Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity,Journal of the American Chemical Society

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Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-01-19 , DOI: 10.1021/jacs.7b11462
Lu Su ₁ , Richen Li ₁ , Sarosh Khan ₁ , Ryan Clanton ₂ , Fuwu Zhang ₁ , Yen-Nan Lin _{1,

3} , Yue Song ₁ , Hai Wang ₁ , Jingwei Fan ₁ , Soleil Hernandez ₂ , Andrew S. Butters ₂ , Gamal Akabani ₂ , Ronan MacLoughlin _{4,

5,

6} , Justin Smolen ₁ , Karen L. Wooley ₁

Affiliation

Although nanomedicines have been pursued for nearly 20 years, fundamental chemical strategies that seek to optimize both the drug and drug carrier together in a concerted effort remain uncommon yet may be powerful. In this work, two block polymers and one dimeric prodrug molecule were designed to be coassembled into degradable, functional nanocarriers, where the chemistry of each component was defined to accomplish important tasks. The result is a poly(ethylene glycol) (PEG)-protected redox-responsive dimeric paclitaxel (diPTX)-loaded cationic poly(d-glucose carbonate) micelle (diPTX@CPGC). These nanostructures showed tunable sizes and surface charges and displayed controlled PTX drug release profiles in the presence of reducing agents, such as glutathione (GSH) and dithiothreitol (DTT), thereby resulting in significant selectivity for killing cancer cells over healthy cells. Compared to free PTX and diPTX, diPTX@CPGC exhibited improved tumor penetration and significant inhibition of tumor cell growth toward osteosarcoma (OS) lung metastases with minimal side effects both in vitro and in vivo, indicating the promise of diPTX@CPGC as optimized anticancer therapeutic agents for treatment of OS lung metastases.

中文翻译：

谷胱甘肽敏感二聚体药物客体和葡萄糖衍生纳米载体宿主的化学设计，以实现增强的骨肉瘤肺转移性抗癌选择性

尽管纳米药物已经被研究了近 20 年，但寻求共同优化药物和药物载体的基本化学策略仍然不常见，但可能是强大的。在这项工作中，两个嵌段聚合物和一个二聚体前药分子被设计为可共同组装成可降解的功能性纳米载体，其中每个组分的化学性质被定义为完成重要任务。结果是聚（乙二醇）（PEG）保护的氧化还原响应二聚紫杉醇（diPTX）负载的阳离子聚（d-葡萄糖碳酸酯）胶束（diPTX@CPGC）。这些纳米结构显示出可调的尺寸和表面电荷，并在还原剂如谷胱甘肽 (GSH) 和二硫苏糖醇 (DTT) 存在下显示受控的 PTX 药物释放曲线，从而导致杀死癌细胞的选择性高于健康细胞。与游离 PTX 和 diPTX 相比，diPTX@CPGC 表现出更好的肿瘤渗透和显着抑制肿瘤细胞向骨肉瘤 (OS) 肺转移的生长，并且在体外和体内副作用最小，表明 diPTX@CPGC 作为优化的抗癌治疗剂的前景用于治疗 OS 肺转移的药物。

更新日期：2018-01-19

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