Tumor physiology and charge dynamics of anticancer drugs: implications for camptothecin-based drug development.
Tumor physiology and charge dynamics of anticancer drugs: implications for camptothecin-based drug development.
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DOI：
10.2174/092986711795029609
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发表时间：
2011
影响因子：
4.1
通讯作者：
Morgan LR
中科院分区：
文献类型：
--
作者：
Adams DJ;Morgan LR
电荷是药物分子的一个重要特征，因为在特定的pH值下，电离位置决定了pKa。PKA又可以影响许多参数，包括溶解度、溶出度、反应动力学、制剂、细胞通透性、组织分布、肾排泄、代谢、蛋白质结合和受体相互作用。在表现糖酵解表型和相关的酸性细胞外微环境的人类实体肿瘤中，电荷动力学的影响被放大。这种表型是由低氧驱动的，并在肿瘤中创造了有利于摄取弱酸和排除弱碱的pH梯度。现有的抗癌药物表现出一系列的PKA，因此利用肿瘤pH梯度的能力是不同的。喜树碱是一个很好的例子，因为它们代表了不同类别的已批准的抗癌药物和候选药物，其电荷分布随着pH值的变化而变化。用电子计算机方法预测了在生理pH和酸性pH条件下，喜树碱在内酯和羧酸两种形式下的电荷分布。预测在酸性pH条件下，大量不带电荷的羧酸盐可以进入肿瘤细胞并在线粒体中积累，从而抑制线粒体拓扑异构酶I。提出了一个模型来描述一种新的喜树碱类似物的电荷动力学及其对核和线粒体作用机制的影响(S)。这个例子说明了将肿瘤生理学和电荷动力学整合到抗癌药物开发中的重要性。
Charge is an important characteristic of drug molecules, since ionization sites determine the pKa at a particular pH. The pKa in turn can affect many parameters, including solubility, dissolution rate, reaction kinetics, formulation, cell permeability, tissue distribution, renal elimination, metabolism, protein binding and receptor interactions. The impact of charge dynamics is amplified in human solid tumors that exhibit the glycolytic phenotype and associated acidic extracellular microenvironment. This phenotype is driven by hypoxia and creates a pH gradient in tumors that favors uptake of weak acids and exclusion of weak bases. Established anticancer drugs exhibit a range of pKa’s and thus variable ability to exploit the tumor pH gradient. The camptothecins are a prime example as they represent a diverse class of approved anticancer drugs and drug candidates whose charge distribution varies with pH. An in silico method was used to predict charge distribution of camptothecins at physiological versus acidic pH in both the lactone and carboxylate forms. A significant amount of uncharged carboxylate was predicted at acidic pH that could enter tumor cells and accumulate in mitochondria to inhibit mitochondrial topoisomerase I. A model is presented to describe the charge dynamics of a new camptothecin analog and the impact on nuclear and mitochondrial mechanism(s) of action. This example illustrates the importance of integrating tumor physiology and charge dynamics into anticancer drug development.