TARGETING LIPOSOMES FOR SELECTIVE INTERACTION WITH SPECIFIC CELLS AND TISSUES

我们研究了三种概念上不同的“靶向”脂质体的方法： (1)抗体介导的靶向。我们发现携带抗体的脂质体 大量结合到带有适当抗原的细胞上。然而，在这方面， 结合的脂质体只有在可能发生内吞作用时才被内化。后 内吞作用，脂质体包埋的甲氨蝶呤（MTX）可以逃脱的 内吞器并结合细胞质二氢叶酸还原酶， 抑制细胞的生长。在这些研究的过程中，我们开发了 第一种将抗体偶联到脂质体上的异双功能方法。 目前的研究针对HIV感染的细胞。 (2)物理瞄准。我们设计了“温度敏感”脂质体， 其在体内分解并选择性地释放包埋的药物， 局部热疗可达到的温度。这些脂质体选择性地 在体内将MTX或顺式铂递送至小鼠肿瘤并抑制它们的生长。 增长 (3)分区瞄准。我们已经证明了脂质体的递送 并在皮下和腹膜内后将药物包埋到淋巴结， 注射并确定了定位的细胞位点。这些研究 已经扩展到携带抗体的脂质体。这些策略 应用于癌症和艾滋病的治疗问题。 与 针对艾滋病，我们研制了含有抗病毒药物的脂质体 （二脱氧核苷三磷酸），通常不进入细胞，但 其可以通过脂质体被携带到单核细胞/巨噬细胞中。 或者，通过我们先前的方法将抗体连接到脂质体上。 开发了用于递送至靶细胞类型的方法。

We have studied three conceptually different ways of "targeting" liposomes: (1) Antibody-mediated targeting. We found that antibody-bearing liposomes bind in large numbers to cells which bear the appropriate antigen. However, the bound liposomes are internalized only if endocytosis is possible. Upon endocytosis, liposome-entrapped methotrexate (MTX) can escape from the endocytic apparatus and bind to cytoplasmic dihydrofolate reductase, inhibiting growth of the cell. In the course of these studies, we developed the first heterobifunctional method for coupling antibody to liposomes. Current studies are directed toward HIV-infected cells. (2) Physical targeting. We designed "temperature-sensitive" liposomes, which break down and selectively release an entrapped drug in vivo at temperatures achievable by local hyperthermia. These liposomes selectively deliver MTX or cis platinum to mouse tumors in vivo and inhibit their growth. (3) Compartmental targeting. We have demonstrated the delivery of liposomes and entrapped drug to lymph nodes after subcutaneous and intraperitoneal, injection and have determined cellular sites of localization. These studies have been extended to antibody-bearing liposomes. These strategies are being applied to problems in the therapy of cancer and AIDS. With respect to AIDS, we have formulated liposomes containing anti-viral drugs (dideoxynucleoside triphosphates)which do not ordinarily enter cells but which can be carried into monocyte/macrophages by the liposomes. Alternatively antibody is attached to the liposomes by our previously developed methods for delivery to targeted cell types.