Shaanxi Key Laboratory of Macromolecular Science and Technology, Ministry of Education Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, School of Chemistry and Chemical Engineering, Northwestern Polytechnical University, 710072 Xi'an, China.
Department of Chemistry, University of Utah, Salt Lake City, UT 84112.
Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):30942-30948. doi: 10.1073/pnas.2007798117. Epub 2020 Nov 23.
Despite the widespread clinical application of chemotherapeutic anticancer drugs, their adverse side effects and inefficient performances remain ongoing issues. A drug delivery system (DDS) designed for a specific cancer may therefore overcome the drawbacks of single chemotherapeutic drugs and provide precise and synergistical cancer treatment by introducing exclusive stimulus responsiveness and combined chemotherapy properties. Herein, we report the design and synthesis of a supramolecular drug delivery assembly 1 constructed by orthogonal self-assembly technique in aqueous media specifically for application in liver cancer therapy. Complex 1 incorporates the β-cyclodextrin host molecule-functionalized organoplatinum(II) metallacycle 2 with two specific stimulus-responsive motifs to the signaling molecule nitric oxide (NO), in addition to the three-armed polyethylene glycol (PEG) functionalized ferrocene 3 with redox responsiveness. With this molecular design, the particularly low critical aggregation concentration (CAC) of assembly 1 allowed encapsulation of the commercial anticancer drug doxorubicin (DOX). Controlled drug release was also achieved by morphological transfer via a sensitive response to the endogenous redox and NO stimuli, which are specifically related to the microenvironment of liver tumor cells. Upon combination of these properties with the anticancer ability from the platinum acceptor, in vitro studies demonstrated that DOX-loaded 1 is able to codeliver anticancer drugs and exhibit therapeutic effectiveness to liver tumor sites via a synergistic effect, thereby revealing a potential DDS platform for precise liver cancer therapeutics.
尽管化疗抗癌药物在临床上得到了广泛应用，但它们的不良反应和低效性能仍然是一个持续存在的问题。因此，为特定癌症设计的药物输送系统（DDS）可以克服单一化疗药物的缺点，并通过引入独特的刺激响应性和联合化疗特性，提供精确的协同癌症治疗。在这里，我们报告了一种超分子药物输送组装体 1 的设计和合成，该组装体 1 通过在水介质中采用正交自组装技术构建，专门用于肝癌治疗。复合物 1 包含β-环糊精主体分子功能化的有机铂（II）金属络合物 2，具有两个特定的刺激响应基序，用于信号分子一氧化氮（NO），以及三臂聚乙二醇（PEG）功能化的二茂铁 3，具有氧化还原响应性。通过这种分子设计，组装体 1 的特别低临界聚集浓度（CAC）允许封装商业抗癌药物阿霉素（DOX）。通过形态转移也实现了药物的控制释放，这种形态转移通过对内源性氧化还原和 NO 刺激的敏感响应来实现，这些刺激与肝癌细胞的微环境密切相关。将这些特性与铂受体的抗癌能力结合起来，体外研究表明，负载 DOX 的 1 能够共同输送抗癌药物，并通过协同作用对肝癌部位发挥治疗效果，从而揭示了一种用于精确肝癌治疗的潜在 DDS 平台。
