Membrane-destabilizing ionizable lipid empowered imaging-guided siRNA delivery and cancer treatment.
Membrane-destabilizing ionizable lipid empowered imaging-guided siRNA delivery and cancer treatment.
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DOI：
10.1002/exp.20210008
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发表时间：
2021-08
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影响因子：
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通讯作者：
Huang, Yuanyu
中科院分区：
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作者：
Guo, Shuai;Li, Kun;Hu, Bo;Li, Chunhui;Zhang, Mengjie;Hussain, Abid;Wang, Xiaoxia;Cheng, Qiang;Yang, Feng;Ge, Kun;Zhang, Jinchao;Chang, Jin;Liang, Xing-Jie;Weng, Yuhua;Huang, Yuanyu
癌症治疗的迫切医疗要求之一是如何建立一种成像引导的纳米载体，将治疗剂和成像剂结合到一个系统中。siRNA疗法在控制危及生命的疾病方面显示出良好的前景。然而，开发具有优异的细胞进入能力、有效的内体逃逸和同时可视化的siRNA制剂仍然具有挑战性。本文中，我们制备了用于靶向递送siRNA和MRI造影剂的多功能可电离脂质纳米粒（iLNP）。iLNP包含DSPC、胆固醇、PEG化脂质、造影剂DTPA-BSA（Gd）和称为iBL 0104的可电离脂质。负载siRNA的iLNP（iLNP/siRNA）可以用肿瘤靶向环肽（c（GRGDSPKC））（称为GARP）或无靶向修饰（称为GAP）修饰。数据显示，GARP/siRNA iLNP表现出比GAP/siRNA iLNP显著更高的细胞进入效率。GARP/siRNA iLNP在内化后迅速有效地从内体和溶酶体逃逸。与GAP/siPLK 1相比，GARP/siPLK 1在细胞系来源的异种移植物和肝癌患者来源的异种移植物小鼠模型中均表现出更好的肿瘤抑制功效。此外，GARP制剂在荷瘤小鼠中显示出理想的MRI效果，并且被测试动物良好耐受。因此，这项研究为实现成像引导和肿瘤靶向siRNA递送和癌症治疗提供了一个很好的例子，突出了其在转化医学应用中的潜力。新型可电离脂质的开发和有效载荷的真实的实时可视化的实现对于siRNA的递送和临床翻译具有重要意义。在此，我们基于新制备的脂质制备了用于靶向递送siRNA和MRI造影剂的多功能可电离iLNP，其在荷瘤小鼠中实现了良好的siRNA转运、良好的成像效果和优异的治疗效果。
One of the imperative medical requirements for cancer treatment is how to establish an imaging‐guided nanocarrier that combines therapeutic and imaging agents into one system. siRNA therapeutics have shown promising prospects in controlling life‐threatening diseases. However, it is still challenging to develop siRNA formulations with excellent cellular entry capability, efficient endosomal escape, and simultaneous visualization. Herein, we fabricated multifunctional ionizable lipid nanoparticles (iLNPs) for targeted delivery of siRNA and MRI contrast agent. The iLNPs comprises DSPC, cholesterol, PEGylated lipid, contrast agent DTPA‐BSA (Gd), and ionizable lipid termed iBL0104. siRNA‐loaded iLNPs (iLNPs/siRNA) could be decorated with a tumor targeting cyclic peptide (c(GRGDSPKC)) (termed GARP), or without targeting modification (termed GAP). Data revealed that GARP/siRNA iLNPs exhibited significantly higher cellular entry efficiency than GAP/siRNA iLNPs. GARP/siRNA iLNPs rapidly and effectively escaped from endosome and lysosome after internalization. Compared with GAP/siPLK1, GARP/siPLK1 exhibited better tumor inhibition efficacy in both cell‐line derived xenograft and liver cancer patient derived xenograft murine models. In addition, GARP formulation displayed ideal MRI effect in tumor‐bearing mice, and was well tolerated by testing animals. Therefore, this study provides an excellent example for achieving imaging‐guided and tumor‐targeted siRNA delivery and cancer treatment, highlighting its promising potential for translational medicine application. Development of novel ionizable lipid and realization of real‐time payload visualization are of great importance for siRNA delivery and clinical translation. Herein, we fabricated multifunctional ionizable iLNPs based on a newly prepared lipid for targeted delivery of siRNA and MRI contrast agent, which achieved good siRNA transportation, well imaging effect and excellent therapeutic outcome in tumor‐bearing mice.