TARGETING LIPOSOMES FOR SELECTIVE INTERACTION WITH SPECIFIC CELLS AND TISSUES

靶向脂质体与特定细胞和组织选择性相互作用

• 批准号: 3916314
• 负责人: J N WEINSTEIN
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3916314
• 关键词: AIDS therapy; antiAIDS agent; antibody; antigen antibody reaction; chemotherapy; dihydrofolate reductase; drug administration rate /duration; drug administration routes; drug vehicle; human immunodeficiency virus 1; human tissue; immunoconjugates; laboratory mouse; liposomes; lymph nodes; membrane activity; methotrexate; multiple myeloma; neoplasm /cancer chemotherapy; neoplasm /cancer thermotherapy; neoplastic cell; pinocytosis; tissue /cell culture

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.

我们研究了三种概念上不同的“目标”方式。 脂质体： (1)抗体介导的靶向。我们发现携带抗体的 脂质体大量结合到细胞上，这些细胞承担着适当的 抗原。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。根据内吞作用，脂质体被包裹 甲氨蝶呤(MTX)可从内吞器官逃逸并结合 到细胞质二氢叶酸还原酶，抑制细胞生长 手机。在这些研究过程中，我们开发了第一个 抗体与脂质体偶联的异双功能方法。 目前的研究针对的是感染艾滋病毒的细胞。 (2)物理靶向。我们设计了“温度敏感型” 脂质体，它分解并选择性地释放被困住的 体内药物在可通过局部热疗达到的温度下。 这些脂质体在体内选择性地将MTX传递给小鼠肿瘤。 并抑制它们的生长。 (3)隔室靶向。我们已经展示了交付 皮下注射后将脂质体和药物包埋于淋巴结 在腹膜内注射，并确定了细胞位置 本地化。这些研究已经扩展到抗体携带。 脂质体。 这些策略正在被应用于治疗中的问题 癌症和艾滋病。关于艾滋病，我们已经制定了 含有抗病毒药物的脂质体，通常不会进入 细胞，但可以被携带到单核细胞/巨噬细胞 脂质体。