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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Multiple event activation of a generic prodrug trigger by antibody catalysis
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Multiple event activation of a generic prodrug trigger by antibody catalysis

机译：通过抗体催化对通用前药触发器进行多事件激活

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摘要

Chemotherapeutic regimes are typically lim- ited by nonspecific toxicity. To address this problem we have developed a broadly applicable drug-masking chemistry that operates in conjunction with a unique broad-scope catalytic antibody. This masking chemistry is applicable to a wide range of drugs because it is compatible with virtually any heteroatom. We demonstrate that generic drug-masking groups may be selectively removed by sequential retro-aldol- retro-Michael reactions catalyzed by antibody 38C2. This reaction cascade is not catalyzed by any known natural enzyme. Application of this masking chemistry to the anti- cancer drugs doxorubicin and camptothecin produced pro- drugs with substantially reduced toxicity. These prodrugs are selectively unmasked by the catalytic antibody when it is applied at therapeutically relevant concentrations. We have demonstrated the efficacy of this approach by using human colon and prostate cancer cell lines. The antibody demon- strated a long in vivo half-life after administration to mice. Bascd on these findings, we believe that the system described here has the potential to become a key tool in selective chemotherapeutic strategies.
机译：化疗方案通常受非特异性毒性限制。为了解决这个问题，我们开发了一种可广泛应用的药物掩盖化学，可与独特的广谱催化抗体结合使用。该掩蔽化学物质可与几乎所有杂原子兼容，因此可用于多种药物。我们证明，通用的药物掩蔽基团可以通过抗体38C2催化的顺序逆向醛醇-逆向迈克尔反应选择性去除。该反应级联不受任何已知的天然酶的催化。将该掩蔽化学物质应用于抗癌药物阿霉素和喜树碱可产生毒性大大降低的前药。当以治疗上相关的浓度施用时，这些前药被催化抗体选择性地掩盖。我们已经通过使用人类结肠和前列腺癌细胞系证明了这种方法的功效。给予小鼠后，该抗体具有较长的体内半衰期。基于这些发现，我们相信这里描述的系统有可能成为选择性化学治疗策略中的关键工具。

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