聚乙二醇含量對磁性微胞攜帶紫杉醇能力之影響

Abstract

紫杉醇（paclitaxel）具顯著抗癌效果卻因其疏水性而不易在人體中遞送，故開發適當劑型已廣為研究。本研究以生物可分解之脂類1,2-二油醯基-3-三甲基氨基丙烷（DOTAP）和外圍接有聚乙二醇長鍊的二硬脂酰磷脂醯乙醇胺（PEG-DSPE）構成兩性高分子微胞（micelle），並在其中混入具鐵磁性的四氧化三鐵（iron (II,III) oxide, Fe3O4）顆粒，當高分子在一定濃度以上時，可在水相溶液中形成粒徑約100-200奈米之磁性顆粒。 以75% DOTAP和25% PEG-DSPE組成之微胞（D75），在臨界微胞濃度（critical micelle concentration）18 μg/mL以上可形成粒徑約200奈米、表面電位50毫伏特的帶正電磁性奈米粒子。D75微胞在第0天時，於攝氏4度的0.5% 白蛋白水溶液中可包覆65% 加入的紫杉醇。而在相同條件下，相較於第0天時D75的包覆量，D75微胞可攜帶包覆量40% 以上的紫杉醇並維持六天以上，且其紫杉醇含量在六天內不隨時間改變。而相較於趨近電中性的D50微胞（DOTAP和PEG-DSPE各50%），其攜帶藥品效率則降低至1% 以下。這可能由於電性相吸使帶負電荷的白蛋白和帶正電荷的D75微胞黏合，可捕捉自微胞洩漏出的紫杉醇使釋放速率降低。 在儲存方面，D75和D50微胞在水、5% 葡萄糖溶液或0.5% 白蛋白溶液中冷凍乾燥（lyophilization）處理後，可維持相似的紫杉醇包覆量；而D75微胞以冷凍乾燥後回溶、或是經過反覆結凍解凍（freeze-and -thawing）處理，其紫杉醇包覆量均相似。 D75微胞具有高包覆量、適當粒徑大小、在特定條件下相當穩定，可望成為紫杉醇藥品的適當載體。

Paclitaxel is an anticancer drug with poor water solubility. The micelles that consist of poly (ethylene glycol)-distearoyl phosphoethanolamine conjugates (PEG-DSPE), iron (II, III) oxide nanoparticles (Fe3O4), and cationic lipids 1,2-dioleoyloxy-3-trimethylammoniumpropane (DOTAP) were prepared as a carrier of hydrophobic drugs. Micelles with 75% DOTAP and 25% PEG-DSPE in the molar ratio (D75 micelles) had average size of about 200 nm, zeta potential of about 50 mV, and the critical micelle concentration of about 18 μg/mL. The paclitaxel encapsulation ratio was 65% of loading in 0.5% albumin solution under 4°C at day 0. More than 40% of encapsulated paclitaxel in micelles comparing to the amount at day 0 could be reserved in D75 micelles for 6 days, but only 20% of paclitaxel were left in D50 micelles (containing 50% DOTAP and 50% PEG-DSPE). D50 and D75 micelles were lyophilized and rehydration in deionized water, 5% glucose solution, and 0.5% albumin solution, the paclitaxel amounts in different medium were similar. Paclitaxel amounts in D75 micelles treated with lyophilization and freeze-and-thawing were also similar. D75 micelles had properties of high encapsulation ratio, long-circulation size, slow release, and magnetic targeting possibility. It could be an ideal drug carrier for paclitaxel in cancer chemotherapy.