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.
In: Frontiers in Chemistry, 2021, 9
doi: 10.26083/tuprints-00019401
Artikel, Zweitveröffentlichung, Verlagsversion
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Kurzbeschreibung (Abstract)
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.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2021 |
| Autor(en): | Schneider, Hendrik ; Englert, Simon ; Macarrón Palacios, Arturo ; Lerma Romero, Jorge Alberto ; Ali, Ataurehman ; Avrutina, Olga ; Kolmar, Harald |
| Art des Eintrags: | Zweitveröffentlichung |
| Titel: | Synthetic Integrin-Targeting Dextran-Fc Hybrids Efficiently Inhibit Tumor Proliferation In Vitro |
| Sprache: | Englisch |
| Publikationsjahr: | 30 August 2021 |
| Ort: | Darmstadt |
| Publikationsdatum der Erstveröffentlichung: | 2021 |
| Verlag: | Frontiers |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Frontiers in Chemistry |
| Jahrgang/Volume einer Zeitschrift: | 9 |
| Kollation: | 11 Seiten |
| DOI: | 10.26083/tuprints-00019401 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/19401 |
| Zugehörige Links: | |
| Herkunft: | Zweitveröffentlichung aus gefördertem Golden Open Access |
| Kurzbeschreibung (Abstract): | 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. |
| Status: | Verlagsversion |
| URN: | urn:nbn:de:tuda-tuprints-194014 |
| Zusätzliche Informationen: | Keywords: integrins, RGD peptide, dextran, drug delivery and targeting, multimerization |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Organische Chemie |
| Hinterlegungsdatum: | 30 Aug 2021 12:23 |
| Letzte Änderung: | 01 Aug 2024 09:31 |
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