Development of Nanotherapy System for Intractable Disease with Hybrid Liposomes-Cancer therapy with hybrid liposomes-

我们已经产生了混合脂质体（HL），它可以通过在缓冲溶液中超声处理囊泡和胶束分子来制备。HL的物理性质，如大小，形状，膜流动性，和相分离的温度可以通过改变组成和组成比例来控制。我们研究了HL的抗肿瘤作用，得到以下结果。(A)用电子显微镜和动态光散射法观察了由二肉豆蔻酰磷脂酰胆碱（DMPC）和聚氧乙烯十二烷基醚（<12>CEO n：n=21~25）组成的HL n的均匀稳定结构，其直径为80 nm。(B)HL在体外对多种肿瘤细胞的生长均有明显的抑制作用。(C)HL处理的肿瘤细胞中观察到线粒体膜电位降低和caspase-8、caspase-9和caspase-3的活化，表明HL-n的凋亡信号应通过线粒体和这些caspase。(D)HL细胞膜流动性与HL对肿瘤细胞的抑制作用有良好的相关性。(E)在体内实验中，使用小鼠肿瘤模型，在没有任何药物的情况下用HL治疗后，获得了显著高的化疗效果。(F)经生物伦理委员会批准，HL静脉注射治疗淋巴瘤患者，生存期延长，无任何毒副作用，首次建立了无药物HL膜靶向化疗。

We have produced hybrid liposomes (HL) which can be prepared by sonication of vesicular and micellar molecules in a buffer solution. The physical properties of HL such as size, shape, membrane fluidity, and the temperature of phase separation can be controlled by changing the constituents and compositional ratio. We have investigated the anticancer effects of HL and following results are obtained.(A) The uniform and stable structure of HL-n composed of dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene dodecyl ethers (C_<12>(EO)_n : n=21～25) with a diameter of 80 nm was observed by electron microscope and dynamic light scattering method.(B) The remarkable inhibitory effects of HL on the growth of various tumor cells were attained in vitro.(C) Reduction of mitochondrial membrane potential and activation of caspase-8, caspase-9, and caspase-3 were observed in the tumor cells treated with HL, indicating that apoptotic signal by HL-n should pass through mitochondria and these caspases.(D) A good correlation between the membrane fluidity of HL and inhibitory effects of HL for tumor cells was obtained.(E) Significantly high chemotherapeutic effects were obtained in vivo experiments using mice model of carcinoma after the treatment with HL without any drug.(F) After the approval of the bioethics committee, prolonged survival was attained in patients with lymphoma after the intravenous injection of HL without any side effect.The membrane targeted chemotherapy with drug-free HL was established for the first time.