title: Anti-angiogenic potential of VEGF blocker dendron loaded on to gellan gum hydrogels for tissue engineering applications.
abstract: Damage of non-vascularised tissues such as cartilage and cornea can result in healing processes accompanied by a non-physiological angiogenesis. Peptidic aptamers have recently been reported to block the vascular endothelial growth factor (VEGF). However, the therapeutic applications of these aptamers are limited due to their short half-life in vivo. In this work, an enhanced stability and bioavailability of a known VEGF blocker aptamer sequence (WHLPFKC) was pursued through its tethering of molecular scaffolds based on hyperbranched peptides, the poly(ɛ-lysine) dendrons, bearing three branching generations. The proposed design allowed simultaneous and orderly-spaced exposure of 16 aptamers per dendrimer to the surrounding biological microenvironent, as well as a relatively hydrophobic core based on di-phenylalanine aiming to promote an hydrophobic interaction with the hydrophobic moieties of ionically crosslinked methacrylated gellan gum (iGG-MA) hydrogels. The VEGF blocker dendrons were entrapped in iGG-MA hydrogels, and their capacity to prevent endothelial cell sprouting was assessed qualitatively and quantitatively using 3D in vitro models and the in vivo chick chorioallantoic membrane assay. The data demonstrate that at nanoscale concentrations, the dendronised structures were able to enhance control of the biological actvity of WHLPFKC at the material/tissue interface and hence the anti-angiogenic capacity of iGG-MA hydrogels not only preventing blood vessel invasion, but also inducing their regression at the tissue/iGG-MA interface. The in ovo study confirmed that iGG-MA functionalised with the dendron VEGF blockers do inhibit angiogenesis by controlling both size and ramifications of blood vessels in the proximity of the implanted gel surface. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Brighton Studies in Tissue-mimicry and Aided Regeneration, Brighton Centre for Regenerative Medicine, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, Huxely Building Lewes Road, UK.
authors.forename: Valeria
authors.initials: V
authors.lastname: Perugini
authors.affiliation: Brighton Studies in Tissue-mimicry and Aided Regeneration, Brighton Centre for Regenerative Medicine, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, Huxely Building Lewes Road, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Guildford
authors.affiliation: 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Silva-Correia
authors.affiliation: 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Joaquim M
authors.initials: JM
authors.lastname: Oliveira
authors.affiliation: Brighton Studies in Tissue-mimicry and Aided Regeneration, Brighton Centre for Regenerative Medicine, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, Huxely Building Lewes Road, UK.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Meikle
authors.affiliation: 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Rui L
authors.initials: RL
authors.lastname: Reis
authors.affiliation: Brighton Studies in Tissue-mimicry and Aided Regeneration, Brighton Centre for Regenerative Medicine, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, Huxely Building Lewes Road, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santin
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020100:Hydrogels / Q000494:pharmacology*; D008689:Methacrylates / Q000494:pharmacology; D055806:Microvessels / Q000000981:diagnostic imaging / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011135:Polysaccharides, Bacterial / Q000494:pharmacology*; D023822:Tissue Engineering / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000873:Anthracenes; D003432:Cross-Linking Reagents; D020100:Hydrogels; D008689:Methacrylates; D011135:Polysaccharides, Bacterial; D042461:Vascular Endothelial Growth Factor A; C501244:dendron; C048288:gellan gum
keywords: angiogenesis; anti-angiogenesis peptide; dendron; gellan gum; tissue regeneration; vascular endothelial growth factor