NanoART Manufacture, Delivery and Pharmacokinetics for Optimizing Drug Adherence

 描述（由申请人提供）：HIV/AIDS疾病结局的局限性受到抗逆转录病毒治疗（ART）依从性差和药物进入病毒库（肠道、淋巴结和中枢神经系统）不足的影响。需要终身每日方案，药丸疲劳，共病，药物滥用和固有的药物毒性往往影响药物方案的依从性。当出现次优的依从性时，它会导致人类免疫缺陷病毒1型（HIV-1）突变和随后疾病进展的加速。我们认为，长效纳米制剂ART（nanoART）的出现可以积极影响这些限制。为了将我们的工作从实验室工作台转移到临床应用，我们提出了一系列下一步研究，以牢固地建立四年前开始的基于细胞的nanoART运载系统。这种药物递送系统已被证明是产生ART储库的高效手段，其限制积极影响免疫和病毒参数的组织和细胞毒性。这些现在被证明为Cabotegravir，一种由GlaxoSmithKline制药公司生产的长效注射整合酶抑制剂，正在进行II期研究，每两个月一次。我们认为，这种和其他抗逆转录病毒药物可以包装成靶向纳米颗粒，以改善药物的生物分布，剂量频率和浓度长达六个月。事实上，初步数据支持这一论点，并在艾滋病毒/艾滋病动物模型中看到了它的前景。其中包括啮齿动物和恒河猴。我们认为，这样的药物输送系统可以不可避免地彻底改变ART治疗，并有可能消除传统的治疗方案。为此，我们建立了一个高度综合和跨学科的研究计划。我们之前已经证明，单剂量的靶向nanoART可以在网状内皮系统（RES;淋巴组织，肝脏和大脑）中产生高持续的组织和血浆药物水平。值得注意的是，这种制剂在RES内的单核细胞-巨噬细胞中显示出长寿命的药物贮库。NanoART可以在几分钟内被循环单核细胞和组织巨噬细胞吸收，并在几个月的时间内释放到组织中。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。T. Bronich和Core B，Y. Alnectin）将与联合国医学院放射科（项目3，M。Boska）和药理学和实验神经科学（项目2，H。Gendelman; Core C，L. Poluektova和H.福克斯），和斯克里普斯研究所（项目3，G。Siuzdak），以优化配方，更好地了解其毒理学特征。这可以 现在，通过整合细胞生物学、药理学、病毒学和分子学测试，将这些技术转化到患者床边，Gendelman，R.L. Mosley和J. McMillan）。这项研究利用了新成立的内布拉斯加州纳米医学生产工厂，该工厂在医学和高分子化学，分子生物成像和制药方面拥有广泛的资源。

 DESCRIPTION (provided by applicant): Limitations in disease outcomes for HIV/AIDS are influenced by poor adherence to antiretroviral therapy (ART) and inadequate drug penetrance into viral reservoirs (gut, lymph node and central nervous system). The need for lifelong daily regimens, pill fatigue, co-morbid diseases, substance abuse and inherent drug toxicities often affect adherence to drug regimens. When suboptimal adherence occurs, it results in accelerated rates of human immunodeficiency virus type one (HIV-1) mutation and consequent disease progression. We posit that the emergence of long-acting nanoformulated ART (nanoART) can positively impact these limitations. In order to move our work beyond the laboratory bench to clinical use, we propose a series of next step investigations to firmly establish the cell-based carriage system for nanoART that began four years ago. Such a system for drug delivery has been demonstrated to be a highly efficient means to generate ART depots that limit tissue and cell toxicities positively affecting immune and viral parameters. These were now demonstrated for Cabotegravir, a long-acting injectable integrase inhibitor made by GlaxoSmithKline Pharmaceuticals that is being tested in phase II investigations for a once every two-month dose. We posit that this and other antiretrovirals can be packaged into targeted nanoparticles to both improve drug biodistribution, dose frequency and concentration for up to six months. Indeed, preliminary data supports this contention and its promise seen in animal models of HIV/AIDS. These include rodents and rhesus macaques. We posit that such a drug delivery system can inevitably revolutionize ART treatment and potentially eliminate conventional therapeutic regimens. To such ends, we have built a highly integrative and cross-disciplinary research program. We have shown previously that a single dose of targeted nanoART can produce high-sustained tissue and plasma drug levels in the reticuloendothelial system (RES; lymphoid tissues, liver and brain). Notably, such formulations have shown long-lived drug depots in monocyte-macrophages within the RES. NanoART can be taken up within minutes by circulating monocytes and tissue macrophages and released in tissues over a period of months. Our partners in the University of Nebraska Medical Center College of Pharmacy (Project 1. T. Bronich and Core B, Y. Alnouti) will be joined with UNMC College of Medicine Departments of Radiology (Project 3, M. Boska) and Pharmacology and Experimental Neuroscience (Project 2, H. Gendelman; Core C, L. Poluektova and H. Fox), and The Scripps Research Institute (Project 3, G. Siuzdak) to optimize the formulations and better appreciate its toxicology profiles. This can now be facilitated through integrated cell biologic, pharmacologic, virologic, and molecular testing to translate the technologies to the patient bedside (Core A, H. Gendelman, R.L. Mosley and J. McMillan). The research takes advantage of the newly minted Nebraska Nanomedicine Production Plant with broad resources in medicinal and polymer chemistry, molecular bioimaging, and pharmaceutics.