Wang Ying, Cui Yu, Zhao Yating, He Bing, Shi Xiaoli, Di Donghua, Zhang Qiang, Wang Siling
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
Eur J Pharm Biopharm. 2017 Aug;117:105-115. doi: 10.1016/j.ejpb.2017.03.019. Epub 2017 Mar 28.
A distinctive and personalized nanocarrier is described here for controlled and targeted antitumor drug delivery and real-time bioimaging by combining a redox/enzyme dual-responsive disulfide-conjugated carbon dot with mesoporous silica nanoparticles (MSN-SS-CD). The carbon dot with controlling and targeting abilities was prepared through a polymerizing reaction by applying citric acid and HA as starting materials (named CD). The as-prepared MSN-SS-CD exhibited not only superior photostability and excellent biocompatibility, but also the ability to target A549 cells with overexpression of CD44 receptors. Upon loading the antitumor drug, doxorubicin (DOX), into the mesoporous channels of MSN nanoparticles, CD with a diameter size of 3nm completely blocked the pore entrance of DOX-encapsulated MSN nanoparticles with a pore size of about 3nm, thus preventing the premature leakage of DOX and increasing the antitumor activity until being triggered by specific stimuli in the tumor environment. The results of the cell imaging and cytotoxicity studies demonstrated that the redox/enzyme dual-responsive DOX-encapsulated MSN-SS-CD nanoparticles can selectively deliver and control the release of DOX into tumor cells. Ex vivo fluorescence images showed a much stronger fluorescence of MSN-SS-CD-DOX in the tumor site than in normal tissues, greatly facilitating the accumulation of DOX in the target tissue. However, its counterpart, MSN-SH-DOX exhibited no or much lower tumor cytotoxicity and drug accumulation in tumor tissue. In addition, MSN-SS-CD was also used as a control to investigate the ability of MSN-SS-CD to target A549 cells. The results obtained indicated that MSN-SS-CD possessed a higher cellular uptake through the CD44 receptor-mediated endocytosis compared with MSN-SS-CD in the A549 cells. Such specific redox/enzyme dual-responsive targeted nanocarriers are a useful strategy achieving selective controlled and targeted delivery of therapeutic reagents with real-time bioimaging, and may also facilitate the development of drug delivery systems for a number of clinical applications.
本文描述了一种独特的个性化纳米载体，通过将氧化还原/酶双响应二硫键共轭碳点与介孔二氧化硅纳米颗粒（MSN-SS-CD）相结合，用于可控和靶向抗肿瘤药物递送及实时生物成像。以柠檬酸和HA为原料，通过聚合反应制备了具有控制和靶向能力的碳点（命名为CD）。所制备的MSN-SS-CD不仅具有优异的光稳定性和良好的生物相容性，还具有靶向CD44受体过表达的A549细胞的能力。将抗肿瘤药物阿霉素（DOX）负载到MSN纳米颗粒的介孔通道中后，直径为3nm的CD完全堵塞了孔径约为3nm的DOX包封的MSN纳米颗粒的孔口，从而防止DOX过早泄漏并增强抗肿瘤活性，直至在肿瘤环境中受到特定刺激而触发。细胞成像和细胞毒性研究结果表明，氧化还原/酶双响应的DOX包封的MSN-SS-CD纳米颗粒可以选择性地将DOX递送至肿瘤细胞并控制其释放。体外荧光图像显示，肿瘤部位的MSN-SS-CD-DOX荧光比正常组织强得多，极大地促进了DOX在靶组织中的积累。然而，其对应物MSN-SH-DOX在肿瘤组织中没有或具有低得多的肿瘤细胞毒性和药物积累。此外，MSN-SS-CD还用作对照来研究MSN-SS-CD靶向A549细胞的能力。获得的结果表明，与A549细胞中的MSN-SS-CD相比，MSN-SS-CD通过CD44受体介导的内吞作用具有更高的细胞摄取率。这种特定的氧化还原/酶双响应靶向纳米载体是实现治疗试剂选择性可控和靶向递送并进行实时生物成像的有用策略，也可能促进用于许多临床应用的药物递送系统的开发。
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