Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
J Mater Chem B. 2021 Feb 15;9(5):1351-1363. doi: 10.1039/d0tb01960g.
In this study, a dual-receptor doxorubicin-targeted delivery system based on mesoporous silica nanoparticles (MSNs) modified with mucine-1 and ATP aptamers (DOX@MSNs-Apts) was developed. An amine-modified mucine-1 (MUC1) aptamer was covalently anchored on the surface of carboxyl-functionalized MSNs. Then, ATP aptamers (ATP1 and ATP2 aptamers) were immobilized on the surface of MSNs through partial hybridization with the MUC1 aptamer by forming a Y-shaped DNA structure on the MSNs surface (DOX@MSNs-Apts) as a gatekeeper. The developed DOX@MSNs-Apts exhibited high DOX loading capacity. In addition, it indicated an ATP-responsive feature, leading to the release of DOX in the environment with high ATP concentration (10 mM), similar to the intracellular environment of tumor cells. This property demonstrated that anticancer drug (DOX) could be entrapped inside the nanocarrier with nearly no leakage in blood and a very low concentration of ATP (1 μM). It was found that after the internalization of DOX@MSNs-MUC1 by cancer cells via the MUC1 receptor-mediated endocytosis, the ATP aptamers left the surface of the nanocarrier, allowing for rapid DOX release. DOX@MSNs-Apts indicated higher cellular uptake in MCF-7 and C26 cancer cells (MUC1+), rather than CHO cells (MUC1-). The in vitro cytotoxicity and the in vivo antitumor efficacy of DOX@MSNs-Apts showed greater cytotoxicity than the nanoparticles decorated with scrambled ATP aptamers (DOX@MSNs-Apts scrambled) in C26 and MCF-7 cell lines (MUC1+). The biodistribution and in vivo anticancer efficacy on the C26 tumor bearing mice indicated that the DOX@MSNs-Apts had a higher tumor accumulation and superior tumor growth inhibitory effect compared to free DOX and their scrambled aptamers, DOX@MSNs-Apts scrambled. Overall, the obtained results indicated that the prepared smart platform could reveal new insights into the treatment of cancer.
在这项研究中，开发了一种基于介孔硅纳米粒子（MSNs）的双受体阿霉素靶向递药系统，该系统通过修饰粘蛋白-1（MUC1）和 ATP 适体（DOX@MSNs-Apts）进行修饰。胺修饰的粘蛋白-1（MUC1）适体通过与羧基功能化的 MSNs 表面的部分杂交被共价固定在表面上。然后，ATP 适体（ATP1 和 ATP2 适体）通过在 MSNs 表面形成 Y 形 DNA 结构而被固定在 MSNs 表面上（DOX@MSNs-Apts）作为门控。所开发的 DOX@MSNs-Apts 具有高 DOX 载药能力。此外，它显示出 ATP 响应的特征，导致在高 ATP 浓度（10 mM）的环境中释放 DOX，类似于肿瘤细胞的细胞内环境。该特性表明，抗癌药物（DOX）可以被包裹在纳米载体中，在血液中几乎没有泄漏，并且 ATP 浓度非常低（1 μM）。结果发现，通过 MUC1 受体介导的内吞作用，癌细胞内化 DOX@MSNs-MUC1 后，ATP 适体离开纳米载体表面，从而允许快速释放 DOX。DOX@MSNs-Apts 在 MCF-7 和 C26 癌细胞（MUC1+）中显示出更高的细胞摄取率，而在 CHO 细胞（MUC1-）中则较低。在 C26 和 MCF-7 细胞系（MUC1+）中，DOX@MSNs-Apts 的体外细胞毒性和体内抗肿瘤功效表明，其具有比用随机化 ATP 适体修饰的纳米粒子（DOX@MSNs-Apts scrambled）更高的细胞毒性。在荷 C26 肿瘤的小鼠中的生物分布和体内抗肿瘤功效表明，与游离 DOX 和它们的随机化适体 DOX@MSNs-Apts scrambled 相比，DOX@MSNs-Apts 具有更高的肿瘤积累和优越的肿瘤生长抑制作用。总的来说，所得结果表明，所制备的智能平台可以为癌症治疗提供新的见解。
