title: Protein polymer hydrogels by in situ, rapid and reversible self-gelation.
abstract: Protein-based biomaterials are an important class of materials for applications in biotechnology and medicine. The exquisite control of their composition, stereochemistry, and chain length offers unique opportunities to engineer biofunctionality, biocompatibility, and biodegradability into these materials. Here, we report the synthesis of a thermally responsive peptide polymer-based hydrogel composed of a recombinant elastin-like polypeptide (ELP) that rapidly forms a reversibly cross-linked hydrogel by the formation of intermolecular disulfide cross-links. To do so, we designed and synthesized ELPs that incorporate periodic cysteine residues (cELPs), and show that cELPs are thermally responsive protein polymers that display rapid gelation under physiologically relevant, mild oxidative conditions. Gelation of cELPs, at concentrations as low as 2.5 wt%, occurs in ≈ 2.5 min upon addition a low concentration of hydrogen peroxide (0.3 wt%). We show the utility of these hydrogels for the sustained release of a model protein in vitro, and demonstrate the ability of this injectable biomaterial to pervade tumors to maximize tumor coverage and retention time upon intratumoral injection. cELPs represent a new class of injectable reversibly cross-linked hydrogels with properties intermediate between ELP coacervates and chemically cross-linked ELP hydrogels that will find useful applications in drug delivery and tissue engineering.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Asai
authors.forename: Donghua
authors.initials: D
authors.lastname: Xu
authors.forename: Wenge
authors.initials: W
authors.lastname: Liu
authors.forename: Felipe
authors.initials: F
authors.lastname: Garcia Quiroz
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Callahan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Craig
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chilkoti
mesh_terms: D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D004549:Elastin / Q000138:chemical synthesis / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D020100:Hydrogels / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011108:Polymers / Q000494:pharmacology*; D012212:Rheology / Q000187:drug effects; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013194:Staining and Labeling; D013696:Temperature
chemical_list: D003432:Cross-Linking Reagents; D004220:Disulfides; D020100:Hydrogels; D010455:Peptides; D011108:Polymers; C039217:fluorescein isothiocyanate bovine serum albumin; D012710:Serum Albumin, Bovine; D003300:Copper; D004549:Elastin; D006861:Hydrogen Peroxide; D016650:Fluorescein-5-isothiocyanate; D003545:Cysteine