brain / ultrastructure
  • Cell Line
  • Cell Survival / drug effects
  • Dogs
  • Drug Carriers*
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Injections, Intravenous
  • Madin Darby Canine Kidney Cells
  • Mice
  • Microscopy, Fluorescence, Multiphoton
  • Models, Biological
  • Molecular Imaging
  • Nanoparticles / chemistry*
  • Nanoparticles / metabolism
  • Nanoparticles / ultrastructure
  • Particle Size
  • Permeability
  • Polyethylene Glycols / chemistry*
  • Polyethyleneimine / analogs & derivatives*
  • Polyethyleneimine / chemistry
  • Rats
  • Silicon Dioxide / chemistry*
  • Surface Plasmon Resonance

Substances

  • Drug Carriers
  • poly(ethylene glycol)-co-poly(ethyleneimine)
  • Polyethylene Glycols
  • Silicon Dioxide
  • Polyethyleneimine

Grant support

Funding for this research work was provided by the Academy of Finland project #140193: "Targeting of cancer cells by design - Nanoparticles as theranostic agents" (JR). Other supporting funding sources the authors acknowledge are Norwegian Research Council projects (Biotek2021 226159 and Nano2021 220005), Academy of Finland projects (#137101, #260599, #137053 and #263861) (CD), Center for Functional Materials (DSK) and Graduate School of Materials Research (AD). Neurotar LtD provided support in the form of salaries for authors EP and LK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.