Linear and Branched Bicin Linkers for Releasable PEGylation of Macromolecules: Controlled Release in Vivo and in Vitro from Mono- and Multi-PEGylated Proteins
| Autor: | Amartya Basu, Hsien-Ching Liu, Karen Yang, Ramesh Chintala, Anthony Martinez, Ahsen Janjua, Maoliang Wang, David Filpula, Hong Zhao |
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| Rok vydání: | 2006 |
| Předmět: |
Stereochemistry
Glycine Biomedical Engineering Pharmaceutical Science Bioengineering Polyethylene Glycols Mice In vivo PEG ratio Animals Prodrugs Pharmacology Bioconjugation Molecular Structure Chemistry Organic Chemistry Proteins Interferon-beta Prodrug Ligand (biochemistry) Combinatorial chemistry Controlled release Rats Cross-Linking Reagents PEGylation Muramidase Chickens Biotechnology Protein ligand |
| Zdroj: | Bioconjugate Chemistry. 17:341-351 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc050270c |
| Popis: | 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 from the inactive PEG-BCN3 conjugates. Pharmacokinetic analysis of the PEGylated interferon-beta-1b administered subcutaneously in mice demonstrated an over 20-fold expansion of the area under the curve exposure of bioactive protein when compared to native protein. |
| Databáze: | OpenAIRE |
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