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

我们制备了混合脂质体(HL)，它可以通过在缓冲溶液中超声作用囊泡分子和胶束分子来制备。通过改变HL的组成和组成比，可以控制HL的大小、形状、膜流动性和相分离温度等物理性质。我们研究了HL的抗癌作用，得到了如下结果：(A)HL-n由二肉豆蔻基磷脂酰胆碱(DMPC)和聚氧乙烯十二烷基醚(C_&lt；12&gt；用电子显微镜和动态光散射法观察到直径为80 nm的(EO)_n：n=21~25)。(2)HL在体外对多种肿瘤细胞的生长有明显的抑制作用。(3)HL处理的肿瘤细胞线粒体膜电位降低，caspase-8、caspase-9和caspase-3活化。(D)HL膜流动性与HL对肿瘤细胞的抑制作用有很好的相关性。(E)在无任何药物的HL治疗小鼠肿瘤模型的体内实验中，化疗效果显著。(F)经生物伦理委员会批准，淋巴瘤患者静脉注射HL可延长生存期，且无任何副作用。首次建立了无药物HL的膜靶向化疗。

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.