title: Zwitterionic gel encapsulation promotes protein stability, enhances pharmacokinetics, and reduces immunogenicity.
abstract: Advances in protein therapy are hindered by the poor stability, inadequate pharmacokinetic (PK) profiles, and immunogenicity of many therapeutic proteins. Polyethylene glycol conjugation (PEGylation) is the most successful strategy to date to overcome these shortcomings, and more than 10 PEGylated proteins have been brought to market. However, anti-PEG antibodies induced by treatment raise serious concerns about the future of PEGylated therapeutics. Here, we demonstrate a zwitterionic polymer network encapsulation technology that effectively enhances protein stability and PK while mitigating the immune response. Uricase modified with a comprehensive zwitterionic polycarboxybetaine (PCB) network exhibited exceptional stability and a greatly prolonged circulation half-life. More importantly, the PK behavior was unchanged, and neither anti-uricase nor anti-PCB antibodies were detected after three weekly injections in a rat model. This technology is applicable to a variety of proteins and unlocks the possibility of adopting highly immunogenic proteins for therapeutic or protective applications.
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
authors.forename: Peng
authors.identifier: http://orcid.org/0000-0002-5409-7480
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
authors.forename: Fang
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
authors.forename: Caroline
authors.initials: C
authors.lastname: Tsao
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195.
authors.forename: Sijun
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
authors.forename: Priyesh
authors.initials: P
authors.lastname: Jain
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
authors.forename: Andrew
authors.initials: A
authors.lastname: Sinclair
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
authors.forename: Hsiang-Chieh
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
authors.forename: Tao
authors.initials: T
authors.lastname: Bai
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195;
authors.forename: Kan
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, WA 98195; Department of Bioengineering, University of Washington, Seattle, WA 98195 sjiang@uw.edu.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001622:Betaine / Q000737:chemistry; D005782:Gels / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D050997:Nanomedicine / Q000379:methods*; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D014503:Urate Oxidase / Q000737:chemistry
chemical_list: D005782:Gels; D011506:Proteins; D001622:Betaine; D014503:Urate Oxidase
keywords: hydrogel; immune response; nanomedicine; protein delivery; zwitterionic polymer