Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Room 607, Tel Aviv University, Tel Aviv, Israel.
QBI Enterprises, Ltd., Ness-Ziona, Israel.
Nanomedicine. 2018 Feb;14(2):303-315. doi: 10.1016/j.nano.2017.10.012. Epub 2017 Nov 7.
RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target "undruggable" oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly(α)glutamate amine (APA) can serve as a cationic carrier to the negatively-charged oligonucleotides. APA polymers complexed with siRNA to form round-shaped, homogenous and reproducible nano-sized polyplexes bearing ~50 nm size and slightly negative charge. In addition, APA:siRNA polyplexes were shown to be potent gene regulators in vitro. In light of these preferred physico-chemical characteristics, their performance as systemically-administered siRNA nanocarriers was investigated. Intravenously-injected APA:siRNA polyplexes accumulated selectively in tumors and did not accumulate in the lungs, heart, liver or spleen. Nevertheless, the polyplexes failed to induce specific mRNA degradation, hence neither reduction in tumor volume nor prolonged mice survival was seen.
RNAi 疗法在个性化医疗领域具有巨大的应用前景：能够靶向“不可用药”的致癌途径。然而，通过系统给药来实现其对肿瘤的高效靶向作用仍未得到解决。两亲性烷基化聚（α）谷氨酸胺（APA）可用作带负电荷的寡核苷酸的阳离子载体。APA 聚合物与 siRNA 复合形成具有 ~50nm 尺寸和轻微负电荷的圆形、均匀且可重现的纳米级聚轮。此外，APA:siRNA 聚轮在体外表现出强大的基因调控作用。鉴于这些理想的物理化学特性，研究了它们作为系统给药的 siRNA 纳米载体的性能。静脉注射的 APA:siRNA 聚轮选择性地在肿瘤中积累，而不会在肺部、心脏、肝脏或脾脏中积累。然而，聚轮未能诱导特定的 mRNA 降解，因此既没有观察到肿瘤体积缩小，也没有延长小鼠的存活时间。
