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Unraveling the role of β1 integrin isoforms in cRGD-mediated uptake of nanoparticles bearing hydrophilized alkyne moieties in epithelial and endothelial cells.

Abstract：

: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 α-ω 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 ε-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 cyclic-arginine-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 β1 integrin impacted the uptake of cRGD-NPs differently. While the expression of high molecular weight 140 kDa form of the β1 integrin enhanced NP uptake, the expression of low molecular 120 kDa form had an inhibitory effect. Furthermore, although, the expression of β3 integrin was enhanced in endothelial cells and breast cancer epithelial cells, no correlation between β3 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 β1 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.

journal_name

Acta Biomater

journal_title

Acta biomaterialia

authors

Zhang W,Teske N,Samadi M,Sarem M,Shastri VP

doi

10.1016/j.actbio.2020.08.038

subject

Has Abstract

pub_date

2020-10-15 00:00:00

pages

344-355

eissn

1742-7061

issn

1878-7568

pii

S1742-7061(20)30507-9

journal_volume

116

pub_type

杂志文章

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Unraveling the role of β1 integrin isoforms in cRGD-mediated uptake of nanoparticles bearing hydrophilized alkyne moieties in epithelial and endothelial cells.