Alibolandi Mona, Taghdisi Seyed Mohammad, Ramezani Pouria, Hosseini Shamili Fazileh, Farzad Sara Amel, Abnous Khalil, Ramezani Mohammad
Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Targeted Drug Delivery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Int J Pharm. 2017 Mar 15;519(1-2):352-364. doi: 10.1016/j.ijpharm.2017.01.044. Epub 2017 Jan 23.
In the current study camptothecin-loaded pegylated PAMAM dendrimer were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against colorectal cancer cells which over expresses nucleolin receptors. The morphological properties and size dispersity of the prepared nanoparticles were evaluated using transmission electron microscope (TEM) and DLS. The drug-loading content and encapsulation efficiency were obtained 8.1% and 93.67% respectively. The in vitro release of camptothecin from the formulation was provided the sustained release of encapsulated camptothecin during 4days. Comparative in vitro cytotoxicity experiments demonstrated that the targeted camptothecin loaded-pegylated dendrimers had higher antiproliferation activity, towards nucleolin-positive HT29 and C26 colorectal cancer cells than nucleolin-negative CHO cell line. Fluorscence microscopy and flow cytometry also confirmed the enhanced cellular uptake of AS1411 targeted pegylated-dendrimer. In vivo study in C26 tumor-bearing BALB/C mice revealed that the AS1411-functionalized camptothecin loaded pegylated dendrimers improved antitumor activity and survival rate of the encapsulated camptothecin. Conjugation of AS1411 aptamer to the camptothecin loaded-pegylated dendrimer surface provides site-specific delivery of camptothecin, inhibit C26 tumor growth in vivo and significantly decrease systemic toxicity. These results suggested that the new nucleolin-targeted pegylated PAMAM dendrimer as a delivery system for camptothecin have the potential for the treatment of nucleolin-overexpressed colorectal cancer.
在当前研究中，合成了负载喜树碱的聚乙二醇化聚酰胺 - 胺（PAMAM）树枝状大分子，并用AS1411抗核仁素适配体进行功能化，以针对过度表达核仁素受体的结肠直肠癌细胞进行位点特异性靶向。使用透射电子显微镜（TEM）和动态光散射（DLS）评估制备的纳米颗粒的形态特性和尺寸分散性。载药量和包封率分别为8.1%和93.67%。喜树碱从制剂中的体外释放显示在4天内包封的喜树碱呈持续释放。比较体外细胞毒性实验表明，靶向负载喜树碱的聚乙二醇化树枝状大分子对核仁素阳性的HT29和C26结肠直肠癌细胞的抗增殖活性高于核仁素阴性的CHO细胞系。荧光显微镜和流式细胞术也证实了AS1411靶向聚乙二醇化树枝状大分子的细胞摄取增强。对携带C26肿瘤的BALB / c小鼠的体内研究表明，AS1411功能化的负载喜树碱的聚乙二醇化树枝状大分子提高了包封喜树碱的抗肿瘤活性和存活率。将AS1411适配体缀合到负载喜树碱的聚乙二醇化树枝状大分子表面可实现喜树碱的位点特异性递送，抑制体内C26肿瘤生长并显著降低全身毒性。这些结果表明，新型核仁素靶向聚乙二醇化PAMAM树枝状大分子作为喜树碱的递送系统具有治疗核仁素过表达的结肠直肠癌的潜力。
