Evans James C, Malhotra Meenakshi, Fitzgerald Kathleen A, Guo Jianfeng, Cronin Michael F, Curtin Caroline M, O'Brien Fergal J, Darcy Raphael, O'Driscoll Caitriona M
Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
Tissue Engineering Research Group, Anatomy Department, Royal College of Surgeons in Ireland , Dublin, Ireland.
Mol Pharm. 2017 Jan 3;14(1):42-52. doi: 10.1021/acs.molpharmaceut.6b00646. Epub 2016 Nov 23.
In recent years, RNA interference (RNAi) has emerged as a potential therapeutic offering the opportunity to treat a wide range of diseases, including prostate cancer. Modified cyclodextrins have emerged as effective gene delivery vectors in a range of disease models. The main objective of the current study was to formulate anisamide-targeted cyclodextrin nanoparticles to interact with the sigma receptor (overexpressed on the surface of prostate cancer cells). The inclusion of octaarginine in the nanoparticle optimized uptake and endosomal release of siRNA in two different prostate cancer cell lines (PC3 and DU145 cells). Resulting nanoparticles were less than 200 nm in size with a cationic surface charge (∼+20 mV). In sigma receptor-positive cell lines, the uptake of anisamide-targeted nanoparticles was reduced in the presence of the sigma receptor competitive ligand, haloperidol. When cells were transfected in 2D, the levels of PLK1 mRNA knockdown elicited by targeted versus untargeted nanoparticles tended to be greater but the differences were not statistically different. In contrast, when cells were grown on 3D scaffolds, recapitulating bone metastasis, targeted formulations showed significantly higher levels of PLK1 mRNA knockdown (46% for PC3 and 37% for DU145, p < 0.05). To our knowledge, this is the first time that a targeted cyclodextrin has been used to transfect prostate cancer cells in a 3D model of bone metastasis.
近年来，RNA干扰（RNAi）已成为一种潜在的治疗方法，为治疗包括前列腺癌在内的多种疾病提供了机会。修饰的环糊精已成为一系列疾病模型中有效的基因传递载体。本研究的主要目的是制备靶向茴香酰胺的环糊精纳米颗粒，使其与前列腺癌细胞表面过表达的σ受体相互作用。纳米颗粒中包含八聚精氨酸可优化两种不同前列腺癌细胞系（PC3和DU145细胞）中siRNA的摄取和内体释放。所得纳米颗粒尺寸小于200 nm，表面带正电荷（约+20 mV）。在σ受体阳性细胞系中，在存在σ受体竞争性配体氟哌啶醇的情况下，靶向茴香酰胺的纳米颗粒的摄取减少。当在二维条件下转染细胞时，靶向纳米颗粒与非靶向纳米颗粒引起的PLK1 mRNA敲低水平往往更高，但差异无统计学意义。相反，当细胞在三维支架上生长以模拟骨转移时，靶向制剂显示出显著更高的PLK1 mRNA敲低水平（PC3细胞为46%，DU145细胞为37%，p<0.05）。据我们所知，这是首次在骨转移三维模型中使用靶向环糊精转染前列腺癌细胞。
