Linear and branched bicin linkers for releasable PEGylation of macromolecules: controlled release in vivo and in vitro from mono- and multi-PEGylated proteins

Bioconjugate Chemistry
Hong ZhaoDavid Filpula

Abstract

The utility of PEGylation for improving therapeutic protein pharmacology would be substantially expanded if the authentic protein drugs could be regenerated in vivo. Diminution of kinetic constants of both enzymes and protein ligands are commonly encountered following permanent bioconjugation with poly(ethylene glycol) polymers. In further development of releasable linker technology, we investigated an amino PEG anchimeric prodrug system, based on either the linear or branched bicin3 (BCN3) linkage, one promising representative of several aliphatic ester structures synthesized from N-modifed bis-2-hydroxyethylglycinamide (bicin). Protein models included an enzyme, lysozyme, and a receptor ligand, interferon-beta-1b, for preparation of linear or branched mono- and multi-PEGylated conjugates as inactive PEG-BCN3 prodrugs. The kinetics of protein release, both in plasma (in vitro) and in mice (in vivo), correlated with the number of PEG attachments, and the plasma half-lives of PEG release spanned a duration of hours to days within the therapeutically relevant window. Capillary electrophoresis, SDS-PAGE, mass determination, and enzymatic and antiviral activity determinations demonstrated regeneration of equivalent native proteins ...Continue Reading

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Citations

Apr 1, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Nadine HammerAchim M Goepferich
Jul 6, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Atul KolateAmbikanandan Misra
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Sep 22, 2007·Advanced Drug Delivery Reviews·David Filpula, Hong Zhao
May 1, 2007·Biomolecular Engineering·David Filpula
Sep 23, 2010·Pharmaceutical Development and Technology·Robert W PayneMark Cornell Manning
Jan 24, 2015·Bioconjugate Chemistry·Yuhui GongMarc A Gauthier
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