Multiplex Nanocarrier-based Hydrogels for Prevention of Vaginal HIV Transmission.

基于多重纳米载体的水凝胶用于预防阴道艾滋病毒传播。

• 批准号: 7737691
• 负责人: Patrick J. Sinko
• 金额: $ 38.63万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737691
• 关键词: Acids; Adhesions; Animal Model; Bacterial Vaginosis; Binding; Biocompatible; Cells; Characteristics; Clinical; Contraceptive Agents; Distant; Epithelial; Failure; Frequencies; Gel; Goals; HIV; HIV Infections; Hydrogels; Immunity; Incidence; Infection; Infection prevention; Inflammatory Response; Life; Liquid substance; Local Microbicides; Mechanics; Mucous Membrane; Persons; Phase Transition; Play; Polyethylene Glycols; Prevention; Property; Public Health; Recruitment Activity; Research; Risk; Role; Series; Spermatocidal Agents; Technology; Time; Tissues; Topical application; Vagina; Viral; Virion; Water; anti-HIV microbicide; base; crosslink; design; design and construction; genital infection; microbicide; nanocarrier; novel; pathogen; prevent; transmission process; vaccine development

DESCRIPTION (provided by applicant): With the incidence of HIV infection on the rise, the development of vaccines and topical microbicides has been a major worldwide priority. However, the results of recent trials have been disappointing. As such, the induction of sterilizing immunity and protection against HIV infection continues to be a major public health goal. 'Microbicides', topically applied agents that prevent HIV transmission from person to person, are still believed to hold considerable promise. In fact, it has been suggested that a microbicide with only 60% efficacy could prevent about 1 million HIV infections per year. Given recent clinical failures, there is an urgent need to rethink the concept of microbicides. Therefore, the long-term objective of the proposed research is to design, construct and evaluate a multiplex nanocarrier-based polyethylene glycol (PEG) vaginal hydrogel for preventing HIV transmission. PEG is nontoxic and biocompatible. Hydrogels resemble living tissue due to their high-water content and soft/rubbery characteristics. The hydrogel is a liquid upon instillation allowing for high vaginal dispersion/mucosal coverage where it then undergoes a rapid phase transition to form a visco-elastic gel. The proposed gel must be multifunctional since it has been shown that (1) sexually transmitted and genital infections such as bacterial vaginosis (BV) increase the risk of HIV transmission by weakening mucosal barriers and by stimulating an inflammatory response that may activate or recruit HIV target cells to the portals of viral entry, (2) low vaginal pH (<4.5) is essential for the prevention of vaginal infections but is not sufficient to inhibit vaginal pathogens and to prevent infection, and (3) cell-associated HIV breaches the normal vagina stratified squamous epithelial barrier but with low frequency. The gel matrix will be formed by crosslinking various PEG nanocarriers each of which plays a unique role in the functional properties of the hydrogel (e.g., promoting mucosal adhesion, maintaining mildly acidic pH, releasing microbicide and spermicides, and preventing HIV virion binding). We will design, synthesize, characterize, and evaluate a series of crosslinking nanocarriers that impart a variety of functional properties to the microbicide hydrogel. Aim 1: To construct an effective physical viral barrier using a fast forming, degradable hydrogel with high vaginal dispersion, high mechanical strength, and viscoelastic properties. Aim 2: To create nanocarriers possessing acidifying agents using natural acids and/or the microbicide/spermicide subtilosin. Aim 3: To fabricate polyanionic or RGD nanocarriers to prevent free or cell-associated HIV binding. Aim 4: To evaluate the various crosslinking nanocarriers and hydrogels in cell, tissue and animal models. If successful, the proposed research will result in a novel multifunctional hydrogel technology that possesses the ideal properties of an anti-HIV microbicide: it will be colorless, odorless, inexpensive to manufacture, safe to use more than once a day and for long periods of time, fast-acting, undetectable to either partner, and available in contraceptive and noncontraceptive forms. With the incidence of HIV infection on the rise, the development of vaccines and topical microbicides has been a major worldwide priority but the results of recent trials have been disappointing. 'Microbicides', topically applied agents that prevent HIV transmission from person to person, are still believed to hold considerable promise. The proposed research seeks to design, construct and evaluate an instantly-forming multifunctional vaginal hydrogel to prevent the initial infection and dissemination of HIV through the vaginal mucosa to distant tissues in the body.

描述(由申请人提供)：随着艾滋病毒感染发病率的上升，疫苗和局部杀微生物剂的开发已成为世界范围内的主要优先事项。然而，最近的试验结果令人失望。因此，诱导灭菌免疫和预防艾滋病毒感染仍然是一项主要的公共卫生目标。“杀微生物剂”是一种局部应用的药物，可以防止艾滋病毒在人与人之间传播，人们仍然认为它有很大的希望。事实上，有人建议，一种只有60%药效的杀微生物剂每年可以防止大约100万人感染艾滋病毒。鉴于最近的临床失败，迫切需要重新考虑杀微生物剂的概念。因此，这项研究的长期目标是设计、构建和评价一种基于聚乙二醇纳米粒的复合阴道水凝胶，用于预防HIV传播。聚乙二醇酯是无毒和生物相容的。水凝胶因其高含水率和柔软/橡胶特性而类似于活组织。这种水凝胶在滴注时是液体，允许高阴道分散度/粘膜覆盖率，然后它经历快速相变形成粘弹性凝胶。建议的凝胶必须是多功能的，因为已经证明(1)性传播和生殖器感染，如细菌性阴道病(BV)，通过削弱粘膜屏障和通过刺激炎症反应来增加艾滋病毒传播的风险，该炎症反应可能激活或招募艾滋病毒靶细胞进入病毒进入门户；(2)低阴道pH值(&lt；4.5)对于预防阴道感染是必不可少的，但不足以抑制阴道病原体和防止感染，以及(3)与细胞相关的艾滋病毒打破正常阴道层状鳞状上皮屏障的频率很低。凝胶基质将由不同的聚乙二醇纳米粒载体交联而成，每个纳米粒在水凝胶的功能特性(例如，促进粘膜黏附、维持温和的酸性pH、释放杀菌剂和杀精剂，以及防止HIV病毒粒子结合)中发挥独特的作用。我们将设计、合成、表征和评价一系列赋予杀微生物剂水凝胶各种功能特性的交联型纳米载体。目的1：利用一种快速形成、可降解的水凝胶构建有效的物理病毒屏障，该水凝胶具有高阴道分散性、高机械强度和粘弹性。目的2：利用自然酸和/或杀菌剂/杀精剂亚硫菌素制备具有酸化剂的纳米载体。目的3：制备多阴离子或RGD纳米载体以防止游离或细胞相关的HIV结合。目的：评价各种交联型纳米载体和水凝胶在细胞、组织和动物模型中的应用。如果成功，这项拟议的研究将产生一种新的多功能水凝胶技术，具有抗艾滋病毒杀菌剂的理想特性：无色、无臭、制造成本低、每天使用一次以上且可长时间安全使用、见效快、任何一方都无法检测到，并可提供避孕和非避孕形式。随着艾滋病毒感染发病率的上升，疫苗和局部杀微生物剂的开发一直是世界范围内的主要优先事项，但最近的试验结果令人失望。“杀微生物剂”是一种局部应用的药物，可以防止艾滋病毒在人与人之间传播，人们仍然认为它有很大的希望。这项拟议的研究旨在设计、构建和评估一种即时形成的多功能阴道水凝胶，以防止艾滋病毒的初始感染和通过阴道粘膜传播到身体的远程组织。