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，结合的脂质体只有在胞吞作用被抑制时才被内化。 可能 内吞作用后，脂质体包埋的甲氨蝶呤（MTX）可 从内吞器中逃逸并与细胞质二氢叶酸结合 还原酶，抑制细胞生长。 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。 目前的研究针对HTLVIII/LAV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包封的药物， 在可通过局部热疗实现的温度下体内。 这些脂质体 在体内选择性地将MTX递送至小鼠肿瘤并抑制其生长。 (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。

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 HTLVIII/LAV-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 selectively 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.