Bioresponsive release of insulin-like growth factor-I from its PEGylated conjugate
Bioresponsive release of insulin-like growth factor-I from its PEGylated conjugate
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DOI：
10.1016/j.jconrel.2018.04.009
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发表时间：
2018-06-10
影响因子：
10.8
通讯作者：
Meinel, Lorenz
中科院分区：
文献类型：
--
作者：
Braun, Alexandra C.;Gutmann, Marcus;Meinel, Lorenz
蛋白质配体的PEG化，即聚乙二醇（PEG）聚合物与治疗性蛋白质的连接，增加了治疗剂的半衰期，但通常以降低的生物活性为代价。我们现在提出了一个生物启发的战略，导致了这个困境。为此，我们选择了胰岛素样生长因子I（IGF-I）内的一个位置，用PEG（30 kDa）修饰的蛋白酶敏感肽接头（PSL）进行修饰，使用酶促和化学生物正交偶联策略的组合。PSL序列响应于基质金属蛋白酶（MMP）以在患病组织中提供靶向释放。与野生型相比，IGF-PSL-PEG缀合物具有不同的结合蛋白亲和力、细胞增殖和内吞模式。将缀合物暴露于升高水平的活化MMP（如存在于发炎组织中），通过有效的PSL切割完全重建野生型性质。总之，这种生物启发的方法为聚乙二醇化治疗提供了一个蓝图，结合了聚乙二醇化的药代动力学优势，同时局部恢复了治疗的全套生物潜力。
PEGylation of protein ligands, the attachment of polyethylene glycol (PEG) polymers to a therapeutic protein, increases therapeutics' half-life but frequently comes at the cost of reduced bioactivity. We are now presenting a bioinspired strategy leading out of this dilemma. To this end, we selected a position within insulin-like growth factor I (IGF-I) for decoration with a PEG(30kDa)-modified protease-sensitive peptide linker (PSL) using a combination of enzymatic and chemical bioorthogonal coupling strategies. The PSL sequence responded to matrix metalloproteinases (MMP) to provide a targeted release in diseased tissue. The IGF-PSL-PEG conjugate had different binding protein affinity, cell proliferation, and endocytosis patterns as compared to the wild type. Exposure of the conjugate to elevated levels of activated MMPs, as present in inflamed tissues, fully reestablished the wild type properties through effective PSL cleavage. In conclusion, this bioinspired approach provided a blueprint for PEGylated therapeutics combining the pharmacokinetic advantages of PEGylation, while locally restoring the full suite of biological potential of therapeutics.