Anti-DLL4 VNAR targeted nanoparticles for targeting of both tumour and tumour associated vasculature

Adam Leach, Peter Smyth, Laura Ferguson, John Steven, Michelle K. Greene, Cristina M. Branco, Aidan P. McCann, Andrew Porter, Caroline Jane Barelle* (Corresponding Author), Christopher J. Scott* (Corresponding Author)

*Corresponding author for this work

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Abstract

Whilst there is an extensive body of preclinical nanomedicine research, translation to clinical settings has been slow. Here we present a novel approach to the targeted nanoparticle (NP) concept: utilizing both a novel targeting ligand, VNAR (Variable New Antigen Receptor), a shark-derived single chain binding domain, and an under-investigated target in delta-like ligand 4 (DLL4). We describe the development of an anti-DLL4 VNAR and the site-specific conjugation of this to poly(lactic-co-glycolic) acid PEGylated NPs using surface maleimide functional groups. These nanoconjugates were shown to specifically bind DLL4 with high affinity and were preferentially internalized by DLL4-expressing pancreatic cancer cell lines and endothelial cells. Furthermore, a distinct anti-angiogenic effect endowed by the anti-DLL4 VNAR was evident in in vitro tubulogenic assays. Taken together these findings highlight the potential of anti-DLL4 targeted polymeric NPs as a novel therapeutic approach in pancreatic cancer.
Original languageEnglish
Pages (from-to)14751-14763
Number of pages13
JournalNanoscale
Volume12
Issue number27
Early online date29 Jun 2020
DOIs
Publication statusPublished - 21 Jul 2020

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    Leach, A., Smyth, P., Ferguson, L., Steven, J., Greene, M. K., Branco, C. M., McCann, A. P., Porter, A., Barelle, C. J., & Scott, C. J. (2020). Anti-DLL4 VNAR targeted nanoparticles for targeting of both tumour and tumour associated vasculature. Nanoscale, 12(27), 14751-14763. https://doi.org/10.1039/D0NR02962A