PDF(Pubmed)
Abstract：
Gene therapies represent promising new therapeutic options for a variety of indications. However, despite several approved drugs, its potential remains untapped. For polymeric gene delivery, endosomal escape represents a bottleneck. SO1861, a naturally occurring triterpene saponin with endosomal escape properties isolated from Saponaria officinalis L., has been described as additive agent to enhance transfection efficiency (sapofection). However, the challenge to synchronize the saponin and gene delivery system in vivo imposes limitations. Herein, we address this issue by conjugating SO1861 to a peptide-based gene vector using a pH-sensitive hydrazone linker programmed to release SO1861 at the acidic pH of the endosome. Nanoplexes formulated with SO1861-equipped peptides were investigated for transfection efficiency and tolerability in vitro and in vivo. In all investigated cell lines, SO1861-conjugated nanoplexes have shown superior transfection efficiency and cell viability over supplementation of transfection medium with free SO1861. Targeted SO1861-equipped nanoplexes incorporating a targeting peptide were tested in vitro and in vivo in an aggressively growing neuroblastoma allograft model in mice. Using a suicide gene vector encoding the cytotoxic protein saporin, a slowed tumor growth and improved survival rate were observed for targeted SO1861-equipped nanoplexes compared to vehicle control.
摘要：
基因疗法代表了各种适应症的有希望的新治疗选择。然而,尽管有几种批准的药物，其潜力仍未开发。对于聚合物基因递送，内体逃逸是一个瓶颈。SO1861，一种天然存在的具有内体逃逸特性的三萜皂苷，从皂甙中分离出来，已被描述为增强转染效率的添加剂(Sapofection)。然而,在体内同步皂苷和基因递送系统的挑战带来了局限性。在这里，我们通过使用pH敏感的腙接头将SO1861与基于肽的基因载体缀合来解决这个问题，该接头被编程为在内体的酸性pH下释放SO1861。研究了用配备SO1861的肽配制的纳米复合物在体外和体内的转染效率和耐受性。在所有研究的细胞系中，与用游离SO1861补充转染培养基相比,SO1861-缀合的纳米复合物显示出优异的转染效率和细胞活力。在小鼠中积极生长的神经母细胞瘤同种异体移植模型中，在体外和体内测试了装有靶向SO1861的包含靶向肽的纳米复合物。使用编码细胞毒性蛋白saporin的自杀基因载体，与媒介物对照相比,配备SO1861的靶向纳米复合物观察到肿瘤生长减慢,生存率提高.
