期刊
JOURNAL OF CONTROLLED RELEASE
卷 309, 期 -, 页码 94-105出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2019.07.026
关键词
Active targeting; Brain; Inflammation; Shape
资金
- Instituto de Salud Carlos III [PI13/00292, PI17/0054]
- Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS [RD12/0014]
- Fundacion Mutua Madrilena
- Ministry of Economy and Competitiveness of Spain [SAF2017-84267-R]
- European Regional Development Fund -ERDF, MADIA project [732678]
- Miguel Servet Program of Instituto de Salud Carlos III [CP14/00154]
- National Science Foundation Graduate Research Fellowship [DGE-1745303]
- University of California, Santa Barbara
- University of California
Endothelial cells represent the first biological barrier for compounds, including nanoparticles, administered via the intravascular route. In the case of ischemic stroke and other vascular diseases, the endothelium overexpresses specific markers, which can be used as molecular targets to facilitate drug delivery and imaging. However, targeting these markers can be quite challenging due to the presence of blood flow and the associated hydrodynamic forces, reducing the likelihood of adhesion to the vessel wall. To overcome these challenges, various parameters including size, shape, charge or ligand coating have been explored to increase the targeting efficiency. Geometric shape can modulate nanoparticle binding to the cell, especially by counteracting part of the hydrodynamic forces of the bloodstream encountered by the classical spherical shape. In this study, the binding affinity of polystyrene nanoparticles with two different shapes, spherical and rod-shaped, were compared. First, vascular adhesion molecule-1 (VCAM-1) was evaluated as a vascular target of inflammation, induced by lipopolysaccharide (LPS) stimulation. To evaluate the effect of nanoparticle shape on particle adhesion, nanoparticles were coated with anti-VCAM-1 and tested under static conditions in cell culture dishes coated with cerebral microvasculature cells (bEnd.3) and under dynamic flow conditions in microfluidic channels lined with hCMEC/D3 cells. Effect of particle shape on accumulation was also assessed in two in vivo models including systemic inflammation and local brain inflammation. The elongated rod-shaped particles demonstrated greater binding ability in vitro, reaching a 2.5-fold increase in the accumulation for static cultures and 1.5-fold for flow conditions. Anti-VCAM-1 coated rods exhibited a 3.5-fold increase in the brain accumulation compared to control rods. These results suggest shape offers a useful parameter in future design of drug delivery nanosystems or contrast agents for neurovascular pathologies.
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