Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice.
Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice.
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DOI：
10.1097/qad.0b013e328357f5ad
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发表时间：
2012-11-13
期刊：
影响因子：
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通讯作者：
Poluektova LY
中科院分区：
文献类型：
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作者：
Dash PK;Gendelman HE;Roy U;Balkundi S;Alnouti Y;Mosley RL;Gelbard HA;McMillan J;Gorantla S;Poluektova LY
长效纳米制剂抗逆转录病毒疗法(NanoArt)具有更好的药代动力学、生物分布和有限的全身毒性，可能会改善药物依从性和获得病毒库的机会。以泊洛沙姆-188为赋形剂，采用高压均质法制备了阿他扎韦和利托那韦纳米微球。这些制剂在人源化NOD/SCID-IL-2Rgcull(NSG)小鼠身上进行了抗逆转录病毒和神经保护活性的评估。对纳米艺术处理的NSG小鼠进行药物生物分布、药效学和纳米毒理学评价。出生时将CD34+人造血干细胞移植到NSG小鼠体内。小鼠在5个月龄时感染HIV-1ADA，8周后，感染动物每周皮下注射纳米制剂ATV和RTV。检测外周血病毒载量、CD4+T细胞计数、淋巴组织及脑组织病理改变。每周注射6次的NanoArt疗法将病毒载量降低了1000倍，并保护了CD4+T细胞群。这与肝、脾和血液中的高ART水平平行，这些水平处于或接近人类最低有效剂量浓度，而没有显著的毒性。重要的是，对感染的脑区的检查显示，与未经治疗的感染病毒的动物相比，NanoArt引发了神经保护反应，微管相关蛋白-2、突触素和神经丝的表达明显增加。治疗中断产生了深刻的病毒反弹。长效纳米艺术具有翻译潜力，具有持续和靶向的疗效，并具有有限的全身毒性。这种成功的药物输送和分配可以改善感染者的药物依从性，降低病毒耐药性。
Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug compliance and access to viral reservoirs. Atazanvir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgcnull (NSG) mice. NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and nanotoxicology. CD34+ human hematopoietic stem cells were transplantation at birth in NSG mice. The mice were infected with HIV-1ADA at 5 months of age and 8 weeks later, infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4+ T cell count, lymphoid tissue and brain pathology were evaluated. NanoART treatments by 6 once a week injections reduced viral loads >1000 fold and protected CD4+ T cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people.