Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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.
Eur J Pharm Biopharm. 2020 Nov;156:84-96. doi: 10.1016/j.ejpb.2020.08.026. Epub 2020 Aug 31.
Simultaneous drug and gene delivery to cancer cells has been introduced to provide advantages of the synergistic effects of gene to sensitize the cancer cells to chemotherapeutic agent. In the current study, nucleolin-targeted co-delivery system, based on PEGylated rod-shaped mesoporous silica NPs was developed as a biocompatible nanocarrier for simultaneous delivery of camptothecin and survivin shRNA-expressing plasmid (iSur-DNA) to colon adenocarcinoma. The structural characterization including hydrodynamic radius and morphological characteristics of the prepared system demonstrated the mesoporous rod-shaped structure of the prepared system with 100-150 nm diameter. Camptothecin was loaded into the rod-shaped MSN NPs with encapsulation efficiency of 32%. At the next stage, the prepared camptothecin-loaded system was PEGylated and then iSur-DNA was condensed with C/P ratio of 6 to form PEG@MSNR-CPT/Sur. Then, the prepared camptothecin-iSur-DNA loaded PEGylated rod-shaped mesoporous silica NPs were tagged with AS1411 DNA aptamer (Apt-PEG@MSNR-CPT/Sur) in order to provide selective therapy against colorectal adenocarcinoma. The obtained results showed that the prepared platform controlled the release of anticancer drug, camptothecin. The experimental results indicated potent synergistic effect of iSur-pDNA and CPT in in vitro cytotoxicity, apoptosis induction and in vivo antitumor effect. In addition, tagging the system with AS1411 DNA aptamer facilitated drug uptake into nucleolin positive colorectal cancer cells leading to higher cellular toxicity and apoptosis induction in C26 cells compared to nucleolin-negative CHO cell line. Apt-PEG@MSNR-CPT/Sur system significantly supressed tumor growth rate in C26 tumor bearing mice while improving survival rate and pharmacokinetics of the platform in comparison with PEG@MSNR-CPT and PEG@MSNR-CPT/Sur. It could be concluded that the developed nucelolin targeted nanomedicine for co-delivery of camptothecin and iSur-DNA could serve as a versatile nanotherapeutic system against colorectal cancer.
将药物和基因同时递送到癌细胞中，以提供基因协同作用的优势，使癌细胞对化疗药物敏感。在本研究中，开发了基于聚乙二醇化棒状介孔硅纳米颗粒的核仁素靶向共递药系统，作为一种生物相容性的纳米载体，用于同时递送喜树碱和生存素 shRNA 表达质粒（iSur-DNA）到结肠腺癌。所制备系统的结构特征，包括水动力半径和形态特征，表明所制备系统具有 100-150nm 直径的介孔棒状结构。喜树碱以 32%的包封效率被载入棒状 MSN NPs 中。在下一步，用聚乙二醇化制备的载药系统，然后用 C/P 比为 6 将 iSur-DNA 凝聚形成 PEG@MSNR-CPT/Sur。然后，用 AS1411 DNA 适体（Apt-PEG@MSNR-CPT/Sur）标记制备的载药的 PEG 化棒状介孔硅纳米颗粒，以提供针对结直肠腺癌的选择性治疗。结果表明，所制备的平台控制了抗癌药物喜树碱的释放。实验结果表明，iSur-pDNA 和 CPT 在体外细胞毒性、细胞凋亡诱导和体内抗肿瘤作用方面具有协同作用。此外，用 AS1411 DNA 适体标记系统有助于将药物摄取到核仁素阳性结肠癌细胞中，与核仁素阴性 CHO 细胞系相比，导致 C26 细胞的细胞毒性和细胞凋亡诱导更高。Apt-PEG@MSNR-CPT/Sur 系统在 C26 荷瘤小鼠中显著抑制肿瘤生长速度，同时与 PEG@MSNR-CPT 和 PEG@MSNR-CPT/Sur 相比，提高了平台的药代动力学和生存率。可以得出结论，开发的核仁素靶向共载药纳米药物用于同时递送喜树碱和 iSur-DNA，可以作为一种针对结直肠癌的多功能纳米治疗系统。
