LIPOSOME TARGETING TO TUMOR CELLS IN VIVO

我们建议使用抗体偶联脂质体在体内实现 在动物肿瘤中定位，从而提高治疗指数 封装的药物。脂质体靶向特定细胞的工作将完成 通过将它们与识别特定基因的免疫球蛋白结合 细胞表面抗原。我们已经证明了这个过程是有效的 在体外非常有效。我们在体内实现靶向的策略 包括三个阶段：1)优化特定结合和 不同抗体与脂质体比例、脂质体大小对体外细胞毒作用的研究 2)体内靶向性的优化 在小鼠中通过使用特定的放射性标记和 脂质体脂和水含量的电子显微镜标记 并通过考察给药途径、脂质体大小、 剂量，网状内皮系统的预饱和，并增加 血管内皮细胞通透性；3)抗肿瘤效果的评价 观察移植瘤的大小变化和因其引起的死亡 血行转移。我们对目标细胞的选择涉及到一个进程 从“可接触”细胞(如淋巴组织)到 细胞可能相对不可接近的系统(例如植入 肿瘤)。我们选择治疗指数最大的药物的策略 包括：非正常运输的药物衍生品 转化为细胞(脂类依赖药物)，以降低系统性 毒性；在低pH值环境中变得具有膜渗透性的药物 内吞后(溶酶体恐惧症药物)，以增加 细胞内给药的效率；以及可以运输的药物 从单纯附着于靶点的脂质体缓慢释放后进入细胞 单元格(局部化仓库效果)。

We propose to use antibody-conjugated liposomes to achieve in vivo localization in animal tumors and thus increase the therapeutic index of encapsulated drugs. Targeting of liposomes to specific cells will be done by conjugating them with immunoglobulins which recognize specific cell-surface antigens. We have already shown that this procedures works very efficiently in vitro. Our strategy for achieveing targeting in vivo involves three stages: 1) optimization of specific binding and cytotoxicity in vitro by varying antibody per liposome ratio, liposome size and composition and type of drug; 2) optimization of in vivo targeting against the same cells in mice by use of specific radiolabelled and electronmicroscopic markers for both liposome lipids and aqueous contents and by examining the effect of route of administration, liposome size, dosage, pre- saturation of the reticulo-endothelial system, and increasing endothelial permeability; and 3) evaluation of anti-tumor effects by observing changes in size of implanted tumors and deaths due to hematogenous metastasis. Our choice of target cells involves a progression from situations where cells are "accessible" (such as lymphoid tissue) to systems where the cells may be relatively inaccessible (such as implanted tumors). Our strategy of selecting drugs for maximal therapeutic index includes the following: drug derivatives that are not normally transported into cells (lipsome-dependent drugs) in order to decrease systemic toxicity; drugs that become membrane permeable in the low pH environment after endocytosis (lysosomophobic drugs) in order to increase the efficiency of intracellular delivery; and drugs that can be transported into cells after slow release from liposomes simply attached to target cells (localized depot effect).