Laboratory of Nanomedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Cancer Lett. 2013 Jul 1;334(2):221-7. doi: 10.1016/j.canlet.2012.08.024. Epub 2012 Aug 27.
RNA interference (RNAi), a natural cellular mechanism for RNA-guided regulation of gene expression could in fact become new therapeutic modality if an appropriate efficient delivery strategy that is also reproducible and safe will be developed. Numerous efforts have been made for the past eight years to address this challenge with only mild success. The majority of these strategies are based on cationic formulations that condense the RNAi payload and deliver it into the cell cytoplasm. However, most of these formulations also evoke adverse effects such as mitochondrial damage, interfering with blood coagulation cascade, induce interferon response, promote cytokine induction and activate the complement. Herein, we present a strategy that is devised from neutral phospholipids and cholesterol that self-assembled into lipid-based nanoparticles (LNPs). These LNPs were then coated with the glycosaminoglycan, hyaluronan (HA). HA-LNPs bound and internalized specifically into cancer cells compared with control, non-coated particles. Next, loaded with siRNAs against the multidrug resistance extrusion pump, p-glycoprotein (P-gp), HA-LNPs efficiently and specifically reduced mRNA and P-gp protein levels compared with control particles and with HA-LNPs loaded with control, non-targeted siRNAs. In addition, no cellular toxicity or cytokine induction was observed when these particles were cultured with human Peripheral Blood Mononuclear Cells (PBMCs). The HA-LNPs may offer an alternative approach to cationic lipid-based formulations for RNAi delivery into cancer cells in an efficient and safe manner.
RNA 干扰（RNAi）是一种自然的细胞内 RNA 指导的基因表达调控机制，如果能够开发出一种合适的、高效的、可重复使用的且安全的传递策略，实际上可以成为新的治疗方式。在过去的八年中，人们做出了无数努力来应对这一挑战，但仅取得了一些微小的成功。这些策略大多数基于阳离子制剂，这些阳离子制剂可以使 RNAi 有效负载浓缩并递送至细胞质中。然而，这些制剂中的大多数还会引起不良反应，例如线粒体损伤、干扰血液凝固级联反应、诱导干扰素反应、促进细胞因子诱导和激活补体。在此，我们提出了一种基于中性磷脂和胆固醇的策略，这些物质可以自组装成脂质纳米颗粒（LNPs）。然后，这些 LNPs 用糖胺聚糖透明质酸（HA）进行涂层处理。与对照、未涂层的颗粒相比，HA-LNPs 特异性地结合并内化进入癌细胞。接下来，负载针对多药耐药外排泵 P-糖蛋白（P-gp）的 siRNA 后，与对照颗粒相比，HA-LNPs 能够高效且特异性地降低 mRNA 和 P-gp 蛋白水平，与负载对照、非靶向 siRNA 的 HA-LNPs 相比也是如此。此外，当这些颗粒与人外周血单核细胞（PBMCs）一起培养时，没有观察到细胞毒性或细胞因子诱导。HA-LNPs 可能为 RNAi 递送至癌细胞提供了一种替代阳离子脂质制剂的方法，具有高效和安全的特点。
