AUTHOR=Sacchi Angelina , Gasparri Anna Maria , Monieri Matteo , Anderluzzi Giulia , Colombo Barbara , Gori Alessandro , Corti Angelo , Curnis Flavio 

TITLE=Nanogold Functionalized With Lipoamide-isoDGR: A Simple, Robust and Versatile Nanosystem for αvβ3-Integrin Targeting

JOURNAL=Frontiers in Chemistry

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2021.690357

DOI=10.3389/fchem.2021.690357

ISSN=2296-2646

ABSTRACT=<p>Gold nanoparticles functionalized with <italic>iso</italic>DGR, a tripeptide motif that recognizes αvβ3 integrin overexpressed in tumor vessels, have been used as nano-vectors for the delivery of cytokines to tumors. Functionalization of nanogold with this peptide has been achieved by coating nanoparticles with a peptide-albumin conjugate consisting of heterogeneous molecules with a variable number of linkers and peptides. To reduce nanodrug heterogeneity we have designed, produced and preclinically evaluated a homogeneous and well-defined reagent for nanogold functionalization, consisting of a head-to-tail cyclized CG<italic>iso</italic>DGRG peptide (<italic>iso1</italic>) coupled <italic>via</italic> its thiol group to maleimide-PEG<sub>11</sub>-lipoamide (LPA). The resulting <italic>iso1</italic>-PEG<sub>11</sub>-LPA compound can react with nanogold <italic>via</italic> lipoamide to form a stable bond. <italic>In vitro</italic> studies have shown that <italic>iso1</italic>, after coupling to nanogold, maintains its capability to bind purified αvβ3 and αvβ3-expressing cells. Nanogold functionalized with this peptide can also be loaded with bioactive tumor necrosis factor-α (TNF) to form a bi-functional nanodrug that can be stored for three days at 37°C or &gt;1 year at low temperatures with no loss αvβ3-binding properties and TNF-cytolytic activity. Nanoparticles functionalized with both <italic>iso1</italic> and TNF induced tumor eradication in WEHI-164 fibrosarcoma-bearing mice more efficiently than nanoparticles lacking the <italic>iso1</italic> targeting moiety. These results suggest that <italic>iso1</italic>-PEG<sub>11</sub>-LPA is an efficient and well-defined reagent that can be used to produce robust and more homogeneous nano-vectors for the delivery of TNF and other cytokines to αvβ3 positive cells.</p>