Vaginal gel formulation based on theaflavin derivatives as a microbicide to prevent HIV sexual transmission.
Vaginal gel formulation based on theaflavin derivatives as a microbicide to prevent HIV sexual transmission.
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DOI：
10.1089/aid.2012.0084
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发表时间：
2012-11
影响因子：
1.5
通讯作者：
Jie Yang;Lin Li;Hong Jin;Suiyi Tan;Jia-yin Qiu;Lei Yang;Yanqing Ding;Zhihong Jiang;Shibo Jiang;Shuwen Liu
中科院分区：
文献类型：
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作者：
Jie Yang;Lin Li;Hong Jin;Suiyi Tan;Jia-yin Qiu;Lei Yang;Yanqing Ding;Zhihong Jiang;Shibo Jiang;Shuwen Liu
我们先前证明了具有高含量（>90%）的茶黄素衍生物（TFmix）的市售天然产物制剂表现出有效的抗HIV活性。在这里，我们开发了TFmix凝胶制剂作为局部杀微生物剂候选物。透射电镜观察TFmix对精液源性病毒感染增强因子（SEVI）肽淀粉样纤维形成的影响。分别使用人阴道和宫颈上皮细胞系和兔阴道刺激模型评价TFmix凝胶的毒性。采用ELISA试剂盒检测宫颈阴道灌洗液（CVL）中促炎细胞因子（IL-1β、IL-6、IL-8和TNF-α）和免疫调节细胞因子（IL-10和GM-CSF）的水平。用增殖细胞核抗原（PCNA）免疫组织化学染色评价阴道组织的炎症反应。TFmix凝胶可降解SEVI特异性淀粉样纤维，对女性生殖道上皮细胞的细胞毒性较低。家兔阴道内给予TFmix凝胶后，在评价的任何时间点均未观察到明显的宫颈阴道毒性，而N-9凝胶的应用导致阴道上皮损伤。TFmix凝胶既不引发促炎细胞因子的产生，也不引发免疫调节细胞因子的产生。TFmix凝胶处理的兔阴道组织中仅观察到低表达的PCNA。TFmix凝胶单次阴道给药后1小时，血浆中TFmix的浓度非常低（低于定量下限）。然而，TFmix在治疗后6 h仍在宫颈阴道灌洗液（CVL）中检测到，表明其可在阴道腔中保留较长时间。TFmix凝胶具有强效的抗HIV-1活性、在酸性条件下的显著稳定性、低粘膜毒性和缺乏全身吸收，可被认为是预防HIV性传播的廉价且安全的杀微生物剂候选物。
We previously demonstrated that a commercially available natural product preparation with high content (>90%) of theaflavin derivatives (TFmix) exhibited potent anti-HIV activities. Here we developed a TFmix gel formulation as a topical microbicide candidate. The effect of TFmix on the amyloid fibril formation of semen-derived enhancer of virus infection (SEVI) peptide was detected by transmission electron microscopy. The toxicity of the TFmix gel was evaluated using human vaginal and cervical epithelial cell lines and rabbit vaginal irritation models, respectively. Levels of proinflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) and immunoregulatory cytokines (IL-10 and GM-CSF) in cervicovaginal lavages (CVLs) were measured by ELISA kits. Proliferating cell nuclear antigen (PCNA) immunostaining was performed to evaluate inflammation in the vaginal tissues. TFmix gel could degrade SEVI-specific amyloid fibrils and showed low cytotoxicity to epithelial cells of the female reproductive tract. No apparent cervicovaginal toxicity was observed at any time point evaluated following the intravaginal administration of TFmix gel to rabbits, whereas application of N-9 gel resulted in damage to the vaginal epithelium. Neither proinflammatory nor immunoregulatory cytokine production was triggered by TFmix gel. Only low expression of PCNA was observed in vaginal tissues of TFmix gel-treated rabbits. The concentration of TFmix in plasma was very low (below the lower limit of quantitation) 1 h after a single vaginal administration of TFmix gel. However, TFmix was still detected in the cervicovaginal lavages (CVLs) 6 h after treatment, indicating that it could be retained in the vaginal cavity for a long period of time. With its potent anti-HIV-1 activity, marked stability at acidic condition, low mucosal toxicity, and lack of systemic absorption, TFmix gel can be considered as an inexpensive and safe microbicide candidate for the prevention of HIV sexual transmission.