Targeted Delivery of siRNA Nanoparticles to Prevent HIV-1 Transmission

描述(由申请人提供)：根据联合国艾滋病毒/艾滋病联合规划署(艾滋病规划署)的估计，到2006年底，全球将有大约4000万人感染艾滋病毒/艾滋病。然而，安全有效的艾滋病疫苗仍然难以开发。小干扰RNA(SiRNA)已成为基因沉默的有力工具，在病毒感染和癌症的治疗中显示出良好的应用前景。SiRNA和壳聚糖纳米颗粒技术的结合导致了能够抑制呼吸道合胞病毒感染的纳米复合抗病毒药物的开发(Zhang et.艾尔《自然医学》，2005)。根据抑制HIV复制的初步体外数据，推测siRNA纳米复合体是一种潜在的抗艾滋病治疗方法。我们提议的长期目标是开发多功能siRNA纳米颗粒来保护艾滋病毒传播。然而，我们将只测试强化多功能的抗病毒活性，因为安全有效的艾滋病疫苗仍然很难开发，而且在本十年内不会出现。小干扰RNA(SiRNA)已成为基因沉默的有力工具，临床前研究已显示出在病毒感染和癌症治疗方面的前景。在呼吸道合胞病毒(RSV)感染的小鼠模型中，使用纳米颗粒递送系统证明了siRNA抑制呼吸道感染的潜力。在RSV感染之前或之后，使用含有针对RSV NS1基因的siRNA的纳米颗粒进行鼻腔治疗，与对照组相比，显著降低了肺部的病毒滴度，并减少了炎症和呼吸道反应性。这些结果导致了一个工作假设，即多功能壳聚糖纳米颗粒(MCNs)可以有效地传递siRNA，而不会产生任何明显的不良反应，并对病毒感染，特别是HIV具有显著的保护作用。该微粒抑制SHVSF163P3在人或猴外周血单核白细胞(PBMC)中复制的具体目的。多功能siRNA纳米颗粒的体外抗病毒活性的确认将确保未来在非人类灵长类动物的研究中取得成功。这项拟议的项目意义重大，成功交付抗HIV-1 siRNA纳米粒子以防止HIV-1在体外复制将有助于我们未来进行非人类灵长类动物研究或临床前试验。因此，新型壳聚糖纳米给药系统不仅可用于艾滋病研究，而且可用于癌症和其他疾病的研究

DESCRIPTION (provided by applicant): According to estimates by the Joint United Nations Program on HIV/AIDS (UNAIDS), approximately 40 million people will be living with HIV/AIDS worldwide by the end of 2006. However, safe and effective AIDS vaccine remains difficult to develop. Small interference RNA (siRNA) has emerged as a powerful tool in gene silencing, and appears promising in treatment of viral infections and cancers. The combination of siRNA and chitosan nanoparticle technology led to the development nanocomplex antivirals capable of inhibiting respiratory syncytial virus infections (Zhang et. al. Nature Medicine, 2005). Based on the preliminary in vitro data for suppressing HIV replication, it is hypothesized that siRNA nanocomplexes comprise a potential therapeutic approach against AIDS. The long-term goal of our proposal is to develop multifunctional siRNA nanoparticles to protect HIV transmission. However, we will only test the antiviral activities of the multifunctio intensified, since a safe and effective AIDS vaccine remains difficult to develop and won't be available in this decade. Small interfering RNA (siRNA) has emerged as a powerful tool in gene silencing, and preclinical studies have shown promise in treatment of viral infection and cancer. The potential of siRNA for inhibiting respiratory infections has been demonstrated using a nanoparticle delivery system in a mouse model of respiratory syncytoial virus (RSV) infection. Intranasal treatment before or after RSV infection with nanoparticles containing siRNA targeting the NS1 gene of RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. These results have led to the working hypothesis that multifunctional chitosan nanoparticles (MCNs) can effectively deliver siRNA without any significant adverse effects and provide significant protection against viral infections, specifically HIV. The specific aims of this proparticles in inhibiting SHVSF163P3 replication in human or monkey peripheral blood mononuclear leukocytes (PBMCs). In vitro confirmation of the antiviral activity of the multifunctional siRNA nanoparticles will ensure the success in future studies in non-human primates. The proposed project is significant, successful delivery of anti-HIV siRNA nanoparticles to prevent HIV-1 replication in vitro will help us in non-human primate studies or preclinical trials in the future. Thus, the novel chitosan nanoparticle drug delivery system will be useful not only in AIDS research but also in studies in cancer and other diseases