Mankertz J, Matthes E, Rokos K, von Baeyer H, Pauli G, Riedel E
Institut für Biochemie, Fachbereich Chemie, Freie Universität Berlin, Germany.
Biochim Biophys Acta. 1996 Dec 16;1317(3):233-7. doi: 10.1016/s0925-4439(96)00059-2.
Drug targeting via lipoproteins may be of benefit for use of cytotoxic drugs like fluorothymidine (FLT) or azidothymidine (AZT). Both drugs are potent inhibitors of the human immunodeficiency virus (HIV) reverse transcriptase and are used in the therapy of HIV infection. With regard to this project, the selective endocytosis in HIV infected human macrophages was studied after covalent coupling of AZT and LDL to low density lipoproteins (LDL). Cultured human macrophages and the lymphocytic Molt 4/8 cell line were infected with HIV-1 in vitro and subsequently treated with FLT-LDL or AZT-LDL. Viral replication was followed by determination of cell-released capsid antigen p24. Internalisation into HIV-1 infected human macrophages by the scavenger receptor pathway leads to a dose dependent inhibition of HIV replication. Otherwise, in HIV infected, but scavenger receptor missing lymphocytes (Molt 4/8 cells), neither endocytosis nor inhibition of HIV replication results. Thus, covalent coupling of drugs to LDL leads to a macrophage specific transport. This strategy could possibly avoid toxic side effects in the therapeutic use of antiretroviral drugs and thus may open a way for an earlier chemotherapy in HIV infection.
通过脂蛋白进行药物靶向递送可能有利于使用诸如氟胸苷（FLT）或叠氮胸苷（AZT）等细胞毒性药物。这两种药物都是人类免疫缺陷病毒（HIV）逆转录酶的有效抑制剂，用于治疗HIV感染。关于该项目，在将AZT和LDL共价偶联到低密度脂蛋白（LDL）后，研究了HIV感染的人类巨噬细胞中的选择性内吞作用。体外培养的人类巨噬细胞和淋巴细胞系Molt 4/8用HIV-1感染，随后用FLT-LDL或AZT-LDL处理。通过测定细胞释放的衣壳抗原p24来跟踪病毒复制情况。通过清道夫受体途径内化到HIV-1感染的人类巨噬细胞中会导致HIV复制的剂量依赖性抑制。否则，在HIV感染但缺乏清道夫受体的淋巴细胞（Molt 4/8细胞）中，既不会发生内吞作用，也不会抑制HIV复制。因此，药物与LDL的共价偶联导致巨噬细胞特异性转运。这种策略可能避免抗逆转录病毒药物治疗使用中的毒副作用，从而可能为HIV感染的早期化疗开辟一条途径。
