兩性離子羥基甜菜鹼聚合物修飾之脂質體的體外抗腫瘤研究

Abstract

聚乙二醇修飾之脂質體已被用來作為穩定脂質體，由於聚乙二醇作為修飾脂質體的材料仍有以下缺點：PEG同時具有疏水及親水性，其疏水性會降低liposome在水相的極性，進而使得其穩定，減少藥物由微脂體內漏出；PEG不利於抗體連結於微脂體上，而且會干擾抗體-抗原的結合，減少細胞攝取。在傳輸基因和核酸有PEG dilemma，也會減少細胞攝取。如果沒有足夠的膽固醇，PEG-磷脂質傾向於相分離並聚集。以Chol-PEG修飾的脂質體的循環持久性比PEG-phospholipids還短。根據推測，因為Chol-PEG中的膽固醇使PEG鏈位於脂雙層中更深處，被認為是Chol-PEG傾向於干擾脂雙層的原因，導致包載藥物相對快速釋放，尤其是在高Chol-PEG密度下。而兩性離子羥基甜菜鹼聚合物修飾之脂質體已被證實同樣具有良好的穩定性效果，且對PH值變化具有反應，PCB修飾脂質體在酸性條件下的持續釋放可能是因為PCB在酸性條件下羧酸基的質子化，而腫瘤環境已被證實比一般組織要來的酸。 我們的研究結果顯示，經羥基甜菜鹼聚合物修飾之脂質體擁有良好的穩定性，接上葉酸後具有標靶的效果，可以增加藥物積累於腫瘤細胞，使細胞死亡，這些體外抗腫瘤結果顯示，此研究可以進一步做體內研究。

Although PEGylated liposomes are a promising application for anti-tumor therapy due to achieving a longer circulation time for the delivery drugs to a tumor via the enhanced permeability and retention (EPR) effect, PEG interferes with antibody-antigen binding, reducing cellular uptake. In this study, we developed a targeted zwitterionic poly(carboxybetaine) (PCB) modified liposomes for anti-tumor therapy in vitro study. PCB raises the polarity of the aqueous phase and enhance the hydration of lipid polar group regions, thus avoiding those membrane-destabilizing issues of PEG. The liposomes were encapsulated with doxorubicin (DOX), which is widely used clinically because of its broad spectrum anti-tumor activity, such as breast cancer and ovarian cancer. Phospholipid DPPE and Cholesterol was modified with PCB. Both modified lipid were used to prepare liposomes. In addition, DPPE-PCB was conjugated with folic acid, which further improved the active targeting to tumors and minimized the nonspecific uptake by normal cells. The FA-PCB-DPPE liposomes were much stable and showed higher cellular uptake to murine breast carcinoma 4T1 cells which overexpressing the folate receptor but not to L929 fibroblast cells. The liposomes composed of DSPC, CHOL-PCB, and DPPE-PCB also achieved high stability; however, due to its prolonged retention, with the lack of targeted effect to cells, the drug could not reach the cells effectively. The results of different liposomes in cell viability were consistent with the results from cellular uptake. PCB-modified liposomes provided slower drug leakage and higher stability than PEGylated liposomes. Furthermore, The FA-PCB-DPPE liposomes loaded with DOX exhibited slowly drug leakage rates, which was similar to DPPE-PCB and DSPE-PEG liposomes. These results indicated that targeted PCB-modified liposomes have great potential as a drug delivery system in anti-tumor therapy.