ABSTRACT
Intimal hyperplasia, a vascular pathology characterized by vessel wall thickening, is implicated in vein graft failures. For efficient prevention, a biodegradable drug delivery system should be applied externally to the graft for an extended time. Finding a gel suitable for such a system is challenging. We have synthesized HA-Dopamine conjugates (HA-Dop) with several degrees of substitution (DS) and used two crosslinking methods: initiator-free crosslinking by basic pH shift or commonly used crosslinking by a strong oxidizer, sodium periodate. The rheological properties, bioadhesion to vascular tissue, cytocompatibility with fibroblasts have been compared for both methods. Our results suggest that initiator-free crosslinking provides HA-Dop gels with more adequate properties with regards to vascular application than crosslinking by strong oxidizer. We have also established the cytocompatibility of the initiator-free crosslinked HA-Dop gels and the cytotoxicity of dopamine-sodium periodate combinations. Furthermore, we have incorporated a drug with anti-restenotic effect in perivascular application, atorvastatin, into the gel, which showed adequate release profile for intimal hyperplasia prevention. The oxidizer-free formulation with improved bioadhesion holds promise as an efficient and safe drug delivery system for vascular applications.
Subject(s)
Hyaluronic Acid , Hydrogels , Biocompatible Materials/chemistry , Cross-Linking Reagents/chemistry , Dopamine/pharmacology , Humans , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Hydrogels/chemistry , Hydrogels/pharmacology , HyperplasiaABSTRACT
The straightforward access to octafunctional "cubic" silsesquioxane platform grafter with pendant glyoxylic aldehydes is described. This clickable hybrid platform readily reacts with oxyamine or hydrazide compounds to provide, respectively, oxime and acylhydrazone conjugates, thereby offering a new and effective access from which one can elaborate multivalent systems for the targeting of biomolecules of interest.
Subject(s)
Aldehydes/chemistry , Organosilicon Compounds/chemistry , Hydrazones/chemistry , Magnetic Resonance Spectroscopy , Organosilicon Compounds/chemical synthesis , Oximes/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
Multivalency has impressive effects on (bio)molecular recognition, through the simultaneous presentation of multiple copies of a ligand, which can change a weak millimolar binder into a potent nanomolar one. The implementation of multivalency in enzyme inhibition is rather recent, being exemplified by few serendipitous discoveries, and hitherto relying on the random exploration of new multivalent structures as potential enzyme inhibitors. Here, a straightforward and versatile method is reported that enables the construction of multivalent systems for the inhibition of carbonic anhydrases (CA), widespread enzymes that catalyze a fundamental biochemical reaction. Oxime and hydrazone click-type bioconjugation techniques were successfully used for the preparation of tetravalent peptide conjugates tethered with sulfonamide CA inhibitors. The enzyme inhibition assays show that multivalent effects were present with these novel compounds, but also reveal various structural effects provided by the scaffolds. The versatility of this approach may facilitate the exploration of structure-activity relationships for other types of enzyme inhibitors.
Subject(s)
Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrases/metabolism , Peptides/chemistry , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/chemistry , Hydrazones/chemistry , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Oximes/chemistry , Structure-Activity RelationshipABSTRACT
Multivalent nanoconstructs, extensively used for enhancing the recognition of biomolecular targets, have been recently exploited for enzyme inhibition showing interesting properties such as improvement of inhibitory potency and selectivity. We review herein the recent results highlighting the potential of multivalent nanoconstructs for the inhibition of different enzymes, and the emerging trends in the generation and identification of multivalent clusters as enzyme inhibitors.
Subject(s)
Drug Discovery/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Nanostructures/chemistry , Animals , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/chemistry , Carbonic Anhydrases/metabolism , Glycoside Hydrolases/antagonists & inhibitors , Glycoside Hydrolases/chemistry , Glycoside Hydrolases/metabolism , Humans , Models, MolecularABSTRACT
Invited for the cover of this issue are Jean-Yves Winum and co-workers at University of Montpellier (France) and University of Florence (Italy). The image depicts the multivalency approach applied to zinc metalloenzyme carbonic anhydrases. Read the full text of the article at 10.1002/chem.201501037.
ABSTRACT
Multifunctional silica nanoparticles decorated with fluorescent and sulfonamide carbonic anhydrase (CA) inhibitors were prepared and investigated as multivalent enzyme inhibitors against the cytosolic isoforms hCAâ I and II and the transmembrane tumor-associated ones hCAâ IX and XII. Excellent inhibitory effects were observed with these nanoparticles, with KI values in the low nanomolar range (6.2-0.67â nM) against all tested isozymes. A significant multivalency effect was seen for the inhibition of the monomeric enzymes hCAâ I and II compared to the dimeric hCAâ IX and hCAâ XII isoforms, where no multivalent effect was observed, suggesting that the multivalent binding is occurring through enzyme clustering.
