基于靶向核仁素的适配子-雷公藤甲素偶合物的制备及其抗乳腺癌的作用研究

Breast cancer has become one of the most frequently-occurred malignant tumors among women, while tumor targeted therapy has turn into a new trend of tumor treatment. Therefore, exploration of new targeted anti-cancer drugs has important significance for treatment of breast cancer. Triptolide as a kind of broad-spectrum and highly effective anticancer drugs has a variety of anticancer mechanisms. However, its poor water solubility and lack of tumor targeting lead to serious toxic and side effects, which restricts its clinical application. Recent studies have shown that nucleolin is overexpressed in a variety of tumor cells and is widely distributed in cell membranes and nuclei. What is more, nucleolin aptamer is a highly water-soluble single stranded oligonucleotide, which can specifically bind to nucleolin on the surface of breast cancer cells with high affinity. In the previous work, we have developed an intelligently water-solubility, tumor targeting aptamer-paclitaxel conjugate for the treatment of ovarian cancer. Therefore, we will bond the nucleolin aptamer to triptolide to form nucleolin aptamer-triptolide conjugate with a special linker containing ester and acetal groups, which can improve the water solubility of triptolide, selectively target to breast cancer cells, reduce side effects and enhance the therapeutic effect. This study will provide other chemotherapeutic drugs with a cell-targeting delivery strategy based on the aptamer modification.

乳腺癌是女性最常见的恶性肿瘤，肿瘤靶向治疗已成为趋势,研发靶向的抑制乳腺癌细胞增殖的药物对乳腺癌治疗具有十分重要的意义。雷公藤甲素是一种广谱高效的抗癌药，具有多种抗癌机制，但其水溶性差和缺乏肿瘤靶向性，存在严重的毒副反应,限制其在临床中的应用。最近研究显示，核仁素在多种肿瘤细胞内过度表达，且广泛分布于细胞膜及胞核。核仁素适配子是一种高水溶性的单链寡核苷酸，能够特异性与乳腺癌细胞表面的核仁素高亲和性的结合。在前期的工作中，我们已经开发了一种高水溶性，肿瘤靶向性的智能型适配子-紫杉醇偶合物用于治疗卵巢癌。在本项目中，我们将核仁素适配子与雷公藤甲素通过酯基与缩醛组成的连接键相连形成核仁素适配子-雷公藤甲素偶合物，可以提高雷公藤甲素的水溶性，有助于其选择性的靶向乳腺癌细胞，减少毒副作用，增强治疗效果。本研究将为其他化疗药物的临床应用提供了一种基于适配子修饰的细胞靶向递送策略。

乳腺癌是女性中最常见的恶性肿瘤，肿瘤靶向治疗已成为趋势,研发靶向的抑制乳腺癌细胞增殖的药物对乳腺癌治疗具有十分重要的意义。最近研究显示，核仁素蛋白在乳腺癌细胞膜表面过表达。雷公藤甲素是一种广谱高效的抗癌药，具有多种抗癌机制，但其水溶性差和缺乏肿瘤靶向性，存在严重的毒副反应,限制其在临床中的应用核仁素适配子是一种高水溶性的单链寡核苷酸，能够特异性与核仁素高亲和性结合。核仁素适配子与雷公藤甲素通过酯基与缩醛组成的连接键相连设计合成一种新型核仁素适配子-雷公藤甲素偶合物，该偶合物水溶性增加且在血浆中稳定，在pH低于5.5的PBS缓冲液中逐渐分解释放出雷公藤甲素。偶合物通过巨饱饮作用进入肿瘤细胞并在溶酶体内断裂释放；其抗肿瘤作用于诱导细胞内活性氧的产生，破坏线粒体膜而引发线粒体途径的凋亡有关；通过体内实验证明在裸鼠乳腺癌模型中，与对照组相比，偶合物在明显聚集于肿瘤部位，对乳腺癌组织具有明显的抑制作用，同时对其他正常组织没有或极少的毒副反应。以上数据证明高水溶性且酸敏感性的核仁素适配子-雷公藤甲素偶合物能靶向递送雷公藤甲素达到核仁素高表达的肿瘤细胞，通过线粒体途径诱导肿瘤细胞凋亡，显著抑制肿瘤组织的生长，极大降低了对正在组织的毒性。该项目资助下，发表SCI学术论文6篇.