Department of Chemical Engineering, College of Materials and Chemistry and Chemical Engineering, Chengdu University of Technology, Chengdu 610059, People's Republic of China.
Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731, People's Republic of China.
Biomed Mater. 2023 May 30;18(4). doi: 10.1088/1748-605X/acd6ca.
Podophyllotoxin (PPT) is an active natural pharmaceutical component with potent anticancer activity. However, due to its poor water solubility and serious side effects, its medical applications are limited. In this work, we synthesized a series of PPT dimers, which can be self-assembled into stable nanoparticles of 124-152 nm in aqueous solution and can significantly increase the solubility of PPT in aqueous solution. In addition, PPT dimer nanoparticles exhibited high drug loading capacity (>80%) and could store at 4 °C in aqueous state with good stability for at least 30 d.release studies showed that nanoparticles with disulfide bonds (SS NPs) can quickly release (about 96.5% drug released within 24 h) the conjugated drug in PBS buffer (pH = 7.4) in the presence of DTT. Cell endocytosis experiments showed that SS NPs enhanced cell uptake (18.56 times higher than PPT for Molm-13, 10.29 times for A2780S and 9.81 times for A2780T) and maintained antitumor effect against human ovarian tumor cells (A2780S and resistant A2780T) and human breast cancer cells (MCF-7). In addition, the endocytosis mechanism of SS NPs was revealed that these nanoparticles were mainly up-taken by macropinocytosis-mediated endocytosis. We believe that these PPT dimer-based nanoparticles will become an alternative formula for PPT, moreover the assembly behavior of PPT dimer can be extended to other therapeutic drugs.
鬼臼毒素（PPT）是一种具有强大抗癌活性的天然药物活性成分。然而，由于其水溶性差和严重的副作用，其在医学上的应用受到限制。在这项工作中，我们合成了一系列 PPT 二聚体，这些二聚体可以在水溶液中自组装成稳定的纳米颗粒，粒径为 124-152nm，可以显著提高 PPT 在水溶液中的溶解度。此外，PPT 二聚体纳米颗粒表现出较高的载药量（>80%），可以在 4°C 下以水溶液形式储存，至少在 30d 内保持良好的稳定性。释放研究表明，含有二硫键（SS NPs）的纳米颗粒可以在 DTT 存在的情况下快速释放（24 小时内约 96.5%的药物释放）PBS 缓冲液（pH=7.4）中连接的药物。细胞内吞实验表明，SS NPs 增强了细胞摄取（Molm-13 比 PPT 高 18.56 倍，A2780S 高 10.29 倍，A2780T 高 9.81 倍），并保持对人卵巢癌细胞（A2780S 和耐药 A2780T）和人乳腺癌细胞（MCF-7）的抗肿瘤作用。此外，揭示了 SS NPs 的内吞机制，这些纳米颗粒主要通过巨胞饮介导的内吞作用被摄取。我们相信，这些基于 PPT 二聚体的纳米颗粒将成为 PPT 的替代配方，此外，PPT 二聚体的组装行为可以扩展到其他治疗药物。
