Efficient loading of drugs in novel delivery agents has the potential to substantially improve therapy by targeting the diseased tissue while avoiding unwanted side effects. Here we report the first systematic study of the loading mechanism of phenanthriplatin and its analogs into tobacco mosaic virus (TMV), previously used by our group as an efficient carrier for anticancer drug delivery. A detailed investigation of the preferential uptake of phenanthriplatin in its aquated form (∼2000 molecules per TMV particle versus ∼1000 for the chlorido form) is provided. Whereas the net charge of phenanthriplatin analogs and their ionic mobilities have no effect on loading, the reactivity of aqua phenanthriplatin with the glutamates, lining the interior walls of the channel of TMV, has a pronounced effect on its loading. MALDI-MS analysis along with NMR spectroscopic studies of a model reaction of hydroxy-phenanthriplatin with acetate establish the formation of stable covalent adducts. The increased number of heteroaromatic rings on the platinum ligand appears to enhance loading, possibly by stabilizing hydrophobic stacking interactions with TMV core components, specifically Pro102 and Thr103 residues neighboring Glu97 and Glu106 in the channel. Electron transfer dissociation MS/MS fragmentation, a technique that can prevent mass-condition-vulnerable modification of proteins, reveals that Glu97 preferentially participates over Glu106 in covalent bond formation to the platinum center.

中文翻译：

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烟草花叶病毒核心中菲铂及其类似物的形态形成

在新型递送剂中有效装载药物有可能通过靶向患病组织同时避免不必要的副作用来显着改善治疗。在这里，我们报告了菲铂及其类似物在烟草花叶病毒 (TMV) 中的加载机制的首次系统研究，该病毒以前被我们的小组用作抗癌药物递送的有效载体。提供了对其水合形式（每个 TMV 颗粒约 2000 个分子，而氯代形式约 1000 个分子）优先摄取菲铂的详细研究。尽管菲铂类似物的净电荷及其离子迁移率对负载没有影响，但菲铂水与谷氨酸盐的反应性，排列在 TMV 通道的内壁，对其负载有显着影响。MALDI-MS 分析以及羟基菲铂与乙酸盐的模型反应的 NMR 光谱研究确定了稳定共价加合物的形成。铂配体上杂环数量的增加似乎增强了负载，这可能是通过稳定与 TMV 核心组分的疏水堆积相互作用，特别是通道中与 Glu97 和 Glu106 相邻的 Pro102 和 Thr103 残基。电子转移解离 MS/MS 碎裂是一种可以防止蛋白质质量条件脆弱修饰的技术，它表明 Glu97 优先参与 Glu106 与铂中心的共价键形成。铂配体上杂环数量的增加似乎增强了负载，这可能是通过稳定与 TMV 核心组分的疏水堆积相互作用，特别是通道中与 Glu97 和 Glu106 相邻的 Pro102 和 Thr103 残基。电子转移解离 MS/MS 碎裂是一种可以防止蛋白质质量条件脆弱修饰的技术，它表明 Glu97 优先参与 Glu106 与铂中心的共价键形成。铂配体上杂环数量的增加似乎增强了负载，这可能是通过稳定与 TMV 核心组分的疏水堆积相互作用，特别是通道中与 Glu97 和 Glu106 相邻的 Pro102 和 Thr103 残基。电子转移解离 MS/MS 碎裂是一种可以防止蛋白质质量条件脆弱修饰的技术，它表明 Glu97 优先参与 Glu106 与铂中心的共价键形成。