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Targeting angiogenic growth factors using therapeutic glycosaminoglycans on doppel-expressing endothelial cells for blocking angiogenic signaling in cancer

Authors
Zhang, XiaojunKarim, MazharulAlam, FarzanaAlqahtani, FalehReddy, Sireesha Y.Kim, In-SanAl-Hilal, Taslim A.Byun, YoungroChoi, Jeong UkHasan, Md MahediChung, Seung Woo
Issue Date
4월-2022
Publisher
ELSEVIER SCI LTD
Citation
BIOMATERIALS, v.283
Indexed
SCIE
SCOPUS
Journal Title
BIOMATERIALS
Volume
283
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/141860
DOI
10.1016/j.biomaterials.2022.121423
ISSN
0142-9612
Abstract
Growth factors (GF) regulate normal development to cancer progression. GFs interact with extracellular matrix (ECM) biomolecules, such as heparin sulfate (HS) glycosaminoglycan (GAG), to enhance their stability and angiogenic signaling. Biomaterials that modulate GF activity by mimicking interactions observed in the native ECM could be designed as an effective treatment strategy. However, these materials failed to attenuate angiogenic signaling site-specifically without sparing normal tissues. In this work, we investigated the effect of a GAG-based biomaterial, which binds to the tumor endothelial cells (TEC), on the interaction among vascular endothelial growth factor (VEGF), its receptors-VEGFR2 and HS-and angiogenesis. Heparin-bile acid based conjugates, as ECM-mimicking component, were synthesized to selectively target the TEC marker doppel and doppel/VEGFR2 axis. The most effective compound LHbisD4 (low molecular weight heparin conjugated with 4 molecules of dimeric dexocholic acid) reduced tumor volume concentrated over doppel-expressing EC, and decreased tumor-interstitial VEGF without affecting its plasma concentration. Doppel-destined LHbisD4 captured VEGF, formed an intermediate complex with doppel, VEGFR2, and VEGF but did not induce active VEGFR2 dimerization, and competitively inhibited HS for VEGF binding. We thus show that GAG-based materials can be designed to imitate and leverage to control tumor microenvironment via bio-inspired interactions.
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