| 摘要: | 脂質體是主要由單層的磷脂質雙層構成的空心球形奈米顆粒，且被廣泛地用作藥物輸送的載體，同時具有靶向輸送的功能。脂質體屬於微粒囊泡，其作為藥物遞送的載體而被廣泛地研究。當脂質體藥物進入人體時，脂質體的磷脂雙層可能會激活所謂的補體系統，從而觸發一系列生化反應，最終導致不良的免疫反應。脂質體所觸發的免疫反應集中在補體激活和相關的生理變異上，從而形成獨特的不良免疫現象，即為與補體激活相關的類過敏(CARPA)。脂質體對補體系統的激活是一個嚴重的醫藥學問題，因為它可以通過釋放有毒蛋白質而引起許多副作用，例如心臟疼痛、皮疹和低血壓、高血壓，這將使新型脂質體藥物的批准或採用變得複雜。然而在補體激活的許多因素中，對表面電荷的研究最為深入；儘管其具有藥學重要性，但是脂質體如何與補體系統的蛋白質相互作用並且激活它，尤其是來自於磷脂質的物理性質之影響仍然未知。這項研究將採用一個模型系統，該系統由補體系統之蛋白質與脂質體組成，以探索脂質體激活補體系統的因素。我們使用表面壓力測量和小角度X射線散射技術來確定脂質彈性性質在脂質體與補體系統之間相互作用的貢獻。通過探索脂質體和補體系統之間的親和力，我們試圖發現磷脂質之彈性性質在補體激活事件中的重要性和關鍵作用。;Liposomes are hollow spherical nanoparticles mainly composed of single layers of phospholipid bilayer and widely used as drug delivery vehicles, sometimes featuring the capability of targeted delivery. Liposomes are microparticulate vesicles which are under extensive study as carriers for improving the delivery of therapeutic drugs. When liposomal drugs enter human bodies, the phospholipid bilayers of the liposomes may activate the so-called complement system, which triggers a cascade of biochemical reactions leading to adverse immune responses. The immune responses of liposomes focus on complement activation and related physiological variation, which build a uniquely adverse immune phenomenon, the complement activation-related pseudoallergy (CARPA). The activation of the complement system by liposomes is a serious pharmaceutical issue, as it can cause many side effects through the release of toxic proteins, such as heart pain, rash and hypo/hypertension, which complicates the approval or adoption of a new liposomal drug. In many factors of complement activation, surface charge is most amply studied. Despite its pharmaceutical importance, how liposomes interact with the protein components of the complement system and activate it, particularly the influences of the physical properties of liposomes (e.g., the bilayer elasticity, which is critical to the lipid-protein interactions) remains largely unknown. This study will employ a model system which consists of the protein domains responsible for the complement system’s interaction with lipid and liposomes of systematically varied compositions, to explore the factors dictating the activation of the complement system by liposomes. The knowledge learned here will be of great value to the designs of liposomal drugs. The current study is to specify the contribution of lipid elastic property to interaction between liposome and complement system by using Langmuir trough and small angle x-ray scattering (SAXS). We choose the part of the complement protein, liposome mediated complement activation binding site, which is the residues 14-26, A-G-R-P-G-R-R-G-R-P-G-L-K, the highly cationic region of the complement system protein. By exploring affinity between liposome and complement system, we aim to find the importance and the role of the elastic properties of liposome in complement activation events. |
