title: Protease degradable tethers for controlled and cell-mediated release of nanoparticles in 2- and 3-dimensions.
abstract: Strategies to control the release rate of bioactive signals from tissue engineering scaffolds are essential for tissue regeneration and tissue engineering applications. Here we report on a strategy to achieve temporal control over nanoparticle release from biomaterials using cell-secreted proteases. This cell-triggered release approach utilizes peptides that are degraded by matrix metalloproteinases (MMPs) at different rates to immobilize nanoparticles directly to the biomaterial surface. Thus, the peptide-immobilized nanoparticles are released with temporal control through the action of cell-released MMPs. We found that release rates of peptide-immobilized nanoparticles were a function of peptide sensitivity to proteases, the number of tethers between the nanoparticle and the surface and the concentration of proteases used to induce release. Cellular internalization of the peptide-immobilized nanoparticles was also a function of the peptide sensitivity to proteases, the number of tethers between the nanoparticle and the surface and MMP expression profile of the cells. Similar trends were observed for peptide-immobilized nanoparticles inside micro-porous hydrogels, indicating protease sensitive tethers are effective in controlling release rate and internalization of nanoparticles. Such a temporal delivery strategy of nanoparticles loaded with therapeutic payloads (e.g. protein, DNA, siRNA) can be an ideal means to guide tissue formation.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095-1592, USA.
authors.forename: Talar
authors.initials: T
authors.lastname: Tokatlian
authors.forename: Chadwick T
authors.initials: CT
authors.lastname: Shrum
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kadoya
authors.forename: Tatiana
authors.initials: T
authors.lastname: Segura
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D020100:Hydrogels / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology; D019904:Polymethyl Methacrylate / Q000494:pharmacology; D016062:Porosity / Q000187:drug effects; D013455:Sulfur / Q000032:analysis; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D020100:Hydrogels; D010455:Peptides; D011092:Polyethylene Glycols; D013455:Sulfur; D019904:Polymethyl Methacrylate; D010447:Peptide Hydrolases