NanoART Manufacture, Delivery and Pharmacokinetics for Optimizing Drug Adherence

虽然抗逆转录病毒疗法（ART）导致HIV-1感染者的发病率改善和死亡率降低，但主要限制在于需要终身每日方案。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连相关，通常导致加速HIV疾病进展。此外，由于担心会促进病毒耐药性，提供者往往不愿意为滥用药物或吸毒成瘾的患者开抗逆转录病毒疗法。复杂的问题还包括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ART（利托那韦、茚地那韦、依法韦仑、阿扎诺韦和依法韦仑）的出现将对这些问题产生积极影响。因此，我们建议开发抗逆转录病毒纳米颗粒（nanoART），其在循环免疫细胞内携带并递送至病毒靶组织。基于细胞的nanoART理论上会到达炎症部位，缓慢释放药物，组织毒性有限。这种药物递送系统如果实现，可以彻底改变ART治疗结果，特别是神经系统内的ART治疗结果。本提案建立在我们实验室之间进行的先前工作（项目1和2，A。Kabanov和H. Gendelman）。初步研究证明了“概念验证”，即单次静脉注射nanoART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。NanoART可以在几分钟内被循环单核细胞吸收，并在两周内释放到组织中。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.卡巴诺夫和核心C，C弗莱彻）将加入我们的医学院放射学，医学，药理学和实验神经科学系（项目2和3和核心B，H。Gendelman，H. Fox和M. Boska），以优化未来人类临床使用的纳米制剂。现在可以通过联合国军事委员会内的综合细胞生物学、药理学、病毒学和分子学测试设施来促进这一点，将一个“想法”从实验室工作台转移到床边。首先，nanoART将在HIV感染的实验室模型中进行生产和优化。第二，将对nanoART进行缩放，以测试啮齿动物和恒河猴中的药物药代动力学。第三，将在感染SIV和HIV的重组慢病毒杂交体（SHIV）的病毒感染恒河猴中进行动物研究，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.