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The Antitumor Efficacy of CpG Oligonucleotides is Improved by Encapsulation in Plant Virus-Like Particles

机译:通过封装在植物病毒样颗粒中提高了CpG寡核苷酸的抗肿瘤功效。

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Oligodeoxynucleotides (ODNs) with CpG motifs have potent immunostimulatory effects on many subsets of immune cells. For example, Class B CpG-ODNs, such as ODN1826 induce the phagocytic activity of macrophages by activating the Toll-like receptor 9 signaling pathway. Systemic ODN delivery results in unfavorable pharmacokinetic profiles and can trigger adverse effects. To address this issue, plant virus-like particles (VLPs) are developed for the targeted delivery of ODN1826 to tumor-associated macrophages (TAMs). ODN1826 is encapsulated by the in vitro disassembly and reassembly of Cowpea chlorotic mottle virus (CCMV), producing VLPs that are structurally analogous to the native virus. The encapsulation of ODN1826 in CCMV-derived VLPs promotes ODN uptake by TAMs ex vivo and significantly enhance their phagocytic activity. The antitumor activity of the VLPs in vivo is also evaluated, revealing that the direct injection of ODN1826 VLPs into established tumors induces a robust antitumor response by increasing the phagocytic activity of TAMs in the tumor microenvironment. CCMV encapsulation significantly enhances the efficacy of ODN1826 compared to the free drug, slowing tumor growth and prolonging survival in mouse models of colon cancer and melanoma.
机译:具有CpG基序的寡脱氧核苷酸(ODN)对免疫细胞的许多亚型具有强大的免疫刺激作用。例如,B类CpG-ODN,例如ODN1826,通过激活Toll样受体9信号传导途径诱导巨噬细胞的吞噬活性。全身性ODN递送导致不利的药代动力学特征,并可能引发不良反应。为了解决此问题,开发了植物病毒样颗粒(VLP),用于将ODN1826靶向递送至肿瘤相关的巨噬细胞(TAM)。 ODN1826通过of豆褪绿斑驳病毒(CCMV)的体外分解和重组进行封装,从而产生结构上与天然病毒相似的VLP。将ODN1826封装在CC​​MV衍生的VLP中可促进TAM体外吸收ODN,并显着增强其吞噬活性。还评估了VLP在体内的抗肿瘤活性,表明将ODN1826 VLP直接注射到已建立的肿瘤中可通过增加肿瘤微环境中TAM的吞噬活性来诱导强大的抗肿瘤反应。与游离药物相比,CCMV封装显着增强了ODN1826的功效,在结肠癌和黑色素瘤的小鼠模型中减慢了肿瘤的生长并延长了存活时间。

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