血清成份對脂微粒包覆薑黃素之藥物釋放效率之研究

Abstract

薑黃素為薑黃中之主要成份，其功能包含治療癌症、抗發炎、抗血管新生等疾病，但因其親脂的特性造成其生物利用性低，因此如何增進其水溶性往往是發展薑黃素藥物第一個要解決的問題。 本實驗利用不同的正價脂質包覆薑黃素後，分析在不同脂質組成下各種奈米粒子對薑黃素之包覆率，並以其處理細胞八小時後觀察不同的奈米粒子其遞送藥物之效率，並且進一步去分析影響藥物釋放的要素，最後將薑黃素脂微粒打入小鼠血液中測量藥物在小鼠體內被清除的速率，並觀察這些粒子在體內器官的分布情形。 利用膽固醇作為基底的脂微粒對薑黃素的包覆率大約在35 %到50 %之間，而磷脂類基底的脂微粒其包覆率則只有不到10 %；而共軛焦顯微鏡的結果顯示當降低奈米粒子中正價脂質比例時可有效降低薑黃素進入細胞中的量，並且血清中蛋白質的主要成份白蛋白對不帶有PEG-Chol 的脂微粒其藥物釋放有顯著的影響，在和白蛋白溶液混合1 小時後，約有80 % 的薑黃素會從不帶有PEG-Chol 之奈米粒子中釋放出去，而帶有PEG-Chol 之奈米粒子則只有約40 % 成的藥物釋放；而在 活體中正價脂質比例及PEG-Chol 的存在與否皆會影響藥物在血液中的清除速度，可以有效地將循環時間由15 分鐘延長至4 小時以上，並且大幅降低了奈米粒子被腎臟清除的比例。 本論文探討了脂微粒包覆薑黃素藥物之基本性質，並分析在體外及活體中影響其藥物釋放之因素，期望可以作為未來可以將此正價奈米粒子應用於活體治療時之參考。

Curcumin is the principle ingredient of the wild-used spice turmeric. It can be used in treating various diseases including cancer, inflammation, or abnormal angiogenesis. But the low bioavailability of curcumin resulting from its lipophilic property leads to poor absorption. As a result, increasing its solubility in vivo is often the major concern when applying curcumin as therapeutic agent. In this research, different cationic lipids were used as curcumin carriers. And their encapsulation efficiencies were assessed first. The drug delivery efficiencies toward different kinds of cell were investigated after 8 hours of treatment and the factors affecting drug release rate were also analyzed. Finally, the in vivo circulation time of curcumin in different lipid formulations were obtained after i.v. injection, and the biodistributions of curcumin-encapsulating cholesterol-based micelles were assessed. The encapsulation efficiencies of cholesterol-based cationic micelles lied between 35 ~ 50 %, while those of phosphor-based cationic micelles were under 10 %. The confocal microscope results demonstrated the ability to greatly reduce the amount of curcumin in cells by lowering cationic lipid ratio in curcumin-encapsulating micelles. Albumin, the major protein in serum, also had profound effect on curcumin releasing rate, causing micelles without PEGylation to release almost 80 % of their payload in one hour, while those with PEG modification only losing 40 %. Similar effects of PEGylation and lowering cationic lipid ratio were also observed in vivo, as the circulation time was effectively increased from 15 minutes to over 4 hours, and the renal clearance was greatly reduced in those groups. These findings provide basic understandings of curcumin-encapsulating cholesterol-based micelles as a possible anti-angiogenesis therapeutic agent in cancer treatmen.