TARGETED DRUG DELIVERY SYSTEM FROM RSV

呼吸道合胞病毒（RSV）的复发感染发生在所有 年龄 然而，它们在婴儿和幼儿中特别令人关注。 RSV是严重急性下呼吸道感染最常见原因的儿童 呼吸道感染 呼吸道合胞病毒是毛细支气管炎的主要原因 在婴儿期和儿童肺炎的主要原因之一。 严重RSV感染的推荐治疗，雾化 利巴韦林仅具有最小的临床功效。 我们提出了一种新 RSV感染的治疗概念。 人工病毒包膜 含有抗病毒药物的病毒颗粒（病毒体）将以这样的形式配制。 以靶向呼吸细胞摄取的方式。病毒体将 用RSV G（附着）和F（融合）表面构建 糖蛋白 目标是模仿所采用的分子策略 通过RSV附着并穿透肺中的上皮细胞（活性 靶向）以及为肺泡提供强刺激 巨噬细胞吞噬含药囊泡（被动 瞄准）。 目标是积累治疗浓度的 抗病毒药物选择性地在RSV的两种主要宿主细胞内， 呼吸道上皮细胞和肺泡巨噬细胞。 具体目标是： 1.为了确定RSV病毒体的最佳组成， 与宿主细胞快速融合。2.为了测量利巴韦林的能力- 加载病毒体以抑制RSV在HEp-2细胞和肺泡中的复制 与游离利巴韦林相比。3.评估的稳定性 这些病毒体在雾化和冻干时。4.评估 负载利巴韦林的病毒体在以下方面的毒性： 肺泡巨噬细胞活力和吞噬功能; B） 上皮细胞形态和纤毛功能; c） d）诱导气道对RSV的敏感性 F或G糖蛋白;和e）气道功能的改变 健康成年志愿者。5.为了比较利巴韦林的疗效- 用游离利巴韦林加载病毒体用于治疗低 呼吸道疾病引起的RSV感染的年轻羔羊和 评估这种治疗干预对再暴露于 病毒

Recurrent infections with respiratory syncytial virus (RSV) occur at all ages. However, they are of particular concern in infants and young children where RSV is the most common cause of severe, acute lower respiratory tract infections. RSV is the major cause of bronchiolitis during infancy and one of the major causes of pneumonia in childhood. The recommended treatment of severe RSV infection, aerosolized ribavirin, has only minimal clinical efficacy. We propose a novel concept for the therapy of RSV infections. Artificial viral envelopes (virosomes) containing an antiviral drug will be formulated in such a manner as to target for respiratory cell uptake. Virosomes will be constructed with RSV G (attachment) and F (fusion) surface glycoproteins. The objective is to mimic the molecular strategy adopted by RSV to attach and penetrate epithelial cells in the lung (active targeting) as well as to provide a strong stimulus for alveolar macrophages to phagocytize the drug-containing vesicle (passive targeting). The goal is to accumulate therapeutic concentrations of antiviral drug selectively within the two major host cells for RSV, the respiratory epithelial cell and the alveolar macrophage. The specific aims are: 1. To determine the optimal composition of RSV virosomes for maximum and rapid fusion with host cells. 2. To measure the ability of ribavirin- loaded virosomes to inhibit RSV replication in HEp-2 cells and alveolar macrophages compared to free ribavirin. 3. To assess the stability of these virosomes upon nebulization and lyophylization. 4. To assess toxicity of ribavirin-loaded virosomes in terms of: a) alterations in alveolar macrophage viability and phagocytic function; b) alterations in epithelial cell morphology and ciliary function; c) alterations in airway function in the lamb; d) induction of airway sensitization to RSV F or G glycoprotein in the lamb; and e) alterations in airway function in healthy adult volunteers. 5. To compare the efficacy of ribavirin- loaded virosomes with free ribavirin for the treatment of lower respiratory tract disease induced by RSV infection in young lambs and to evaluate the effects of this therapeutic intervention on reexposure to the virus.