Department of Pathology & Medical Biology, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Liposome Res. 2023 Dec;33(4):328-337. doi: 10.1080/08982104.2023.2187821. Epub 2023 Mar 15.
Increased understanding of chronic inflammatory diseases and the role of endothelial cell (EC) activation herein, have urged interest in sophisticated strategies to therapeutically intervene in activated EC to treat these diseases. Liposome-mediated delivery of therapeutic siRNA in inflammation-activated EC is such a strategy. In this study, we describe the design and characterisation of two liposomal siRNA delivery systems formulated with the cationic MC3 lipid or MC3/SAINT mixed lipids, referred to as MC3-O-Somes (MOS) and MC3/SAINT-O-Somes (MSS). The two formulations showed comparable physicochemical properties, except for better siRNA encapsulation efficiency in the MSS formulation. Antibody-mediated VCAM-1 targeting (Ab) increased the association of the targeted MOS and MSS with activated EC, although the targeted MOS showed a significantly higher VCAM-1 specific association than the targeted MSS. Ab MSS containing RelA siRNA achieved significant downregulation of RelA expression, while Ab MOS containing RelA siRNA did not downregulate RelA expression in activated EC. Additionally, Ab MSS containing RelA siRNA showed low cytotoxicity in EC and at the same time prohibited endothelial inflammatory activation by reducing expression of cell adhesion molecules. The Ab MSS formulation is a novel siRNA delivery system based on a combination of the cationic lipids MC3 and SAINT, that shows good physicochemical characteristics, enhanced endothelial cell association, improved transfection activity, low toxicity and significant anti-inflammatory effect, thereby complying with the requirements for future in vivo investigations.
对慢性炎症性疾病以及内皮细胞 (EC) 在此类疾病中的激活作用的深入了解，促使人们产生了利用复杂策略来对激活的 EC 进行治疗干预以治疗此类疾病的兴趣。脂质体介导的治疗性 siRNA 递送至炎症激活的 EC 就是这样一种策略。在本研究中，我们描述了两种脂质体 siRNA 递送系统的设计和特性，这两种系统是由阳离子 MC3 脂质或 MC3/SAINT 混合脂质制成的，分别称为 MC3-O-囊泡（MOS）和 MC3/SAINT-O-囊泡（MSS）。这两种制剂具有相似的理化性质，但 MSS 制剂的 siRNA 包封效率更好。抗体介导的 VCAM-1 靶向（Ab）增加了靶向 MOS 和 MSS 与激活的 EC 的结合，尽管靶向 MOS 与靶向 MSS 相比，具有更高的 VCAM-1 特异性结合。载有 RelA siRNA 的 Ab MSS 实现了 RelA 表达的显著下调，而载有 RelA siRNA 的 Ab MOS 则未下调激活的 EC 中的 RelA 表达。此外，载有 RelA siRNA 的 Ab MSS 表现出对 EC 的低细胞毒性，同时通过降低细胞黏附分子的表达来阻止内皮炎症激活。Ab MSS 制剂是一种新型的 siRNA 递送系统，基于阳离子脂质 MC3 和 SAINT 的组合，具有良好的理化特性、增强的内皮细胞结合、改善的转染活性、低毒性和显著的抗炎作用，因此符合未来体内研究的要求。
