Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer.
Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer.
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DOI：
10.1016/j.omtn.2020.10.001
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发表时间：
2020-12-04
期刊：
影响因子：
--
通讯作者：
Obika S
中科院分区：
文献类型：
--
作者：
Kanda M;Kasahara Y;Shimizu D;Miwa T;Umeda S;Sawaki K;Nakamura S;Kodera Y;Obika S
胃癌腹膜转移患者预后不佳，主要原因是腹膜肿瘤的全身给药效率低下。我们旨在利用氨基桥接核酸（AmNA）修饰的反义寡核苷酸（ASOs）开发针对synaptotagmin XIII （SYT13）的腹腔内治疗策略，并确定SYT13在胃癌细胞中的功能。我们根据syt13的敲除效果、体外活性和脱靶效应筛选了71个候选寡核苷酸序列。我们评估了SYT13敲低对细胞功能和信号通路的影响，以及腹腔注射amna修饰的抗SYT13 ASOs对小鼠的影响。我们选择了敲除效率最高、脱靶效应最低的ASOs（编号为hSYT13-4378和hSYT13-4733），并测定了它们抑制与胃癌细胞转移潜能相关的细胞功能的能力。我们发现SYT13干扰了focal adhesion kinase （FAK）介导的细胞内信号。腹腔注射hSYT13-4378和hSYT13-4733小鼠转移瘤模型可抑制腹膜结节的形成，显著提高生存率。ASO治疗可诱导可逆性、剂量依赖性和序列依赖性的肝损伤，但不会引起大脑的异常形态学和组织学改变。腹腔内给药amna修饰的抗syt13 ASOs是治疗胃癌腹膜转移的一种有希望的策略。为了给胃癌腹膜转移患者提供一种新的治疗选择，我们设计了靶向synaptotagmin XIII （SYT13）的氨基桥接核酸（AmNA）修饰反义寡核苷酸（ASOs）。腹腔内给药amna修饰的抗syt13 ASOs是治疗胃癌腹膜转移的一种有希望的策略。
Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13) and to identify the function of SYT13 in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to SYT13-knockdown efficacy, in vitro activity, and off-target effects. We evaluated the effects of SYT13 knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that SYT13 interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer. To propose a novel treatment option for patients with peritoneal metastasis of gastric cancer, we designed amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13). Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.
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