Specific Hybrid Liposomes with Markedly Enhanced Inhibitory Effects on the Growth of Tumor Cells

我们研制了新型脂质体，杂化脂质体，包括囊状和胶束表面活性剂，其大小、相变温度、疏水性和流动性可通过添加胶束来控制。近年来，杂交脂质体对b淋巴瘤细胞的生长有抑制作用。此外，混合脂质体（含药物）治疗的胶质瘤模型大鼠存活时间明显延长。本研究考察了由二肉豆烯酰基磷脂酰胆碱（DMPC）和聚氧乙烯十二烷基醚（C_<12>(EO)_n）组成的杂交脂质体对t -淋巴瘤细胞体外生长的抑制作用。有趣的是，使用DMPC/C_<12>(EO)_8和DMPC/C_<12>(EO)_<12>的混合脂质体可以获得几乎完全的抑制效果。提示C_<12>(EO)_n胶束的亲疏水平衡对增强肿瘤细胞生长抑制作用具有重要意义。荧光测定结果表明，杂化脂质体的膜流动性与抑制效果一致。我们还研究了由90mol%DMPC和10mol% C_<12>(EO)_<12>组成的杂交脂质体的形态。值得注意的是，混合脂质体的水动力直径为120-130nm，且分布单一且狭窄，其清液可保存30天以上。以上结果提示，由90mol% DMPC和10mol% C_<12>(EO)_<12>组成的均匀稳定的杂化脂质体适合于临床化疗。此外，由90mol% DMPC和10mol% C_<12>(EO)_<12>组成的杂交脂质体在体内对正常大鼠无毒副作用，这一点很重要。目前正在进行大鼠模型治疗实验。

We have produced new-type liposomes, hybrid liposomes, including vesicular and micellar surfactants, whose sizes, phase transition temperature, hydrophobicity and fluidity could be controlled by adding micelles. Recently, the inhibitory effect of hybrid liposomes on the growth of B-lymphoma cells have been obtained in vitro. Furthermore, significantly prolonged survival was attained in rat model of gliomatosis treated with hybrid liposomes including drugs.In this study, we examined the inhibitory effect of hybrid liposomes composed of dimyristoylphosphatidylcholine (DMPC) and poly (oxyethylene) dodecyl ether (C_<12>(EO)_n) on the growth of T-lymphoma cells in vitro.Interestingly, the almost completely inhibitory effects were attained by employing the hybrid liposomes of DMPC/C_<12>(EO)_8 and DMPC/C_<12>(EO)_<12>. This result suggests that the hydrophilic-hydrophobic balance in C_<12>(EO)_n micelles should be of importance for the enhancement of inhibitory effect on the growth of tumor cells. The membrane fluidity of hybrid liposomes on the basis of fluorescence measurements was in harmony with the inhibitory effects.We also examined the morphology of the hybrid liposomes composed of 90mol%DMPC and 10mol% C_<12>(EO)_<12>. It is worthy to note that the clear solutions of the hybrid liposomes having a hydrodynamic diameter of 120-130nm with a single and narrow distribution could be kept over 30 days. The above mentioned results suggest that the uniform and stable hybrid liposomes composed of 90mol% DMPC and 10mol% C_<12>(EO)_<12> should be suitable for clinical chemotherapy.Furthermore, it is of importance that no toxic and side effects to normal rats in vivo were observed in the hybrid liposomes composed of 90mol% DMPC and 10mol% C_<12>(EO)_<12>. Therapeutic experiments are in progress by using rat model.