Multilevel Targeted Therapeutics Using Surface Functionalized Nanoparticles encap

使用表面功能化纳米颗粒 encap 的多层次靶向治疗

• 批准号: 8203042
• 负责人: Jill Steinbach-Rankins
• 金额: $ 4.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203042
• 关键词: Adult; Affect; Antigens; Antiviral Agents; Avidin; Binding; Biocompatible; Biotin; Cell-Cell Adhesion; Cells; Chlamydia; DNA-Binding Proteins; Developing Countries; Development; Drug Delivery Systems; Drug Formulations; Encapsulated; Gene Proteins; Glycolates; Glycoproteins; HIV; HIV-1; Health Care Costs; Human; Human Herpesvirus 2; Immune; Immune response; Immunologic Deficiency Syndromes; In Vitro; Incidence; Individual; Infection; Intercept; Laboratories; Ligands; Messenger RNA; Methodology; Monoclonal Antibodies; Mus; Newborn Infant; Novartis brand of milbemycin oxime; PVRL1; Penetration; Peptides; Prevalence; Prevention; Prevention strategy; Property; Proteins; RNA; RNA Interference; Recurrence; Research; Role; Sexually Transmitted Diseases; Simplexvirus; Surface; Syphilis; System; Testing; Therapeutic Effect; Therapeutic Uses; Tissues; Topical application; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; Virus-Cell Membrane Interaction; Woman; Work; adhesion receptor; base; combat; controlled release; density; design; global health; health care service utilization; improved; in vivo; microbicide; nanoparticle; nectin; prevent; prototype; receptor; surface coating; therapeutic target; treatment strategy; uptake; vaccine delivery; vaccine development

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.

性传播疾病（STD）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，特别是由于其对妇女，新生儿和免疫受损个体的影响不成比例。此外，现在清楚的是，HSV-2感染使人类免疫缺陷（HIV）合并感染的可能性增加6倍，并增加第三世界国家的HIV、衣原体和梅毒患病率。因此，更好的治疗或预防HSV-2的策略有望有助于减少STD传播。目前预防和治疗HSV-2的选择包括抗病毒药物和局部应用的杀微生物剂。然而，主要是由于交付困难和缺乏对免疫应答的理解，抗病毒策略和疫苗开发已被证明仅取得了适度的成功，尽管识别了基于抗原的靶标。然而，如果应用于杀微生物剂设计，疫苗的典型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（使用靶向短干扰RNA（SiRNA）分子）可以下调特定蛋白质，例如UL29.2（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）对于初始病毒结合和随后的传播是不可或缺的）。与此同时，蛋白质水平的研究已经发现了单克隆抗体（mAb），可以拦截病毒附着到宿主受体，如nectin-1。此外，有许多新的分子可用于增强药物递送和组织渗透，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。该项目将测试以下假设，即施用基于聚合物PLGA纳米颗粒的杀微生物剂，该杀微生物剂包含：（1）siRNA以提供RNAi，（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）用于粘膜渗透的隐形性质，和（4）控制释放以使包封的试剂能够延长治疗效果，具有在体外和体内增加病毒抑制的潜力。我希望这种方法将改善目前的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。 公共卫生相关性：性传播疾病（STD）对全球健康构成重大威胁，单纯疱疹病毒2型（HSV-2）尤其普遍;其在STD合并感染、医疗保健成本、社会影响、对新生儿和免疫受损个体的影响以及复发性感染中的突出作用，都促使迫切需要开发有效的治疗策略。该项目的短期意义是开发一种封装短干扰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）同时靶向病毒和宿主来干扰HSV-2感染。这种多模式方法将改善目前的HSV-2治疗，并可扩展到多种STD组合，包括难以捉摸的病毒，如HIV。