Department of General Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
J Control Release. 2009 Dec 16;140(3):277-83. doi: 10.1016/j.jconrel.2009.08.013. Epub 2009 Aug 21.
Targeting of a specific subset of cells is mandatory for the successful application of siRNA mediated silencing in anticancer therapy. A recent theory suggests that colon cancer is sustained by a small subpopulation of cells, termed cancer stem cells (CSCs). These cells are characterized by their innate drug resistance properties, which is one of the key factors of chemotherapy failure. The goal of this study was to assess whether a novel siRNA delivery carrier, with an appropriate siRNA, targeted to CD133+ cells has the potential to improve the efficacy of conventional chemotherapy.
In this study, a novel synthetic siRNA carrier platform was designed and synthesized. This carrier was composed of a cationic oligomer (PEI(1200)), a hydrophilic polymer (polyethylene glycol) and a biodegradable lipid-based crosslinking moiety. Libraries of polymers were synthesized by varying their lipid composition. Their transfection efficacy was evaluated in vitro using CHOK1 cells. The polymer was characterized using molecular weight, particle encapsulation assay, particle size and surface charge analysis.
It was demonstrated that the lipid composition in the polymer plays a critical role in transfection. Optimizing the physicochemical properties of the polymers is crucial in achieving favorable knockdown. Lipid nano complex with composition PEI-Lipid(1:16) was the optimum ratio for gene silencing. Additionally, silencing of multidrug resistance gene (MDR1) and treatment with paclitaxel play a synergistic role in increasing the efficacy as compared to the drug alone.
In the present study a novel siRNA delivery carrier system with an MDR1-targeting siRNA (siMDR1) effectively reduced the expression of MDR1 in human colon CSCs (CD133+ enriched cell population), resulting in significantly increasing the chemosensitivity to paclitaxel.
在癌症治疗中，成功应用 siRNA 介导的沉默需要靶向特定的细胞亚群。最近的一种理论认为，结肠癌是由一小部分细胞维持的，这些细胞被称为癌症干细胞（CSCs）。这些细胞的固有耐药性是化疗失败的关键因素之一。本研究的目的是评估一种新型的 siRNA 递药载体，携带靶向 CD133+细胞的合适 siRNA，是否有可能提高常规化疗的疗效。
在这项研究中，设计并合成了一种新型的合成 siRNA 载体平台。该载体由阳离子聚合物（PEI(1200)）、亲水性聚合物（聚乙二醇）和可生物降解的脂质交联部分组成。通过改变其脂质组成合成了聚合物文库。使用 CHOK1 细胞在体外评估它们的转染效率。使用分子量、颗粒包封测定、颗粒大小和表面电荷分析对聚合物进行了表征。
研究表明，聚合物中的脂质组成在转染中起着关键作用。优化聚合物的物理化学性质对于实现有效的基因敲低至关重要。脂质纳米复合物的组成（PEI-脂质（1:16））是基因沉默的最佳比例。此外，多药耐药基因（MDR1）的沉默和紫杉醇的治疗在增加疗效方面与单独使用药物相比发挥协同作用。
在本研究中，一种新型的靶向 MDR1 的 siRNA（siMDR1）递送载体系统有效地降低了人结肠癌 CSCs（CD133+富集细胞群）中 MDR1 的表达，显著增加了对紫杉醇的化疗敏感性。
