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Synthetic Integrin-Targeting Dextran-Fc Hybrids Efficiently Inhibit Tumor Proliferation In Vitro

Schneider, Hendrik ; Englert, Simon ; Macarrón Palacios, Arturo ; Lerma Romero, Jorge Alberto ; Ali, Ataurehman ; Avrutina, Olga ; Kolmar, Harald (2021):
Synthetic Integrin-Targeting Dextran-Fc Hybrids Efficiently Inhibit Tumor Proliferation In Vitro. (Publisher's Version)
In: Frontiers in Chemistry, 9, Frontiers, e-ISSN 2296-2646,
DOI: 10.26083/tuprints-00019401,

Copyright Information: CC BY 4.0 International - Creative Commons, Attribution.

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Item Type: Article
Origin: Secondary publication via sponsored Golden Open Access
Status: Publisher's Version
Title: Synthetic Integrin-Targeting Dextran-Fc Hybrids Efficiently Inhibit Tumor Proliferation In Vitro
Language: English

Herein, we present the design, synthesis, and biological evaluation of novel integrintargeting molecular hybrids combining RGD peptides and a potent cytotoxin presented on dextran polysaccharides. Based on an aglycosylated Fc as a centerpiece, endosomalcleavable cytotoxic agent monomethyl auristatin E (MMAE) and dextran as multimerization site were covalently connected by two bioorthogonal enzyme-mediated reactions sitespecifically. Decoration of dextran with cyclic RGD peptides, introduced by copper “click” reaction, resulted in the final constructs with the potential to kill integrin-overexpressing tumor cells. We found that these modifications had little impact on the stability of the Fc scaffold and the RGD-bearing construct showed good binding properties of αvβ3-expressing U87MG cells. Furthermore, the construct showed a remarkable antiproliferative activity. These results demonstrate the general capability of our design to provoke receptor-mediated endocytosis upon binding to the cellular surface, followed by endosomal cleavage of the linkage between Fc-dextran and MMAE and its subsequent release. Our approach opens new avenues to transcribe small molecule binders into tailormade multimeric molecular hybrids with antitumor potential.

Journal or Publication Title: Frontiers in Chemistry
Volume of the journal: 9
Place of Publication: Darmstadt
Publisher: Frontiers
Collation: 11 Seiten
Classification DDC: 500 Naturwissenschaften und Mathematik > 540 Chemie
Divisions: 07 Department of Chemistry > Fachgebiet Biochemie
Date Deposited: 30 Aug 2021 12:23
Last Modified: 24 Jun 2022 18:02
DOI: 10.26083/tuprints-00019401
Corresponding Links:
URN: urn:nbn:de:tuda-tuprints-194014
Additional Information:

Keywords: integrins, RGD peptide, dextran, drug delivery and targeting, multimerization

URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/19401
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