Department of Neurology and Stroke Center of The First Affiliated Hospital, and Department of Chemistry, Jinan University, Guangzhou 510632, China.
Biomater Sci. 2021 Jul 7;9(13):4691-4700. doi: 10.1039/d1bm00348h. Epub 2021 May 21.
To overcome drug resistance in hypoxic tumors and the limitations of radiation impedance and radiation dose, we developed a nano-radiosensitizer to improve the efficacy of cancer radiotherapy. We used multifunctional mesoporous silica nanoparticles (MSNs) as the carriers for a novel anticancer selenadiazole derivative (SeD) and modified its surface with folic acid (FA) to enhance its cervical cancer-targeting effects, forming the nanosystem named SeD@MSNs-FA. Upon radiation, SeD@MSNs-FA inhibits the growth of cervical cancer cells by inducing apoptosis through the death receptor-mediated apoptosis pathway and S phase arrest, significantly improving the sensitivity of cervical cancer cells to X-ray radiation. The combined activity of SeD@MSN-FA and radiation can promote excessive production of intracellular reactive oxygen species (ROS) and induce cell apoptosis by affecting p53, protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) pathways. Furthermore, SeD@MSNs-FA can effectively inhibit tumor growth of xenografted HeLa tumors in nude mice. The toxicity analysis of SeD@MSNs-FA nanoparticles in vivo and the histological analysis performed in the mouse model showed that under the current experimental conditions, the nanoparticles induced no significant damage to the heart, liver, spleen, lungs, kidneys, or other major organs. Taken together, this study provides a translational nanomedicine-based strategy for the simultaneous chemo- and radiotherapy of cervical cancer and sheds light on potential mechanisms that can be used to overcome radiotherapeutic resistance.
为了克服缺氧肿瘤的耐药性和辐射阻抗及辐射剂量的限制，我们开发了一种纳米增敏剂来提高癌症放射治疗的效果。我们使用多功能介孔硅纳米粒子（MSNs）作为载体，负载一种新型抗癌硒二唑衍生物（SeD），并通过叶酸（FA）对其表面进行修饰，以增强其对宫颈癌的靶向作用，形成了名为 SeD@MSNs-FA 的纳米系统。在辐射下，SeD@MSNs-FA 通过死亡受体介导的凋亡途径和 S 期阻滞诱导细胞凋亡，抑制宫颈癌细胞的生长，显著提高宫颈癌细胞对 X 射线辐射的敏感性。SeD@MSN-FA 与辐射的联合作用可通过影响 p53、蛋白激酶 B（AKT）和丝裂原活化蛋白激酶（MAPK）通路，促进细胞内活性氧（ROS）的过度产生，诱导细胞凋亡。此外，SeD@MSNs-FA 能有效抑制裸鼠异种移植 HeLa 肿瘤的生长。体内 SeD@MSNs-FA 纳米粒的毒性分析和小鼠模型中的组织学分析表明，在当前的实验条件下，纳米粒对心脏、肝脏、脾脏、肺、肾脏或其他主要器官没有引起明显的损伤。综上所述，该研究为宫颈癌的化疗和放疗联合治疗提供了一种基于转化医学的策略，并为克服放射治疗抵抗提供了潜在的机制。
