Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Canada.
Hum Gene Ther. 2019 Dec;30(12):1531-1546. doi: 10.1089/hum.2019.096. Epub 2019 Oct 29.
Preclinical studies showed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is safe and effective to combat cancers, but clinical outcomes have been less than optimal due to short half-life of TRAIL protein, insufficient induction of apoptosis, and TRAIL resistance displayed in many tumors. In this study, we explored co-delivery of a TRAIL expressing plasmid (pTRAIL) and complementary small interfering RNAs (siRNAs) (silencing [BCL2L12] and [SOD1]) to improve the response of breast cancer cells against TRAIL therapy. It is desirable to co-deliver the pDNA along with siRNA using a single delivery agent, but this is challenging given different structures of long/flexible pDNA and short/rigid siRNA. Toward this goal, we identified an aliphatic lipid-grafted low-molecular weight polyethylenimine (PEI) that accommodated both pDNA and siRNA in a single complex. The co-delivery of pTRAIL with BCL2L12- or SOD1-specific siRNAs resulted more significant cell death in different breast cancer cells compared with separate delivery without affecting nonmalignant cells viability. Ternary complexes of lipopolymer with pTRAIL and BCL2L12 siRNA significantly retarded the growth of breast cancer xenografts in mice. The enhanced anticancer activity was attributed to increased secretion of TRAIL and sensitization of breast cancer cells against TRAIL by the co-delivered siRNAs. The lipid-grafted PEIs capable of co-delivering multiple types of nucleic acids can serve as powerful carriers for more effective complementary therapeutics. Graphical Abstract [Figure: see text].
临床前研究表明，肿瘤坏死因子相关凋亡诱导配体（TRAIL）疗法在对抗癌症方面是安全有效的，但由于 TRAIL 蛋白半衰期短、凋亡诱导不足以及许多肿瘤中显示出的 TRAIL 耐药性，临床疗效一直不尽人意。在这项研究中，我们探索了共递送 TRAIL 表达质粒（pTRAIL）和互补小干扰 RNA（siRNA）（沉默 [BCL2L12] 和 [SOD1]）以提高乳腺癌细胞对 TRAIL 治疗的反应。理想情况下，使用单一递送剂共递送 pDNA 和 siRNA，但鉴于长/灵活的 pDNA 和短/刚性 siRNA 的不同结构，这具有挑战性。为此，我们鉴定了一种脂肪族脂质接枝的低分子量聚乙烯亚胺（PEI），可在单个复合物中容纳 pDNA 和 siRNA。与单独递送相比，pTRAIL 与 BCL2L12 或 SOD1 特异性 siRNA 的共递送导致不同乳腺癌细胞的细胞死亡更显著，而不影响非恶性细胞的活力。带有 pTRAIL 和 BCL2L12 siRNA 的脂质聚合物三元复合物显著抑制了乳腺癌异种移植瘤在小鼠中的生长。增强的抗癌活性归因于共递送的 siRNA 增加了 TRAIL 的分泌和使乳腺癌细胞对 TRAIL 敏感。能够共递送多种类型核酸的脂质接枝 PEI 可以作为更有效的互补治疗的有效载体。
