School of Pharmacy, Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, China.
Molecules. 2024 Sep 5;29(17):4223. doi: 10.3390/molecules29174223.
Oligonucleotide drugs are shining in clinical therapeutics, but efficient and safe delivery systems severely limit their widespread use. A disulfide unit technology platform based on dynamic thiol exchange chemistry at the cell membrane has the potential for drug delivery. However, the alteration of the disulfide unit CSSC dihedral angle induced by different substituents directly affects the effectiveness of this technology and its stability. Previously, we constructed a trivalent low dihedral angle disulfide unit that can effectively promote the cellular uptake of small molecules. Here, we constructed a novel disulfide unit-masked oligonucleotide hybrid based on a low dihedral angle disulfide unit, motivated by prodrug design. Cellular imaging results showed that such a system exhibited superior cellular delivery efficiency than the commercial Lipo2000 without cytotoxicity. The thiol reagents significantly reduced its cellular uptake (57-74%), which proved to be endocytosis-independent. In addition, in vivo distribution experiments in mice showed that such systems can be rapidly distributed in liver tissues with a duration of action of more than 24 h, representing a potential means of silencing genes involved in the pathogenesis of liver-like diseases. In conclusion, this trivalent disulfide unit-masked system we constructed can effectively deliver large oligonucleotide drugs.
寡核苷酸药物在临床治疗中大放异彩，但高效且安全的递送系统严重限制了其广泛应用。基于细胞膜动态硫醇交换化学的二硫键单元技术平台具有药物递送的潜力。然而，不同取代基诱导的二硫键单元 CSSC 二面角的改变直接影响该技术的有效性及其稳定性。此前，我们构建了一种具有低二面角的三价低二硫键单元，可有效促进小分子的细胞摄取。在这里，受前药设计的启发，我们基于低二面角二硫键单元构建了一种新型的二硫键单元掩蔽寡核苷酸杂合体。细胞成像结果表明，该系统表现出优于具有细胞毒性的商业 Lipo2000 的细胞递药效率。硫醇试剂显著降低了其细胞摄取（57-74%），这被证明与内吞作用无关。此外，在小鼠体内分布实验中表明，此类系统可以快速分布在肝脏组织中，作用持续时间超过 24 小时，这代表了沉默与肝样疾病发病机制相关基因的潜在手段。总之，我们构建的这种三价二硫键单元掩蔽系统可以有效地递送大型寡核苷酸药物。
