基于功能化金属有机框架的短发夹 RNA 和辛伐他汀的受控双药物递送系统用于治疗结直肠癌铁死亡,Advanced Therapeutics

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基于功能化金属有机框架的短发夹 RNA 和辛伐他汀的受控双药物递送系统用于治疗结直肠癌铁死亡
Advanced Therapeutics ( IF 3.7 ) Pub Date : 2023-04-20 , DOI: 10.1002/adtp.202200356
Haixia Liu ₁ , Xianxian Yao ₂ , Weichu Zhu ₂ , Jiaxin Zhang ₂ , Shuangping Ma ₁ , Daru Lu ₁ , Wuli Yang ₂

Affiliation

结直肠癌是全球癌症相关死亡的最常见原因之一。铁死亡是一种非凋亡形式的受调节细胞死亡，可由过度的脂质过氧化引发，并提供了另一种癌症治疗选择。为了设计针对铁死亡的纳米药物，合成了一种新型纳米颗粒。将抗肿瘤剂辛伐他汀 (SIM) 和专门设计的短发夹 RNA (shRNA) 共同负载到涂有聚羧基甜菜碱甲基丙烯酸酯 (PCBMA) 的沸石咪唑酯框架 8 (ZIF-8) 纳米颗粒中。构建的shRNA/ZIF-8@PCBMA-SIM纳米颗粒可有效消除体内人结直肠癌细胞，由于其改进的靶向能力和在肿瘤部位递送的抗肿瘤药物的高度保留，显示出优异的抗肿瘤细胞毒性。此外，SIM和shRNA下调铁死亡相关酶3-羟基-3-甲基戊二酰辅酶A还原酶和谷胱甘肽过氧化物酶4的表达，从而引发癌细胞铁死亡。鉴于 SIM 已被批准用于临床，并且 shRNA 具有高效下调胱氨酸/谷氨酸逆向转运蛋白 (x-CT) 系统蛋白（亚基 SLC7A11）的能力，shRNA/ZIF-8@PCBMA-SIM 纳米粒子显示出巨大的临床治疗潜力结直肠癌通过铁死亡。这提出了一种解决化疗局限性的替代疗法。shRNA 可高效下调胱氨酸/谷氨酸逆向转运蛋白 (x-CT) 系统蛋白（亚基 SLC7A11），shRNA/ZIF-8@PCBMA-SIM 纳米粒子显示出通过铁死亡治疗结直肠癌的巨大临床潜力。这提出了一种解决化疗局限性的替代疗法。shRNA 可高效下调胱氨酸/谷氨酸逆向转运蛋白 (x-CT) 系统蛋白（亚基 SLC7A11），shRNA/ZIF-8@PCBMA-SIM 纳米粒子显示出通过铁死亡治疗结直肠癌的巨大临床潜力。这提出了一种解决化疗局限性的替代疗法。

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A Functionalized Metal–Organic Framework-Based Controlled Dual-Drug Delivery System with Short Hairpin RNA and Simvastatin for Ferroptosis in Colorectal Cancer

Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. Ferroptosis is a non-apoptotic form of regulated cell death that can be triggered by excessive lipid peroxidation and provides an alternative cancer treatment option. To design ferroptosis-targeted nanomedicine, a new type of nanoparticle is synthesized. The antineoplastic agent simvastatin (SIM) and specifically designed short hairpin RNA (shRNA) are co-loaded into zeolitic imidazolate framework-8 (ZIF-8) nanoparticles coated with poly(carboxybetaine methacrylate) (PCBMA). The constructed shRNA/ZIF-8@PCBMA-SIM nanoparticles effectively eliminate human colorectal carcinoma cells in vivo, showing superior cytotoxicity against tumors owing to their improved targeting ability and the high retention of antineoplastic agents delivered at tumor sites. Furthermore, SIM and shRNA downregulate the expression of ferroptosis-related enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and glutathione peroxidase 4, thus, triggering ferroptosis in cancer cells. Given that SIM is already approved for clinical use, and shRNA offers high potency to downregulate the cystine/glutamate antiporter (x-CT) system protein (subunit SLC7A11), shRNA/ZIF-8@PCBMA-SIM nanoparticles show great clinical potential to treat colorectal cancer via ferroptosis. This presents an alternative therapy that addresses the limitations of chemotherapy.

更新日期：2023-04-20

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