NanoART Manufacture, Delivery and Pharmacokinetics for Optimizing Drug Adherence

虽然抗逆转录病毒疗法(ART)可以改善HLV-1感染者的发病率和降低死亡率，但一个主要限制在于需要终生每日服药。不理想的依从性会增加治疗失败的风险。药物滥用障碍与这种零星的粘连有关，通常导致艾滋病毒疾病加速发展。此外，由于担心促进病毒学耐药性，提供者往往不愿给滥用或对药物上瘾的患者开ART。更复杂的问题包括常见的认知和运动障碍。这些风险因素往往导致不良的治疗结果。缓释抗逆转录病毒药物(利托那韦、依地那韦、依法韦林、阿扎诺韦和依法韦仑)的出现将对这些担忧产生积极影响。因此，我们建议开发抗逆转录病毒纳米颗粒(NanoArt)，这种纳米颗粒可以携带在循环免疫细胞中，并被输送到病毒靶向组织。以细胞为基础的纳米艺术理论上会进入炎症部位，缓慢释放药物(S)，组织毒性有限。这种药物输送系统如果实现，可以彻底改变ART治疗结果，特别是神经系统内的治疗结果。这项建议建立在我们实验室(项目1和项目2，A.Kabanov和H.Gendelman)之间先前进行的工作的基础上。初步研究表明，单次静脉注射NanoArt可以在网状内皮系统和大脑中诱导出高持续的组织和血浆药物水平，这是“概念证明”。纳米艺术可以在几分钟内被循环中的单核细胞摄取，并在两周内在组织中释放。我们在内布拉斯加大学医学中心药学院的合作伙伴(项目1.A.Kabanov和核心C，C，Fletcher)将与我们医学院的放射学、医学系、药理学和实验神经科学系(项目2和3以及核心B、H.Gendelman、H.Fox和M.Boska)一起优化纳米制剂，以供未来人类临床使用。现在可以通过UNMC内集成的细胞生物学、药理学、病毒学和分子测试设施来促进这一点，将“想法”从实验室工作台通过翻译转移到床边。首先，纳米艺术将被制造出来，然后在艾滋病毒感染的实验室模型中进行优化。其次，NanoArt将被用于测试啮齿动物和恒河猴的药物动力学。第三，将在感染了SIV和HIV(SIV)的重组慢病毒杂交体(SIV)的恒河猴身上进行动物研究，分别进行安全性和有效性调查。

While antiretroviral therapy (ART) leads to improved morbidity and reduced mortality for HlV-1 infected people, a major limitation rests in the need for lifelong daily regimens. Suboptimal adherence causes increased risk of treatment failure. Drug abuse disorders correlate with such sporadic adherences commonly resulting in accelerated HIV disease progression. Moreover, providers are often reluctant to prescribe ART to patients who abuse or are addicted to drugs because of concerns about the promotion of virologic resistance. Complicating matters further include common cognitive and motor disorders. These risk factors often result in poor treatment outcomes. The advent of slow release ART (ritonavir, indinavir, efavirenz, atazanovir and efavirenz) will positively impact these concerns. Thus, we propose to develop antiretroviral nanoparticles (nanoART) that are carried within circulating immunocytes and delivered to virus-target tissues. Cell-based nanoART theoretically would travel to sites of inflammation and release drug(s) slowly with limited tissue toxicities. Such a drug delivery system, if realized, can revolutionize ART treatment outcomes particularly those within the nervous system. This proposal builds on prior works conducted between our laboratories (Project 1 and 2, A. Kabanov and H. Gendelman). Preliminary investigations demonstrated "proof of concept" in that a single intravenous dose of the nanoART can elicit high-sustained tissue and plasma drug levels in the reticuloendothelial system and brain. NanoART can be taken up within minutes by circulating monocytes and released in tissues over a period of two weeks. Our partners in the University of Nebraska Medical Center College of Pharmacy (Project 1. A. Kabanov and Core C, C Fletcher) will be joined with our College of Medicine Departments of Radiology, Medicine, and Pharmacology and Experimental Neuroscience (Projects 2 and 3 and Core B, H. Gendelman, H. Fox, and M. Boska) to optimize nanoformulations for future human clinical use. This can now be facilitated through integrated cell biologic, pharmacologic, virologic, and molecular testing facilities within UNMC to move an "idea" from the laboratory bench through its translation to the bedside. First, nanoART will be manufactured then optimized in laboratory models of HIV infection. Second, the nanoART will be scaled for testing drug pharmacokinetics in rodents and rhesus macaques. Third, animal studies will be performed in virus-infected rhesus macaques infected with recombinant lentivirus hybrids of SIV and HIV (SHIV) for safety and efficacy investigations, respectively.