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）：随着艾滋病毒感染的发生率，疫苗和局部杀菌剂的发展一直是全球的主要优先事项。但是，最近的试验结果令人失望。因此，对艾滋病毒感染的免疫力和保护的诱导仍然是一个主要的公共卫生目标。局部应用的药物“微生物”仍然被认为具有相当大的希望。实际上，有人提出，只有60％疗效的杀菌剂每年可以预防约100万名HIV感染。鉴于最近的临床失败，迫切需要重新考虑生液的概念。因此，拟议的研究的长期目标是设计，构建和评估基于多重纳米载体的聚乙烯乙二醇（PEG）阴道水凝胶，以防止HIV传播。 PEG无毒且具有生物相容性。水凝胶由于其高水量和柔软/橡胶特性而类似于生物组织。水凝胶是一种液体灌输后的液体，可以进行高阴道分散/粘膜覆盖范围，然后经过快速的相过渡以形成粘弹性凝胶。所提出的凝胶必须具有多功能性，因为已经表明（1）通过弱化粘膜屏障并刺激炎症反应并刺激炎症反应并刺激可能激活或招募HIV靶细胞的炎症性per（2）缺乏症状（2）是<4.5）的炎症反应（<4.4），从而增加了性传播和生殖器感染（例如细菌性阴道病（BV））增加HIV传播的风险（抑制阴道病原体并防止感染，（3）与细胞相关的HIV违反正常的阴道分层的鳞状上皮屏障，但频率低。凝胶矩阵将通过交联的各种PEG纳米载体来形成，这些纳米载体在水凝胶的功能特性中起着独特的作用（例如，促进粘膜粘附，维持轻度酸性pH，释放浅糖苷和精子，并防止HIV病毒率结合）。我们将设计，合成，表征和评估一系列交联的纳米载体，这些纳米载体将各种功能特性赋予菌心水凝胶。目标1：使用快速形成，具有高阴道分散体，高机械强度和粘弹性特性的快速形成，可降解的水凝胶来构建有效的物理病毒屏障。目标2：使用天然酸和/或杀菌剂/杀菌剂/精子剂枯草丝创建具有酸化剂的纳米载体。 AIM 3：制造聚苯故或RGD纳米载体以防止自由或与细胞相关的HIV结合。目标4：评估细胞，组织和动物模型中的各种交联纳米载体和水凝胶。如果成功的话，拟议的研究将产生一种新型的多功能水凝胶技术，具有抗HIV杀生型的理想特性：它将是无色的，无味的，无味的，可用于制造的，可以安全地每天使用一次，并且长时间的时间不止一段时间，快速效果，无与伦比的伴侣，可用于构造和不受控制的形式。随着艾滋病毒感染的发生率越来越大，疫苗和局部杀菌剂的发展一直是全球的主要优先事项，但是最近的试验结果令人失望。局部应用的药物“微生物”仍然被认为具有相当大的希望。拟议的研究旨在设计，构建和评估即时形成的多功能阴道水凝胶，以防止HIV通过阴道粘膜的初始感染和传播到体内远的组织。