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: 8309071
• 负责人: Patrick J. Sinko
• 金额: $ 37.86万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309071
• 关键词: Acids; Adhesions; Animal Model; Bacteria; Bacterial Vaginosis; Binding; Biocompatible; Cell model; Cells; Characteristics; Clinical; Contraceptive Agents; Crosslinker; Development; Distant; Environment; Epithelial; Failure; Frequencies; Gel; Goals; HIV; HIV Infections; HIV-1; Hydrogels; Immunity; Incidence; Infection; Infection prevention; Inflammatory Response; Lactic acid; Lactobacillus; Life; Liquid substance; Local Microbicides; Mechanics; Mucous Membrane; Persons; Phase Transition; Play; Polyethylene Glycols; Polymers; Prevention; Probiotics; Property; Proteins; Public Health; Recruitment Activity; Research; Risk; Role; Series; Spermatocidal Agents; Technology; Temperature; Time; Tissue Model; Tissues; Topical application; Vagina; Viral; Virion; Water; anti-HIV microbicide; base; crosslink; design; design and construction; genital infection; killings; 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.

描述（由申请人提供）：随着艾滋病毒感染率的上升，疫苗和局部杀菌剂的开发已成为世界范围内的一个主要优先事项。然而，最近的试验结果却令人失望。因此，诱导绝育免疫力和预防艾滋病毒感染仍然是一个主要的公共卫生目标。人们仍然相信，局部使用的“杀微生物剂”能够防止艾滋病毒在人与人之间传播，具有相当大的前景。事实上，有人认为，效力仅为 60% 的杀菌剂每年可以预防约 100 万例 HIV 感染。鉴于最近的临床失败，迫切需要重新思考杀菌剂的概念。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，用于预防艾滋病毒传播。 PEG无毒且具有生物相容性。水凝胶由于其高含水量和柔软/橡胶特性而类似于活体组织。水凝胶在滴注时为液体，可实现高阴道分散/粘膜覆盖，然后经历快速相变形成粘弹性凝胶。所提出的凝胶必须是多功能的，因为已经表明：(1) 性传播和生殖器感染，如细菌性阴道病 (BV)，会通过削弱粘膜屏障和刺激可能激活或招募 HIV 靶细胞到病毒进入门户的炎症反应，增加 HIV 传播的风险，(2) 低阴道 pH 值 (<4.5) 对于预防阴道感染至关重要，但不足以预防阴道感染。 抑制阴道病原体并预防感染；(3)细胞相关的HIV突破正常阴道复层鳞状上皮屏障，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、维持弱酸性 pH 值、释放杀微生物剂和杀精子剂以及防止 HIV 病毒粒子结合）。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菌剂水凝胶多种功能特性。目标 1：利用具有高阴道分散性、高机械强度和粘弹性的快速成型、可降解水凝胶构建有效的物理病毒屏障。目标 2：使用天然酸和/或杀微生物剂/杀精剂枯草溶菌素创建具有酸化剂的纳米载体。目标 3：制造聚阴离子或 RGD 纳米载体以防止游离或细胞相关的 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，拟议的研究将产生一种新型多功能水凝胶技术，该技术具有抗艾滋病毒杀菌剂的理想特性：它无色、无味、制造成本低廉、每天可以安全使用一次以上并长时间使用、起效快、任何一方都无法检测到，并且可以避孕和非避孕形式使用。

项目成果

Elucidation of the Molecular Mechanisms of Action of the Natural Antimicrobial Peptide Subtilosin Against the Bacterial Vaginosis-associated Pathogen Gardnerella vaginalis.

• DOI: 10.1007/s12602-010-9061-4
• 发表时间: 2011-03
• 期刊: PROBIOTICS AND ANTIMICROBIAL PROTEINS
• 影响因子: 4.9
• 作者: Noll, Katia Sutyak;Sinko, Patrick J.;Chikindas, Michael L.
• 通讯作者: Chikindas, Michael L.

Evaluation of intraductal delivery of poly(ethylene glycol)-doxorubicin conjugate nanocarriers for the treatment of ductal carcinoma in situ (DCIS)-like lesions in rats.

• DOI: 10.1002/jin2.51
• 发表时间: 2018-09
• 期刊: Journal of interdisciplinary nanomedicine
• 作者: Gu Z;Al-Zubaydi F;Adler D;Li S;Johnson S;Prasad P;Holloway J;Szekely Z;Love S;Gao D;Sinko PJ
• 通讯作者: Sinko PJ

Poly(ethylene glycol) (PEG)-lactic acid nanocarrier-based degradable hydrogels for restoring the vaginal microenvironment.

• DOI: 10.1016/j.jconrel.2014.08.031
• 发表时间: 2014-11-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Sundara Rajan S;Turovskiy Y;Singh Y;Chikindas ML;Sinko PJ
• 通讯作者: Sinko PJ

Antiherpes simplex virus type 2 activity of the antimicrobial peptide subtilosin.

• DOI: 10.1111/jam.12618
• 发表时间: 2014-11
• 期刊: Journal of applied microbiology
• 影响因子: 4
• 作者: Quintana VM;Torres NI;Wachsman MB;Sinko PJ;Castilla V;Chikindas M
• 通讯作者: Chikindas M

Safety, formulation, and in vitro antiviral activity of the antimicrobial peptide subtilosin against herpes simplex virus type 1.

• DOI: 10.1007/s12602-012-9123-x
• 发表时间: 2013-03-01
• 期刊: PROBIOTICS AND ANTIMICROBIAL PROTEINS
• 影响因子: 4.9
• 作者: Torres, Nicolas I.;Noll, Katia Sutyak;Xu, Shiqi;Li, Ji;Huang, Qingrong;Sinko, Patrick J.;Wachsman, Monica B.;Chikindas, Michael L.
• 通讯作者: Chikindas, Michael L.