Multilevel Targeted Therapeutics Using Surface Functionalized Nanoparticles encap

描述（由申请人提供）：性传播疾病（STDs）每年影响3.4亿新患者，其中单纯疱疹病毒2型（HSV-2）感染影响了惊人的17%的美国成年人和全球5.36亿人。迫切需要开发更好的治疗方法，特别是因为它对妇女、新生儿和免疫功能低下的个体产生了不成比例的影响。此外，现在很清楚，2型单纯疱疹病毒感染使人类免疫缺陷（HIV）合并感染的可能性增加了6倍，并使第三世界国家的HIV、衣原体和梅毒患病率增加。因此，治疗或预防2型单纯疱疹病毒的更好策略有望有助于减少性病传播。目前预防和治疗2型单纯疱疹病毒的选择包括抗病毒药物和局部应用的杀微生物剂。然而，主要由于递送困难和缺乏对免疫反应的了解，尽管确定了基于抗原的靶点，但抗病毒策略和疫苗开发仅证明了适度的成功。然而，如果应用于杀微生物剂设计，疫苗典型的多治疗靶向方法可能会提高效力。为了帮助抑制病毒，RNA干扰（RNAi）等机制-使用靶向短干扰RNA （siRNA）分子-可以下调特定蛋白质，如UL29.2（影响病毒复制的DNA结合蛋白）和nectin-1（初始病毒结合和随后传播不可或缺的宿主细胞受体蛋白）。与此同时，在蛋白质水平上的研究已经发现了单克隆抗体（mab），它可以拦截病毒附着在宿主受体上，如nectin-1。此外，有许多新分子可用于增强药物传递和组织渗透，包括细胞穿透肽、内体逃逸肽和通过多种机制起作用的隐形配体。该项目将测试基于聚合PLGA纳米颗粒的杀微生物剂的假设，该杀微生物剂包含：(1)提供RNAi的siRNA，(2)通过增强NP摄取来调节细胞-病毒相互作用的表面功能化，(3)渗透粘膜的隐身特性，以及(4)控制释放以延长封装剂的治疗效果，具有在体外和体内增加病毒抑制的潜力。我希望这种方法可以改善目前的HSV-2治疗，并可以扩展到多种性病组合，包括难以捉摸的病毒，如艾滋病毒。

DESCRIPTION (provided by applicant): Sexually transmitted diseases (STDs) affect 340 million new people per year, with herpes simplex virus type 2 (HSV-2) infection impacting a startling ~17 percent of U.S. adults and 536 million people worldwide. Development of better treatments is an urgent need, particularly due to its disproportional effect on women, newborns and immune-compromised individuals. In addition, it is now clear that HSV-2 infection increases the likelihood of human immunodeficiency (HIV) coinfection 6-fold and increases HIV, Chlamydia, and syphilis prevalence in third-world countries. Therefore better strategies to treat or prevent HSV-2 are expected to help decrease STD spread. Current options for prevention and treatment of HSV-2 include antivirals and topically applied microbicides. However, primarily due to difficulties in delivery and a lack of understanding of the immune response, antiviral strategies and vaccine development have proven only moderately successful, despite the identification of antigen-based targets. However, if applied to microbicide design, the multi-therapeutic targeting methodology typical of vaccines may enable increased efficacy. To aid in viral inhibition, mechanisms such as RNA interference (RNAi) - using targeted short interfering RNA (siRNA) molecules - can down-regulate specific proteins such as UL29.2 (a DNA binding protein affecting virus replication) and nectin-1 (a host cell receptor protein integral to initial viral binding and subsequent spread). In parallel, research at the protein level has uncovered monoclonal antibodies (mAbs) that can intercept virus attachment to host receptors such as nectin-1. Additionally, there are many new molecules available to enhance drug delivery and tissue penetration, including cell penetrating peptides, endosomal escape peptides, and stealth ligands that act through a variety of mechanisms. This project will test the hypotheses that administration of a polymeric PLGA nanoparticle-based microbicide, that incorporates: (1) siRNA to provide RNAi, (2) surface functionalization that modulates cell-virus interactions by enhancing NP uptake, (3) stealth properties for mucosal penetration, and (4) controlled release to enable prolonged therapeutic effect of the encapsulated agents, has the potential to increase viral inhibition both in vitro and in vivo. I expect this approach will improve current HSV-2 therapy and can be extended to multiple STD combinations, including elusive viruses such as HIV.