自组装喜树碱和卡培他滨杂合前药的协同抗肿瘤活性，提高疗效。
Synergistic antitumor activity of a self-assembling camptothecin and capecitabine hybrid prodrug for improved efficacy.
机构信息
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China.
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA.
出版信息
J Control Release. 2017 Oct 10;263:102-111. doi: 10.1016/j.jconrel.2017.01.015. Epub 2017 Jan 10.
The direct use of anticancer drugs to create their own nanostructures is an emerging concept in the field of drug delivery to obtain nanomedicines of high drug loading and high reproducibility, and the combination use of two or more drugs has been a proven clinical strategy to enhance therapeutic outcomes. We report here the synthesis, assembly and cytotoxicity evaluation of self-assembling hybrid prodrugs containing both camptothecin (CPT) and a capecitabine (Cap) analogue. CPT and Cap molecules were conjugated onto a short β-sheet-forming peptide (Sup35) to yield three different self-assembling prodrugs (dCPT-Sup35, CPT-Cap-Sup35 and dCap-Sup35). We found that the chemical structure of conjugated drugs could strongly influence their assembled morphology as well as their structural stability in aqueous solution. With a decrease in number of CPT units, the resulting nanostructures exhibited a morphological transformation from nanofibers (dCPT-Sup35) to filaments (CPT-Cap-Sup35) then to spherical particles (dCap-Sup35). Notably, the hybrid CPT-Cap prodrug showed a synergistic effect and significantly enhanced potency against three esophageal adenocarcinoma cell lines compared with the two homo-prodrugs (dCPT-Sup35 and dCap-Sup35) as well as free parent drugs (CPT, 5-Fu and CPT/5-FU mixture (1:1)). We believe this work represents a conceptual advancement in integrating two structurally distinct drugs of different action mechanisms into a single self-assembling hybrid prodrug to construct self-deliverable nanomedicines for more effective combination chemotherapy.
将抗癌药物直接用于构建自身纳米结构是药物输送领域的一个新兴概念，可获得载药量高、重现性好的纳米药物，并且联合使用两种或更多药物已被证明是提高治疗效果的临床策略。我们在此报告了含有喜树碱（CPT）和卡培他滨（Cap）类似物的自组装杂化前药的合成、组装和细胞毒性评价。CPT 和 Cap 分子被连接到短 β-折叠形成肽（Sup35）上，得到三种不同的自组装前药（dCPT-Sup35、CPT-Cap-Sup35 和 dCap-Sup35）。我们发现，连接药物的化学结构强烈影响它们的组装形态以及它们在水溶液中的结构稳定性。随着 CPT 单元数量的减少，所得纳米结构表现出从纳米纤维（dCPT-Sup35）到纤维（CPT-Cap-Sup35）再到球形颗粒（dCap-Sup35）的形态转变。值得注意的是，与两种同型前药（dCPT-Sup35 和 dCap-Sup35）以及游离母体药物（CPT、5-Fu 和 CPT/5-FU 混合物（1:1）相比，杂化 CPT-Cap 前药显示出协同作用，对三种食管腺癌细胞系的活性显著增强。我们相信这项工作代表了将两种结构不同、作用机制不同的药物整合到单个自组装杂化前药中的概念上的进步，以构建自递送纳米药物，实现更有效的联合化疗。
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