BACKGROUND The polymer-based drug/gene delivery is promising for the treatment of inherent or acquire disease, because of the polymer's structural flexibility, larger capacity for therapeutic agent, low host immunogenicity and less cost. Antisense therapy is an approach to fighting genetic disorders or infections using antisense oligonucleotides (AOs). Unfortunately, the naked AOs showed low therapeutic efficacy in vivo and in clinical trial due to their poor cellular uptake and fast clearance in bloodstream. In this study, a series of triazine-cored amphiphilic polymers (TAPs) were investigated for their potential to enhance delivery of AOs, 2'-O-methyl phosphorothioate RNA (2'-OMePS) and phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. RESULTS TAPs significantly enhanced AO-induced exon-skipping in a GFP reporter-based myoblast and myotube culture system, and observed cytotoxicity of the TAPs were lower than Endoporter, Lipofectamine-2000 or PEI 25K. Application of optimized formulations of TAPs with AO targeted to dystrophin exon 23 demonstrated a significant increase in exon-skipping efficiency in dystrophic mdx mice. The best ones for PMO and 2'-OMePS delivery have reached to 11-, 15-fold compared with the AO only in mdx mice, respectively. CONCLUSION The study of triazine-cored amphiphilic polymers for AO delivery in vitro and in mdx mice indicated that the carrier's performances are related to the molecular size, compositions and hydrophilic-lipophilic balance (HLB) of the polymers, as well as the AO's structure. Improved exon-skipping efficiency of AOs observed in vitro and in mdx mice accompanied with low cytotoxicity demonstrated TAP polymers are potentials as safe and effective delivery carrier for gene/drug delivery.

中文翻译：

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用于体外和体内反义寡核苷酸递送的三嗪核心聚合载体。


背景技术基于聚合物的药物/基因递送由于聚合物的结构灵活性、较大的治疗剂容量、较低的宿主免疫原性和较低的成本而有望用于治疗先天性疾病或获得性疾病。反义疗法是一种使用反义寡核苷酸（AO）对抗遗传性疾病或感染的方法。不幸的是，由于细胞摄取差和血流清除快，裸露的 AO 在体内和临床试验中表现出较低的治疗效果。在本研究中，研究了一系列以三嗪为核心的两亲聚合物 (TAP) 的体外增强 AO、2'-O-甲基硫代磷酸酯 RNA (2'-OMePS) 和磷酸二酰胺吗啉低聚物 (PMO) 递送的潜力。和体内。结果 在基于 GFP 报告基因的成肌细胞和肌管培养系统中，TAP 显着增强了 AO 诱导的外显子跳跃，并且观察到的 TAP 细胞毒性低于 Endoporter、Lipofectamine-2000 或 PEI 25K。应用针对肌营养不良蛋白外显子 23 的 AO 优化 TAP 配方，证明营养不良 mdx 小鼠的外显子跳跃效率显着增加。与仅在 mdx 小鼠中使用 AO 相比，PMO 和 2'-OMePS 递送的最佳效果分别达到了 11 倍和 15 倍。结论 三嗪核两亲性聚合物在体外和 mdx 小鼠中用于 AO 递送的研究表明，载体的性能与聚合物的分子大小、组成和亲水亲油平衡 (HLB) 以及 AO 的结构有关。在体外和 mdx 小鼠中观察到的 AO 外显子跳跃效率提高，且细胞毒性低，证明 TAP 聚合物有可能作为安全有效的基因/药物递送载体。