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Framework nucleic acid-based nanoparticles enhance temozolomide sensitivity in glioblastoma
Drug Resistance Updates ( IF 15.8 ) Pub Date : 2024-07-27 , DOI: 10.1016/j.drup.2024.101122 Yufei Lan 1 , Xiaodie Li 1 , Boyang Liu 2 , Jiankun Lu 1 , Boming Zuo 1 , Yue Wang 3 , Shuting Cao 4 , Xin Fu 1 , Qu Yue 1 , Xin Luo 1 , Xiangyang Zhong 1 , Yaoyuan Dong 1 , Zhao Wang 1 , Tao Yang 1 , Xinyun Xie 1 , Tianci Zeng 1 , Manqing Zhang 1 , Yuankai Wang 1 , Yixiong Shen 1 , Huaqin Zuo 5 , Yan Zhao 6 , Chao Zhang 1 , Hongbo Guo 1
Drug Resistance Updates ( IF 15.8 ) Pub Date : 2024-07-27 , DOI: 10.1016/j.drup.2024.101122 Yufei Lan 1 , Xiaodie Li 1 , Boyang Liu 2 , Jiankun Lu 1 , Boming Zuo 1 , Yue Wang 3 , Shuting Cao 4 , Xin Fu 1 , Qu Yue 1 , Xin Luo 1 , Xiangyang Zhong 1 , Yaoyuan Dong 1 , Zhao Wang 1 , Tao Yang 1 , Xinyun Xie 1 , Tianci Zeng 1 , Manqing Zhang 1 , Yuankai Wang 1 , Yixiong Shen 1 , Huaqin Zuo 5 , Yan Zhao 6 , Chao Zhang 1 , Hongbo Guo 1
Affiliation
O-methylguanine DNA methyltransferase (MGMT) is a crucial determinant of temozolomide (TMZ) sensitivity in patients with glioblastoma (GBM). The therapeutic potential of small interfering RNA (siRNA) targeting MGMT to enhance TMZ sensitivity has been hampered by serum nuclease degradation, off-target effects, poor accumulation at tumor sites, and low circulation in blood stream. In this study, we developed a framework nucleic acid-based nanoparticles (FNN), which is constructed from a six-helix DNA bundle, to encapsulate and protect siMGMT for improving TMZ sensitivity in GBM treatment. For better blood-brain barrier (BBB) penetration and GBM targeting, we conjugated Angiopep-2 (ANG) targeting modules to each end of the FNN. Nucleolin (NCL)-responsive locks were engineered along the sides of the six-helix DNA bundle, which safeguard siMGMT before tumor entry. Upon interaction with tumor-overexpressed NCL, these locks unlock, exposing siMGMT, this allows for effective suppression of MGMT, resulting in a significant improvement of TMZ therapeutic efficacy in GBM. This innovative strategy has the potential to transform the current treatment landscape for GBM.
中文翻译:
基于核酸的纳米粒子框架增强胶质母细胞瘤中替莫唑胺的敏感性
O-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 是胶质母细胞瘤 (GBM) 患者替莫唑胺 (TMZ) 敏感性的关键决定因素。靶向 MGMT 的小干扰 RNA (siRNA) 增强 TMZ 敏感性的治疗潜力受到血清核酸酶降解、脱靶效应、肿瘤部位积聚不良和血流低循环等因素的阻碍。在这项研究中,我们开发了一种基于核酸的框架纳米颗粒(FNN),它由六螺旋DNA束构建,用于封装和保护siMGMT,以提高GBM治疗中TMZ的敏感性。为了更好地穿透血脑屏障 (BBB) 和 GBM 靶向,我们将 Angiopep-2 (ANG) 靶向模块结合到 FNN 的两端。核仁素 (NCL) 响应锁沿着六螺旋 DNA 束的侧面设计,可在肿瘤进入之前保护 siMGMT。当与肿瘤过度表达的 NCL 相互作用时,这些锁会解锁,暴露 siMGMT,从而有效抑制 MGMT,从而显着提高 TMZ 在 GBM 中的治疗效果。这一创新策略有可能改变当前 GBM 的治疗格局。
更新日期:2024-07-27
中文翻译:
基于核酸的纳米粒子框架增强胶质母细胞瘤中替莫唑胺的敏感性
O-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 是胶质母细胞瘤 (GBM) 患者替莫唑胺 (TMZ) 敏感性的关键决定因素。靶向 MGMT 的小干扰 RNA (siRNA) 增强 TMZ 敏感性的治疗潜力受到血清核酸酶降解、脱靶效应、肿瘤部位积聚不良和血流低循环等因素的阻碍。在这项研究中,我们开发了一种基于核酸的框架纳米颗粒(FNN),它由六螺旋DNA束构建,用于封装和保护siMGMT,以提高GBM治疗中TMZ的敏感性。为了更好地穿透血脑屏障 (BBB) 和 GBM 靶向,我们将 Angiopep-2 (ANG) 靶向模块结合到 FNN 的两端。核仁素 (NCL) 响应锁沿着六螺旋 DNA 束的侧面设计,可在肿瘤进入之前保护 siMGMT。当与肿瘤过度表达的 NCL 相互作用时,这些锁会解锁,暴露 siMGMT,从而有效抑制 MGMT,从而显着提高 TMZ 在 GBM 中的治疗效果。这一创新策略有可能改变当前 GBM 的治疗格局。