Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo
Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo
复制标题
DOI：
10.1073/pnas.1312782110
复制
发表时间：
2013-11-05
影响因子：
11.1
通讯作者：
Bogyo, Matthew
中科院分区：
文献类型：
--
作者：
Deu, Edgar;Chen, Ingrid T.;Bogyo, Matthew
细胞毒剂精确靶向特定细胞类型或细胞区室在医学领域具有重要意义，特别是与传染病和癌症相关。在这里，我们描述了一种利用异常水平的可移动二价铁 (Fe-II) 进行体内选择性药物递送的方法。该方法利用了 1,2,4-三氧戊环部分，该部分作为 Fe-II 敏感的“触发器”，使药物释放取决于 Fe-II 促进的三氧戊环断裂。我们用鼠疟疾的伯氏疟原虫模型证明了这种方法的体内验证。疟疾寄生虫由于受感染红细胞中宿主血红蛋白的分解代谢而产生高浓度的移动亚铁。使用基于活性的探针，我们成功地证明了有效的二肽基氨肽酶抑制剂的 Fe-II 依赖性和寄生虫选择性递送。我们发现，以 Fe-II 靶向形式递送该化合物可导致更持久的靶点抑制，并大大减少对哺乳动物组织蛋白酶的脱靶抑制。这种选择性药物输送转化为改善的功效和耐受性。这些发现证明了纯化学方法在体内实现选择性药物靶向的效用。这种方法可能在寄生虫感染中得到有用的应用，更广泛地在任何以活性亚铁异常产生为特征的疾病状态中得到应用。
The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe-II) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe-II-sensitive "trigger," making drug release contingent on Fe-II-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe-II-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe-II-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron.