Enzymatic activation of second-generation dendritic prodrugs: Conjugation of self-immolative dendrimers with poly(ethylene glycol) via click chemistry
Enzymatic activation of second-generation dendritic prodrugs: Conjugation of self-immolative dendrimers with poly(ethylene glycol) via click chemistry
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DOI：
10.1021/bc060180n
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发表时间：
2006-11-15
影响因子：
4.7
通讯作者：
Shabat, Doron
中科院分区：
文献类型：
--
作者：
Gopin, Anna;Ebner, Sharon;Shabat, Doron
单触发解离树枝状大分子是最近开发和引入的一种潜在的多前药平台。这些独特的结构树状大分子可以通过树枝状大分子核心的单个裂解引发的自焚链断裂来释放其所有的尾部单元。第一代自焚树突状前体药物的生物激活有几个例子。然而，对于第二代自焚的树枝状大分子，酶激活失败。树枝状前药的疏水大分子结构导致在水条件下聚集，阻止酶到达触发底物。在这里，我们展示了一个简单的解决方案的酶激活的第二代自焚树枝状大分子。通过点击化学方法将聚乙二醇偶联到树枝状平台上。聚乙二醇尾极大地降低了树枝状大分子的疏水性能，从而阻止了聚集体的形成。我们设计并合成了一种树枝状前药，它含有四个分子的抗癌药物喜树碱和一个可被青霉素-G-酰胺酶激活的触发器。在生理条件下，青霉素-G-酰胺酶能有效地激活PEG5000偶联的自焚树突状前药，并将游离喜树碱释放到反应介质中。细胞生长抑制实验表明，树突状前体药物与酶孵育后毒性增加。
Single-triggered disassemble dendrimers were recently developed and introduced as a potential platform for a multi-prodrug. These unique structural dendrimers can release all of their tail units through a self-immolative chain fragmentation initiated by a single cleavage at the dendrimer's core. There are several examples for the bioactivation of first-generation self-immolative dendritic prodrugs. However, enzymatic activation failed for second-generation self-immolative dendrimers. The hydrophobic large molecular structure of the dendritic prodrugs results in aggregation under aqueous conditions and prevented the enzyme from reaching the triggering substrate. Here we show a simple solution for the enzymatic activation of second-generation self-immolative dendrimers. Poly( ethylene glycol) ( PEG) was conjugated to the dendritic platform via click chemistry. The poly( ethylene glycol) tails significantly decreased the hydrophobic properties of the dendrimers and thereby prevented aggregate formation. We designed and synthesized a dendritic prodrug with four molecules of the anticancer agent camptothecin and a trigger that can be activated by penicillin-G-amidase. The PEG5000-conjugated, self-immolative dendritic prodrug was effectively activated by penicillin-G-amidase under physiological conditions and free camptothecin was released to the reaction media. Cell-growth inhibition assays demonstrated increased toxicity of the dendritic prodrug upon incubation with the enzyme.