Readily adaptable release kinetics of prodrugs using protease-dependent reversible PEGylation

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• 作者：Roland Bö ; ttger ; Daniel Knappe ; Ralf Hoffmann ; ^{bioanaly@bbz.uni-leipzig.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Oncocin Onc112 ; Protease cleavage ; Peptide therapeutics ; Polyethylene glycol (PEG) ; Serum degradation ; Thioether
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 May 2016
• 年：2016
• 卷：230
• 期：Complete
• 页码：88-94
• 全文大小：557 K

文摘

Protein and peptide therapeutics with good in vitro activities often fail due to poor bioavailability, circulation lifetime, and immunogenicity. PEGylation, i.e. conjugation of polyethylene glycol (PEG), significantly improves serum stability and renal clearance besides reducing the immunogenicity and thus enhances pharmacokinetics and tolerance in vivo. Several PEGylated drugs are marketed including several top-selling blockbusters. However, PEGylation can mask the binding site, especially in peptides, and thereby reduce the activity drastically, which is only rarely compensated by the improved bioavailability. Prodrug strategies using temporary PEGylation, i.e. the authentic drug is released from a PEG-linked precursor by hydrolysis or enzymatic degradation, can overcome these weaknesses. Recently, we reported a strategy coupling PEG via a peptide linker cleaved C-terminally by trypsin-like proteases in blood to release the unmasked therapeutic peptide. Here, we designed twelve short peptide linkers (four or five residues) to tune the release-rates of oncocin Onc112, a proline-rich antimicrobial peptide. In 25% aqueous mouse serum, Onc112 was released with half-life times from 0.5 to 12 h. When elongated N-terminally with 5 kDa ɑ-methoxy-ω-mercapto PEG as thioether, the half-life times of the prodrugs ranged from 7 to 42 h in full mouse serum. Conjugation of a 20 kDa instead of the 5 kDa PEG increased the half-life times more than twofold, whereas longer peptide linkers up to twelve residues increased them only slightly. In all cases, Onc112 was released continuously providing stable peptide levels for at least 16 h. The kinetics will allow the specific design of PEG-linker-drug-combinations for optimizing the pharmacokinetics of promising peptide therapeutics.