The development of a specific, effective method for the delivery of therapeutics including small molecules and nucleic acids to tumor tissue remains to be solved. Numerous types of lipid nanoparticles (LNPs) have been developed in attempts to achieve this goal. However, LNPs are probably not taken up by target cells because cancer-targeting LNPs are typically modified with poly(ethylene glycol) (PEG), which inhibits the cellular uptake of LNPs, to passively accumulate in tumor tissue via the enhanced permeability and retention (EPR) effect. It would clearly be important to develop a LNP with both a prolonged circulation and cancer-specific efficient uptake for use in an innovative nanodrug delivery system. Herein, we assessed the effect of nonstandard macrocyclic peptides against the epithelial cell adhesion molecule (EpCAM) Epi-1, which was discovered by a random nonstandard peptides integrated discovery (RaPID) system, on the cellular uptake and therapeutics delivery of LNPs. A liposomal siRNA delivery system (MEND) was modified with an Epi-1 lipid-derivative (EpCAM-targeting MEND; ET-MEND). The resulting ET-MEND showed a more than 27-fold increase in cellular uptake in EpCAM-positive cell lines. In the case of negative cells, cellular uptake and the efficiency of the ET-MEND for delivering therapeutics were comparable with those of nonmodified MEND. In addition, when systemically injected, the ET-MEND successfully inhibited gene expression in the tumor tissue at a dose of 0.5 mg siRNA/kg without any obvious toxicity. These results suggest that a combination of a specific peptide ligand can be used to identify a RaPID system and that the use of such a MEND for liposomal drug delivery has the potential for use in developing a system for the efficacious delivery of pharmaceuticals to various cancer cells.

中文翻译：

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通过用非标准大环肽修饰的脂质纳米颗粒对EpCAM进行靶向的高效siRNA递送

用于将包括小分子和核酸的治疗剂递送至肿瘤组织的特异性，有效方法的开发仍有待解决。为了实现该目标，已经开发了多种类型的脂质纳米颗粒（LNP）。但是，LNP可能不会被靶细胞吸收，因为靶向癌症的LNP通常会被聚乙二醇（PEG）修饰，从而抑制LNP的细胞摄取，从而通过增强的通透性和保留力被动地蓄积在肿瘤组织中（ EPR）效果。开发具有延长的循环时间和特定于癌症的有效摄取的LNP，用于创新的纳米药物输送系统显然很重要。在这里，我们评估了非标准大环肽对上皮细胞粘附分子（EpCAM）Epi-1的影响，它是由随机非标准肽整合发现（RaPID）系统发现的，对LNPs的细胞吸收和治疗作用有关。用Epi-1脂质衍生物（靶向EpCAM的MEND； ET-MEND）修饰脂质体siRNA递送系统（MEND）。所得的ET-MEND在EpCAM阳性细胞系中的细胞摄取增加了27倍以上。在阴性细胞的情况下，细胞吸收和ET-MEND递送治疗剂的效率与未修饰的MEND相当。此外，当全身注射时，ET-MEND以0.5 mg siRNA / kg的剂量成功抑制了肿瘤组织中的基因表达，而没有任何明显的毒性。