Spitzenberger Timothy J, Heilman David, Diekmann Casey, Batrakova Elena V, Kabanov Alexander V, Gendelman Howard E, Elmquist William F, Persidsky Yuri
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
J Cereb Blood Flow Metab. 2007 May;27(5):1033-42. doi: 10.1038/sj.jcbfm.9600414. Epub 2006 Oct 25.
Most potent antiretroviral drugs (e.g., HIV-1 protease inhibitors) poorly penetrate the blood-brain barrier. Brain distribution can be limited by the efflux transporter, P-glycoprotein (P-gp). The ability of a novel drug delivery system (block co-polymer P85) that inhibits P-gp, to increase the efficacy of antiretroviral drugs in brain was examined using a severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE). Severe combined immunodeficiency mice inoculated with HIV-1 infected human monocyte-derived macrophages (MDM) into the basal ganglia were treated with P85, antiretroviral therapy (ART) (zidovudine, lamivudine and nelfinavir (NEL)), or P85 and ART. Mice were killed on days 7 and 14, and brains were evaluated for levels of viral infection. Antiviral effects of NEL, P85, or their combination were evaluated in vitro using HIV-1 infected MDM and showed antiretroviral effects of P85 alone. In SCID mice injected with virus-infected MDM, the combination of ART-P85 and ART alone showed a significant decrease of HIV-1 p24 expressing MDM (25% and 33% of controls, respectively) at day 7 while P85 alone group was not different from control. At day 14, all treatment groups showed a significant decrease in percentage of HIV-1 infected MDM as compared with control. P85 alone and combined ART-P85 groups showed the most significant reduction in percentage of HIV-1 p24 expressing MDM (8% to 22% of control) that were superior to the ART alone group (38% of control). Our findings indicate major antiretroviral effects of P85 and enhanced in vivo efficacy of antiretroviral drugs when combined with P85 in a SCID mouse model of HIVE.
大多数强效抗逆转录病毒药物（如HIV-1蛋白酶抑制剂）很难穿透血脑屏障。脑部分布可能会受到外排转运蛋白P-糖蛋白（P-gp）的限制。使用HIV-1脑炎（HIVE）的严重联合免疫缺陷（SCID）小鼠模型，研究了一种新型抑制P-gp的药物递送系统（嵌段共聚物P85）提高抗逆转录病毒药物在脑中疗效的能力。将接种了HIV-1感染的人单核细胞衍生巨噬细胞（MDM）的严重联合免疫缺陷小鼠注射到基底神经节，然后用P85、抗逆转录病毒疗法（ART）（齐多夫定、拉米夫定和奈非那韦（NEL））或P85与ART进行治疗。在第7天和第14天处死小鼠，并评估脑内的病毒感染水平。使用HIV-1感染的MDM在体外评估NEL、P85或其组合的抗病毒效果，结果显示单独使用P85具有抗逆转录病毒作用。在注射了病毒感染MDM的SCID小鼠中，ART-P85组合和单独使用ART在第7天时均显示表达HIV-1 p24的MDM显著减少（分别为对照组的25%和33%），而单独使用P85组与对照组无差异。在第14天，与对照组相比，所有治疗组的HIV-1感染MDM百分比均显著降低。单独使用P85组和ART-P85组合组中表达HIV-1 p24的MDM百分比降低最为显著（为对照组的8%至22%），优于单独使用ART组（对照组的38%）。我们的研究结果表明，在HIVE的SCID小鼠模型中，P85具有主要的抗逆转录病毒作用，并且与P85联合使用时抗逆转录病毒药物的体内疗效增强。
