Redox-Responsive Disulfide Cyclic Peptides: A New Strategy for siRNA Delivery
Redox-Responsive Disulfide Cyclic Peptides: A New Strategy for siRNA Delivery
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DOI：
10.1021/acs.molpharmaceut.1c00879
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发表时间：
2022-03-16
影响因子：
4.9
通讯作者：
Aliabadi, Hamidreza Montazeri
中科院分区：
文献类型：
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作者：
Mandal, Dindyal;Mohammed, Eman H. M.;Aliabadi, Hamidreza Montazeri
RNA干扰（RNAi）是一种强大的工具，可以靶向几乎任何蛋白质，而无需耗时和昂贵的药物开发研究。然而，由于面临高效和安全递送的障碍，基于rnai的治疗方法仍然是一个挑战。在此，我们利用色氨酸和精氨酸残基设计并合成了一些限制二硫的环状肽和杂化肽。我们的假设是肽结构会被细胞内谷胱甘肽（在癌细胞中更丰富）还原，并从肽/siRNA复合物中解开小干扰RNA（siRNA）。一部分新发育的肽（特别是c4和h4）表现出sirna的有效细胞内化(类似于70%的细胞群；通过流式细胞术和共聚焦显微镜监测)，保护siRNA免受核酸酶早期降解的能力（通过凝胶电泳监测），在选定的细胞系中最小的细胞毒性（通过细胞活力和lc50计算研究），以及在人三阴性乳腺癌（TNBC） MDA-MB-231细胞中靶向信号转导和转录激活因子3 （STAT3）表达减少70-75%的有效蛋白质沉默。采用Western blot技术分析。我们的研究结果表明，即使在核酸酶存在的情况下，一个有希望的siRNA递送系统新家族的诞生也能够安全有效地递送
RNA interference (RNAi) is a powerful tool capable of targeting virtually any protein without time-consuming and expensive drugdevelopment studies. However, due to obstacles facing efficient and safedelivery, RNAi-based therapeutic approach remains a challenge. Herein, wehave designed and synthesized a number of disulfide-constraining cyclic andhybrid peptides using tryptophan and arginine residues. Our hypothesis wasthat peptide structures would undergo reduction by intracellular glutathione(more abundant in cancer cells) and unpack the small interfering RNA(siRNA) from the peptide/siRNA complexes. A subset of newly developedpeptides (specifically,C4andH4) exhibited effective cellular internalization ofsiRNA (similar to 70% of the cell population; monitored byflow cytometry andconfocal microscopy), the capability of protecting siRNA against earlydegradation by nucleases (monitored by gel electrophoresis), minimalcytotoxicity in selected cell lines (studied by cell viability and LC50calculations), and efficient protein silencing by 70-75%reduction in the expression of targeting signal transducer and activator of transcription 3 (STAT3) in human triple-negative breastcancer (TNBC) MDA-MB-231 cells, analyzed using the Western blot technique. Our results indicate the birth of a promising newfamily of siRNA delivery systems that are capable of safe and efficient delivery, even in the presence of nucleases