Disulfide Bond-Driven Oxidation- and Reduction-Responsive Prodrug Nanoassemblies for Cancer Therapy
Disulfide Bond-Driven Oxidation- and Reduction-Responsive Prodrug Nanoassemblies for Cancer Therapy
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用于癌症治疗的二硫键驱动的氧化和还原响应前药纳米组件
DOI：
10.1021/acs.nanolett.8b00737
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发表时间：
2018-06-01
期刊：
影响因子：
10.8
通讯作者：
Sun, Jin
中科院分区：
文献类型：
--
作者：
Sun, Bingjun;Luo, Cong;Sun, Jin
二硫键已被广泛用于开发用于癌症治疗的还原响应性药物递送系统（DDS）。我们建议，二硫键也可能被用作氧化响应连接就像硫醚键，它可以被氧化为亲水性亚砜或砜在氧化刺激的存在下。为了验证我们的假设，我们设计了三种新型的紫杉醇-香茅醇共轭物，通过不同长度的含二硫键的碳链连接。前药可以自组装成具有令人印象深刻的高载药量（>55%）的均匀尺寸的纳米颗粒。正如预期的那样，二硫键桥接的前药纳米颗粒显示出氧化还原双重响应的药物释放。更有趣的是，碳链连接中二硫键的位置对氧化还原双重响应性具有深远的影响，从而影响前药纳米组装体的药物释放、细胞毒性、药代动力学、生物分布和体内抗肿瘤功效。阐明了氧化还原双重响应机制，并阐明了碳链中二硫键的位置如何影响前药纳米组装体的氧化还原双重响应性和抗肿瘤效率。我们的研究结果为二硫键的刺激响应性提供了新的见解，并为开发用于癌症治疗的新型氧化还原双响应DDS提供了良好的基础。
Disulfide bonds have been widely used to develop reduction-responsive drug-delivery systems (DDS) for cancer therapy. We propose that disulfide bonds might be also used as an oxidation-responsive linkage just like thioether bonds, which can be oxidized to hydrophilic sulfoxide or sulphone in the presence of oxidation stimuli. To test our hypothesis, we design three novel paclitaxel-citronellol conjugates linked via different lengths of disulfide-bondcontaining carbon chain. The prodrugs can self-assemble into uniform-size nanoparticles with impressively high drug loading (>55%). As expected, the disulfide-bond-bridged prodrug nanoparticles show redox dual-responsive drug release. More interestingly, the position of disulfide bonds in the carbon chain linkage has profound impacts on the redox dual responsiveness, thereby affecting the drug release, cytotoxicity, pharmacokinetics, biodistribution, and in vivo antitumor efficacy of prodrug nanoassemblies. The redox dual-responsive mechanism is elucidated, and how the position of disulfide bonds in the carbon chain affects the redox dual responsiveness and antitumor efficiency of prodrug nanoassemblies is also clarified. Our findings give new insight into the stimuli responsiveness of disulfide bonds and provide a good foundation for the development of novel redox dual-responsive DDS for cancer therapy.