NanoART Manufacture, Delivery and Pharmacokinetics for Optimizing Drug Adherence

虽然抗逆转录病毒疗法（ART）改善了1型肝炎病毒感染者的发病率并降低了死亡率，但主要的限制在于需要终生每日治疗。次优依从性导致治疗失败的风险增加。药物滥用障碍与这种散发性粘附相关，通常导致艾滋病毒疾病加速进展。此外，由于担心促进病毒学耐药性，提供者往往不愿给滥用药物或吸毒成瘾的患者开抗逆转录病毒药物。更复杂的是常见的认知和运动障碍。这些风险因素往往导致治疗效果不佳。缓释抗逆转录病毒治疗（利托那韦、因地那韦、依非韦伦、阿他诺韦和依非韦伦）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），它可以在循环免疫细胞内携带并递送到病毒靶组织。理论上，基于细胞的纳米抗逆转录病毒疗法可以到达炎症部位，缓慢释放药物，并限制组织毒性。这样的药物输送系统，如果实现，可以彻底改变抗逆转录病毒治疗的结果，特别是在神经系统内。该建议建立在我们实验室之前进行的工作基础上（项目1和2，A. Kabanov和H. Gendelman）。初步研究表明，单次静脉注射纳米art可以在网状内皮系统和大脑中引起高持续的组织和血浆药物水平，这证明了“概念证明”。纳米art可以在几分钟内被循环的单核细胞吸收，并在两周内释放到组织中。我们的合作伙伴内布拉斯加大学医学中心药学院（项目1）。A. Kabanov和核心C， C . Fletcher)将与我们的医学院放射学，医学，药理学和实验神经科学部门（项目2和3和核心B， H. Gendelman， H. Fox和M. Boska）一起优化纳米配方，用于未来的人类临床应用。现在可以通过UNMC内整合的细胞生物学、药理学、病毒学和分子测试设施来促进这一点，将“想法”从实验室工作台转移到床边。首先，纳米art将被制造出来，然后在HIV感染的实验室模型中进行优化。其次，纳米art将被用于在啮齿类动物和恒河猴体内测试药物的药代动力学。第三，将在感染SIV和HIV的重组慢病毒杂交（SHIV）的病毒感染恒河猴中进行动物实验，分别进行安全性和有效性研究。

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.