Combination therapy based on dual-target biomimetic nano-delivery system for overcoming cisplatin resistance in hepatocellular carcinoma.
Combination therapy based on dual-target biomimetic nano-delivery system for overcoming cisplatin resistance in hepatocellular carcinoma.
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DOI：
10.1186/s12951-023-01840-3
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发表时间：
2023-03-14
影响因子：
10.2
通讯作者：
Li, Jian
中科院分区：
文献类型：
--
作者：
Huang, Yufen;Kou, Qinjie;Su, Yanrong;Lu, Lu;Li, Xisheng;Jiang, Haiye;Gui, Rong;Huang, Rong;Nie, Xinmin;Li, Jian
靶向治疗肝细胞癌（HCC）迫切需要克服化疗药物毒性和耐药性的策略。先前的研究表明，含氧化硝基结构域蛋白1（NOR1）在HCC中的高表达与顺铂（DDP）耐药有关。本文提出了一种新的双靶向纳米载体系统AR-NADR，用于治疗肝癌DDP耐药。纳米载体体系的核心是核定位序列修饰的金属有机骨架（MOF），其上装载DDP和NOR1 shRNA (R)。其外壳是插入红细胞膜（AR）的A54肽。我们的研究结果表明，AR-NADR由于其特异性结合在HCC细胞表面大量表达的A54受体和NLS肽介导的核进入而被肿瘤细胞有效内化。此外，在酸性肿瘤微环境中，由于Ag-MOF的降解，DDP更容易被释放。此外，AR-NADR作为基因传递的载体，通过抑制NOR1的表达，有效抑制肿瘤耐药，从而诱导细胞内DDP积累，使细胞对DDP敏感。最后，通过HepG2/DDP细胞模型和肿瘤模型系统阐明AR-NADR的抗hcc作用及其机制。因此，AR-NADR是实现良好基因沉默和抗肿瘤疗效的关键策略，为肝癌顺铂耐药提供了有效的基因治疗和精准的治疗策略。
Strategies to overcome toxicity and drug resistance caused by chemotherapeutic drugs for targeted therapy against hepatocellular carcinoma (HCC) are urgently needed. Previous studies revealed that high oxidored-nitro domain-containing protein 1(NOR1) expression in HCC was associated with cisplatin (DDP) resistance. Herein, a novel dual-targeting nanocarrier system AR-NADR was generated for the treatment of DDP resistance in HCC. The core of the nanocarrier system is the metal–organic frameworks (MOF) modified with nuclear location sequence (NLS), which loading with DDP and NOR1 shRNA (R). The shell is an A54 peptide inserted into the erythrocyte membrane (AR). Our results show that AR-NADR efficiently internalized by tumor cells due to its specific binding to the A54 receptors that are abundantly expressed on the surface of HCC cells and NLS peptide-mediated nuclear entry. Additionally, DDP is more likely to be released due to the degradation of Ag-MOF in the acidic tumor microenvironment. Moreover, by acting as a vector for gene delivery, AR-NADR effectively inhibits tumor drug resistance by suppressing the expression of NOR1, which induces intracellular DDP accumulation and makes cells sensitive to DDP. Finally, the anti-HCC efficacy and mechanisms of AR-NADR were systematically elucidated by a HepG2/DDP cell model as well as a tumor model. Therefore, AR-NADR constitutes a key strategy to achieve excellent gene silencing and antitumor efficacy, which provides effective gene therapy and precise treatment strategies for cisplatin resistance in HCC.
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影响因子：
17.1
作者：
Kim H;Yuk SA;Dieterly AM;Kwon S;Park J;Meng F;Gadalla HH;Cadena MJ;Lyle LT;Yeo Y
通讯作者：
Yeo Y
影响因子：
2.9
作者：
Li DQ;Qiu M;Nie XM;Gui R;Huang MZ
通讯作者：
Huang MZ
影响因子：
11.2
作者：
Hou, Guanghui;Qian, Junmin;Suo, Aili
通讯作者：
Suo, Aili
A54 肽功能化聚合物胶束实现肿瘤细胞特异性靶向递送
影响因子：
14
作者：
Du, Yong-Zhong;Cai, Li-Li;Hu, Fu-Qiang
通讯作者：
Hu, Fu-Qiang
影响因子：
5.8
作者：
Hassan, Eman M.;Zou, Shan
通讯作者：
Zou, Shan