Multilevel Targeted Therapeutics Using Surface Functionalized Nanoparticles encap

描述(申请人提供)：性传播疾病(STD)每年影响3.4亿新增人口，其中单纯疱疹病毒2型(HSV-2)感染影响到惊人的约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、新生儿和免疫受损个人的影响不成比例。此外，现在清楚的是，单纯疱疹病毒2型感染使人类免疫缺陷病毒(HIV)合并感染的可能性增加6倍，并增加了第三世界国家艾滋病毒、衣原体和梅毒的流行。因此，更好的治疗或预防HSV-2的策略有望有助于减少STD的传播。目前预防和治疗HSV-2的选择包括抗病毒药物和局部使用的杀微生物剂。然而，主要由于交付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，但抗病毒战略和疫苗开发被证明只取得了一定程度的成功。然而，如果应用于杀微生物剂的设计，疫苗典型的多治疗靶向方法可能会提高疗效。为了帮助抑制病毒，RNA干扰(RNAi)等机制--使用靶向的短干扰RNA(SiRNA)分子--可以下调特定蛋白质的表达，如UL29.2(一种影响病毒复制的DNA结合蛋白)和Nectin-1(一种宿主细胞受体蛋白，最初与病毒结合和随后的传播不可或缺)。与此同时，蛋白质水平的研究也发现了可以拦截病毒与Nectin-1等宿主受体结合的单抗。此外，还有许多新的分子可用于增强药物传递和组织渗透，包括细胞穿透性多肽、内体逃逸多肽和通过各种机制发挥作用的隐形配体。本项目将测试以下假设：(1)提供RNAi的siRNA；(2)通过增强NP摄取来调节细胞与病毒相互作用的表面功能化；(3)粘膜渗透的隐形特性；以及(4)控制释放以使微囊化制剂能够延长治疗效果的假说，其中包括：(1)提供RNAi的siRNA；(2)通过增强NP摄取来调节细胞与病毒相互作用的表面功能化；以及(4)在体外和体内都有可能提高病毒抑制作用。我预计这种方法将改进目前的HSV-2治疗，并可以扩展到多种STD组合，包括难以捉摸的病毒，如艾滋病毒。 公共卫生相关性：性传播疾病(STD)是一个重大的全球健康威胁，而单纯疱疹病毒2型(HSV-2)尤其普遍；它在STD合并感染、医疗费用、社会影响、对新生儿和免疫功能受损个人的影响以及反复感染方面的突出作用，所有这些都加剧了制定有效治疗战略的紧迫性。该项目的短期意义是开发一种包裹短干扰RNA(SiRNA)分子的纳米颗粒递送系统，具有表面功能化，通过多种机制(干扰结合、摄取和复制)同时针对病毒和宿主来干扰HSV-2感染。这种多模式方法将改进目前的HSV-2治疗，并可扩展到多种STD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. PUBLIC HEALTH RELEVANCE: Sexually transmitted diseases (STDs) pose a significant global health threat, and herpes simplex virus type 2 (HSV-2) is particularly pervasive; its prominent role in STD coinfection, healthcare costs, societal ramifications, the impact on newborns and immune-compromised individuals, and recurrent infections, all contribute to the urgency to develop an efficacious treatment strategy. The short-term significance of this project is to develop a nanoparticle delivery system encapsulating short interfering RNA (siRNA) molecules, with surface functionalization, that interferes with HSV-2 infection by targeting the virus and host simultaneously, through multiple mechanisms (interfering with binding, uptake, and replication). This multimodal approach will improve current HSV-2 therapy and can be extended to multiple STD combinations, including elusive viruses such as HIV.