TARGETING LIPOSOMES FOR SELECTIVE INTERACTION WITH SPECIFIC CELLS AND TISSUES

我们研究了三种概念上不同的“瞄准”方式 脂质体： (1)抗体介导的靶向。 我们发现携带抗体的 脂质体大量结合到携带适当的 抗原的 然而，结合的脂质体只有在以下情况下才被内化： 内吞作用是可能的。 内吞后，脂质体包埋 甲氨蝶呤（MTX）可以从内吞装置逃逸并结合 细胞质二氢叶酸还原酶，抑制生长的 cell. 在这些研究的过程中，我们开发了第一个 将抗体偶联到脂质体异型双功能方法。 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，其分解并选择性地释放截留的 在局部高热可达到的温度下进行体内给药。 这些脂质体在体内选择性地将MTX递送至小鼠肿瘤 抑制它们的生长 (3)分区瞄准。 我们展示了 脂质体和包封的药物在皮下和皮下给药后转移到淋巴结， 腹膜内注射，并确定了 本地化 这些研究已经扩展到携带抗体的 脂质体。 这些策略正被应用于治疗中的问题， 癌症和艾滋病。 关于艾滋病，我们制定了 含有抗病毒药物的脂质体， 细胞，但可被携带到单核细胞/巨噬细胞 脂质体。

We have studied three conceptually different ways of "targeting" liposomes: (1) Antibody-mediated targeting. We find 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 have designed "temperature-sensitive" liposomes, which break down and selectively release an entrapped drug in vivo at temperatures achievable by local hyperthermia. These liposomes ppselectively deliver MTX 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 which do not ordinarily enter cells but which can be carried into monocyte/macrophages by the liposomes.