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Open AccessArticle

Endothelial Cell Targeting by cRGD-Functionalized Polymeric Nanoparticles under Static and Flow Conditions

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
CDL Research, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Hubrecht Imaging Center, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
Division of Cell Biology, Neurobiology and Biophysics, Department of Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
Author to whom correspondence should be addressed.
Nanomaterials 2020, 10(7), 1353;
Received: 2 June 2020 / Revised: 30 June 2020 / Accepted: 7 July 2020 / Published: 10 July 2020
(This article belongs to the Special Issue Nanomaterials for Biomedical Applications)
Since αvβ3 integrin is a key component of angiogenesis in health and disease, Arg-Gly-Asp (RGD) peptide-functionalized nanocarriers have been investigated as vehicles for targeted delivery of drugs to the αvβ3 integrin-overexpressing neovasculature of tumors. In this work, PEGylated nanoparticles (NPs) based on poly(lactic-co-glycolic acid) (PLGA) functionalized with cyclic-RGD (cRGD), were evaluated as nanocarriers for the targeting of angiogenic endothelium. For this purpose, NPs (~300 nm) functionalized with cRGD with different surface densities were prepared by maleimide-thiol chemistry and their interactions with human umbilical vein endothelial cells (HUVECs) were evaluated under different conditions using flow cytometry and microscopy. The cell association of cRGD-NPs under static conditions was time-, concentration- and cRGD density-dependent. The interactions between HUVECs and cRGD-NPs dispersed in cell culture medium under flow conditions were also time- and cRGD density-dependent. When washed red blood cells (RBCs) were added to the medium, a 3 to 8-fold increase in NPs association to HUVECs was observed. Moreover, experiments conducted under flow in the presence of RBC at physiologic hematocrit and shear rate, are a step forward in the prediction of in vivo cell–particle association. This approach has the potential to assist development and high-throughput screening of new endothelium-targeted nanocarriers. View Full-Text
Keywords: nanoparticles; endothelial cells; RGD; targeting; physiological flow; PLGA nanoparticles; endothelial cells; RGD; targeting; physiological flow; PLGA
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Martínez-Jothar, L.; Barendrecht, A.D.; de Graaff, A.M.; Oliveira, S.; van Nostrum, C.F.; Schiffelers, R.M.; Hennink, W.E.; Fens, M.H.A.M. Endothelial Cell Targeting by cRGD-Functionalized Polymeric Nanoparticles under Static and Flow Conditions. Nanomaterials 2020, 10, 1353.

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