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    Unraveling the role of beta 1 integrin isoforms in cRGD-mediated uptake of nanoparticles bearing hydrophilized alkyne moieties in epithelial and endothelial cells

    Year: 2020

    Journal: Acta Biomater., Volume 116, OCT 15, page 344–355

    Authors: Zhang, Weihai; Teske, Nele; Samadi, Mariam; Sarem, Melika; Shastri, V. Prasad

    Organizations: China Scholarship CouncilChina Scholarship Council; Excellence Initiative of The German Federal Government [EXC 294]; Excellence Initiative of The German State Government [EXC 294]

    Keywords: Integrin beta 1; Cyclic-RGD; Click chemistry; Caveolae; Endothelial cells; Epithelial cells

    The uptake and trafficking of NPs is impacted by several attributes such as size, shape, surface charge and importantly by surface ligands that can interact with the cell plasma membrane. We envision that NPs which can be readily modified in aqueous environments will be key to engineering patient-specific nanotherapeutics. Towards such systems that can be functionalized "on demand" in aqueous environments, an alpha-omega epoxy ester monomer that bears an alkyne group at the end of an oligoethylene glycol moiety was designed and synthesized. Copolymerization of this monomer with epsilon-caprolactone yielded polymers that present hydrophilized alkyne groups along the backbone. This enabled the direct modification of the surface of NPs, as suspensions in aqueous phase, with cell interaction peptides such cyclicarginine-glycine-aspartic acid (cRGD) using the "click reaction". Uptake of cRGD modified NPs (cRGD-NPs) in human endothelial and tumor epithelial cells revealed that cRGD surprisingly diminished uptake in both tumor epithelial and microvascular endothelial cells by 40-50 percent in comparison to unmodified particles. Probing the mechanism of uptake revealed that the expression pattern of two isoforms of beta(1) integrin impacted the uptake of cRGD-NPs differently. While the expression of high molecular weight 140 kDa form of the beta(1) integrin enhanced NP uptake, the expression of low molecular 120 kDa form had an inhibitory effect. Furthermore, although, the expression of beta(3) integrin was enhanced in endothelial cells and breast cancer epithelial cells, no correlation between beta(3) integrin and NP uptake was observed. Additionally, in presence of clathrin and caveolae pathway inhibitors the uptake of cRGD-NPS was in general diminished with a 25-75% decrease in presence of Filipin, a caveolae inhibitor; suggesting a role for lipid rafts in the beta(1) integrin-mediated uptake of cRGD-NP NPs. In sum, the polymer system described can be readily adapted to engineer other targeting peptide-based nanotherapeutics, especially for the delivery across difficult penetrate biological barriers such as the blood brain barrier. The main findings of this study have significant implication for the development of integrin targeted nanotherapeutics for anti-tumor therapy. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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