Abstract:
A short 19 bp dsRNA with 3\'-trinucleotide overhangs acting as immunostimulating RNA (isRNA) demonstrated strong antiproliferative action against cancer cells, immunostimulatory activity through activation of cytokines and Type-I IFN secretion, as well as anti-tumor and anti-metastatic effects in vivo. The aim of this study was to determine the tolerance of chemical modifications (2\'-F, 2\'-OMe, PS, cholesterol, and amino acids) located at different positions within this isRNA to its ability to activate the innate immune system. The obtained duplexes were tested in vivo for their ability to activate the synthesis of interferon-α in mice, and in tumor cell cultures for their ability to inhibit their proliferation. The obtained data show that chemical modifications in the composition of isRNA have different effects on its individual functions, including interferon-inducing and antiproliferative effects. The effect of modifications depends not only on the type of modification but also on its location and the surrounding context of the modifications. This study made it possible to identify leader patterns of modifications that enhance the properties of isRNA: F2/F2 and F2_S/F2 for interferon-inducing activity, as well as F2_S5/F2_S5, F2-NH2/F2-NH2, and Ch-F2/Ch-F2 for antiproliferative action. These modifications can improve the pharmacokinetic and pharmacodynamic properties, as well as increase the specificity of isRNA action to obtain the desired effect.
摘要:
具有3'-三核苷酸突出的短19bpdsRNA作为免疫刺激RNA(isRNA)表现出对癌细胞的强烈抗增殖作用。通过激活细胞因子和I型IFN分泌的免疫刺激活性,以及体内抗肿瘤和抗转移作用。这项研究的目的是确定化学修饰的耐受性(2'-F,2\'-OMe,PS,胆固醇,和氨基酸)位于此isRNA内的不同位置,以激活先天免疫系统。在体内测试获得的双链体激活小鼠干扰素-α合成的能力,以及在肿瘤细胞培养物中抑制其增殖的能力。获得的数据表明,isRNA组成中的化学修饰对其个体功能有不同的影响,包括干扰素诱导和抗增殖作用。修改的效果不仅取决于修改的类型,还取决于其位置和修改的周围环境。这项研究使得确定增强isRNA的特性的修饰的前导模式成为可能:F2/F2和F2_S/F2用于干扰素诱导活性,以及F2_S5/F2_S5,F2-NH2/F2-NH2和Ch-F2/Ch-F2的抗增殖作用。这些修饰可以改善药代动力学和药效学特性,以及增加isRNA作用的特异性以获得所需的效果。