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

描述（由申请人提供）：随着艾滋病毒感染的发病率不断上升，疫苗和局部杀微生物剂的开发一直是世界范围内的一个主要优先事项。然而，最近的试验结果令人失望。因此，诱导绝育免疫和防止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”是一种局部应用的预防艾滋病毒在人与人之间传播的药剂，人们仍然认为它具有相当大的前景。事实上，有研究表明，一种杀菌剂只有60%的效力，每年可以预防大约100万例艾滋病毒感染。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，本研究的长期目标是设计、构建和评估一种基于多重纳米载体的聚乙二醇（PEG）阴道水凝胶用于预防HIV传播。聚乙二醇无毒且具有生物相容性。水凝胶类似于活组织，因为它们的高含水量和柔软/橡胶特性。水凝胶在滴入后是液体，允许高阴道分散/粘膜覆盖，然后经历快速相变以形成粘弹性凝胶。拟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刺激炎症反应，可能激活或招募HIV靶细胞进入病毒进入的入口，从而增加HIV传播的风险；(2)低阴道pH值（<4.5）对预防阴道感染至关重要，但不足以抑制阴道病原体和预防感染。(3)细胞相关HIV破坏正常阴道分层鳞状上皮屏障，但频率较低。凝胶基质将通过交联各种PEG纳米载体形成，每种纳米载体在水凝胶的功能特性中发挥独特的作用（例如，促进粘膜粘附，维持温和的酸性pH，释放杀微生物剂和杀精子剂，以及防止HIV病毒颗粒结合）。我们将设计、合成、表征和评估一系列交联纳米载体，这些纳米载体赋予杀微生物剂水凝胶各种功能特性。目的1：利用快速成型、可降解、高阴道分散、高机械强度和粘弹性的水凝胶构建有效的物理病毒屏障。目标2：利用天然酸和/或杀微生物剂/杀精子剂subtilosin制造具有酸化剂的纳米载体。目的3：制造多阴离子或RGD纳米载体，以防止游离或细胞相关的HIV结合。目的4：评价各种交联纳米载体和水凝胶在细胞、组织和动物模型中的作用。如果成功，这项研究将产生一种新的多功能水凝胶技术，它具有抗艾滋病毒杀菌剂的理想特性：无色、无味、制造成本低廉、每天使用一次以上且长时间使用安全、快速起效、伴侣中的任何一方都无法检测到，并且有避孕和非避孕形式。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一个主要优先事项，但最近的试验结果令人失望。“杀微生物剂”是一种局部应用的预防艾滋病毒在人与人之间传播的药剂，人们仍然认为它具有相当大的前景。本研究旨在设计、构建和评估一种即时形成的多功能阴道水凝胶，以防止HIV通过阴道黏膜向体内远处组织的初始感染和传播。

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.