Center for RNA Nanobiotechnology and Nanomedicine, The Ohio State University, Columbus, OH, 43210, USA.
Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
Nat Commun. 2020 Feb 20;11(1):972. doi: 10.1038/s41467-020-14780-5.
Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as carriers increases the water-solubility of paclitaxel by 32,000-fold. Intravenous injections of RNA-paclitaxel nanoparticles with specific cancer-targeting ligand dramatically inhibit breast cancer growth, with nearly undetectable toxicity and immune responses in mice. No fatalities are observed at a paclitaxel dose equal to the reported LD. The use of ultra-thermostable RNA nanoparticles to deliver chemical prodrugs addresses issues with RNA unfolding and nanoparticle dissociation after high-density drug loading. This finding provides a stable nano-platform for chemo-drug delivery as well as an efficient method to solubilize hydrophobic drugs.
紫杉醇被广泛应用于癌症治疗，但较差的水溶性和毒性引起了严重的关注。在这里，我们报告了一种具有超热力学稳定性的 RNA 四链结纳米颗粒，可用于溶解和负载紫杉醇以进行靶向癌症治疗。每个 RNA 纳米颗粒共价负载二十四紫杉醇分子作为前药。RNA-紫杉醇复合物结构刚性且稳定，通过低温电子显微镜的亚纳米分辨率成像得到证实。使用 RNA 纳米颗粒作为载体可将紫杉醇的水溶性提高 32,000 倍。具有特定癌症靶向配体的 RNA-紫杉醇纳米颗粒静脉注射可显著抑制乳腺癌的生长，在小鼠中几乎检测不到毒性和免疫反应。在与报道的 LD 相等的紫杉醇剂量下未观察到死亡。使用超热力学稳定的 RNA 纳米颗粒来递送化学前药解决了高密度药物负载后 RNA 展开和纳米颗粒解离的问题。这一发现为化学药物递送提供了一个稳定的纳米平台，以及一种有效溶解疏水性药物的方法。
