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.
|Publication status||Published - 2022 Apr|
Bibliographical noteFunding Information:
This study was supported by National Research Foundation (NRF) funded by the Korean Government Ministry of Science and ICT . (Grant no. 2020R1A2C2015026 and 2016M3A9B5941836 ). The work was also supported by the Start-up Package from the School of Pharmacy UTEP, TTUHSC-UTEP Seed Grant mechanism, and the Cancer Prevention and Research Institute of Texas: RP210153. The authors extend their appreciation to the Distinguished Scientist Fellowship program at King Saud University , Riyadh, Saudi Arabia, for funding this work through research support project number ( RSP-2021/131 ).
© 2022 Elsevier Ltd
ASJC Scopus subject areas
- Ceramics and Composites
- Mechanics of Materials