College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
Biomed Pharmacother. 2011 Feb;65(1):2-8. doi: 10.1016/j.biopha.2010.10.003. Epub 2010 Nov 4.
Folate polyethylene glycol-cholesterol hemisuccinate (folate-PEG-CHEMS) is a novel folate ligand firstly synthesized by our group and demonstrated good stability and potential targeting results on KB cells in vitro. The current study further explored endocytosis mechanisms of liposomes via folate receptor on L1210JF cells and assessed targeted therapeutic efficacy of folate-PEG-CHEMS anchored liposomes loading daunorubicin (F-L-DNR) in vivo. Folate-PEG-CHEMS was synthesized by a modified method. The liposome properties, cell cytotoxicity, intracellular and intratumoral localization, and therapeutic efficacy on a murine tumor model bearing L1210JF cells were evaluated. High encapsulation efficiency (95.1%±1.5%) and appropriate particle size (76.0±35.5nm) and zeta potential (-12.83±1.36mV) were achieved for F-L-DNR. IC(50) of F-L-DNR on L1210JF cells was 2-3-folds lower than that of non-targeted liposomal daunorubicin (L-DNR). Anticancer efficacy on L1210JF tumor model indicated that mice survival time of F-L-DNR group at doses of 5mg/kg and 10mg/kg was significantly longer than that of L-DNR or free DNR. Confocal fluorescence photographs of F-L-DNR indicated enhanced endocytosis of liposomes via folate receptor on L1210JF cells, prolonged retaining time in tumors and improved drug release in the tumor site at 24h post intravenous injection of F-L-DNR. In conclusion, folate-PEG-CHEMS is an effective ligand for folate-targeted daunorubicin liposomes to achieve increased drug release in tumor and therapeutic efficacy.
叶酸聚乙二醇-胆固醇琥珀酸酯（叶酸-PEG-CHEMS）是本课题组首次合成的一种新型叶酸配体，在体外实验中证明对 KB 细胞具有良好的稳定性和潜在的靶向作用。本研究进一步探讨了脂质体通过 L1210JF 细胞上的叶酸受体的内吞作用机制，并评估了载有柔红霉素的叶酸-PEG-CHEMS 锚定脂质体（F-L-DNR）在体内的靶向治疗效果。叶酸-PEG-CHEMS 采用改良方法合成。评价了脂质体特性、细胞毒性、细胞内和肿瘤内定位以及对携带 L1210JF 细胞的小鼠肿瘤模型的治疗效果。F-L-DNR 具有较高的包封率（95.1%±1.5%）、合适的粒径（76.0±35.5nm）和 zeta 电位（-12.83±1.36mV）。F-L-DNR 对 L1210JF 细胞的 IC50 比非靶向脂质体柔红霉素（L-DNR）低 2-3 倍。在 L1210JF 肿瘤模型上的抗癌效果表明，5mg/kg 和 10mg/kg 剂量的 F-L-DNR 组小鼠的存活时间明显长于 L-DNR 或游离柔红霉素组。F-L-DNR 的共聚焦荧光照片表明，通过 L1210JF 细胞上的叶酸受体增强了脂质体的内吞作用，在静脉注射 F-L-DNR 24 小时后，延长了在肿瘤中的保留时间，并改善了肿瘤部位的药物释放。总之，叶酸聚乙二醇-胆固醇琥珀酸酯是叶酸靶向柔红霉素脂质体的有效配体，可实现肿瘤内药物释放增加和治疗效果提高。
