title: Engineered peptides with enzymatically cleavable domains for controlling the release of model protein drug from "soft" nanoparticles.
abstract: Matrix metalloproteinase-2 (MMP-2) is an endopeptidase that has been shown to be present in high concentrations during most tissue remodeling events, including disease states like active tumor sites, thus making it an attractive molecule for use in effecting local delivery of therapeutic molecules. Moreover, the use of non-toxic and biodegradable nanoparticles for controlled drug delivery is highly sought after. To this end, bovine serum albumin (BSA) nanoparticles (NPs) were stabilized with coatings formed using domains of varying sensitivity to MMP-2, viz. K6GPQG/IASQK6 and K6HPVG/LLARK6, lysine residues being used to facilitate peptide immobilization to the BSA NPs via electrostatic interactions, and peptide domains that have a high (HPVG/LLAR) and low (GPQG/IASQ) MMP-2 cleavage rate. The MMP-2-induced cleavage rates of these two domains (the position of action being noted with a "/") have differing kinetics that can be used to provide a novel mechanism for facilitating the controlled release of molecules where local concentrations of MMP-2 are high. It was found that both surface concentration and cleavage domain type influenced the release of the model drug (BSA) from these NPs. This stratagem may provide a novel pathway for developing multi-functional coatings for controlling the local delivery of therapeutics at sites where the presence of various enzymes exist as a function of tissue state.
authors: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada T6G 2G6.
authors: Harsh Deep
authors: HD
authors: Singh
authors: Ibraheem
authors: I
authors: Bushnak
authors: Larry D
authors: LD
authors: Unsworth
mesh_terms: D000327:Adsorption / Q000187:drug effects; D000818:Animals; D002417:Cattle; D003692:Delayed-Action Preparations; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D015202:Protein Engineering / Q000379:methods*; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D055672:Static Electricity
chemical_list: D003692:Delayed-Action Preparations; D010455:Peptides; D012710:Serum Albumin, Bovine; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D016650:Fluorescein-5-isothiocyanate