Many novel vaginal/rectal microbicide formulations failed clinically due to safety concerns, indicating the need for the early investigation of lead microbicide formulations. In this study, the preclinical safety of an HIV-1 gp120 and mannose responsive microbicide delivery system (MRP) is evaluated in C57BL/6 mice. MRP was engineered through the layer-by-layer coating of calcium carbonate (CaCO₃) with Canavalia ensiformis lectin (Con A) and glycogen. MRP mean particle diameter and zeta potential were 857.8 ± 93.1 nm and 2.37 ± 4.12 mV, respectively. Tenofovir (TFV) encapsulation and loading efficiencies in MRP were 70.1% and 16.3% w/w, respectively. When exposed to HIV-1 rgp120 (25 μg/mL), MRP released a significant amount of TFV (∼5-fold higher) in vaginal and seminal fluid mixture compared to the control (pre-exposure) level (∼59 μg/mL) in vaginal fluid alone. Unlike the positive control treated groups (e.g., nonoxynol-9), no significant histological damages and CD45+ cells infiltration were observed in the vaginal and major reproductive organ epithelial layers. This was probably due to MRP biocompatibility and its isosmolality (304.33 ± 0.58 mOsm/kg). Furthermore, compared to negative controls, there was no statistically significant increase in pro-inflammatory cytokines such as IL1α, Ilβ, IL7, IP10, and TNFα. Collectively, these data suggest that MRP is a relatively safe nanotemplate for HIV-1 gp120 stimuli responsive vaginal microbicide delivery system.

中文翻译：

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C57BL/6 雌性小鼠 HIV-1 gp120 反应性杀微生物剂递送系统的临床前安全性评价

由于安全问题，许多新型阴道/直肠杀微生物剂制剂在临床上失败，表明需要对先导杀微生物剂制剂进行早期研究。在这项研究中，在 C57BL/6 小鼠中评估了 HIV-1 gp120 和甘露糖反应性杀菌剂递送系统 (MRP) 的临床前安全性。_{MRP 是通过碳酸钙 (CaCO 3} ) 与刀豆的逐层包被而设计的凝集素 (Con A) 和糖原。MRP 平均粒径和 zeta 电位分别为 857.8 ± 93.1 nm 和 2.37 ± 4.12 mV。MRP 中替诺福韦 (TFV) 的包封和装载效率分别为 70.1% 和 16.3% w/w。当暴露于 HIV-1 rgp120 (25 μg/mL) 时，与对照（暴露前）水平（～59 μg/mL）相比，MRP 在阴道和精液混合物中释放了大量的 TFV（高～5 倍） ) 仅在阴道液中。与阳性对照治疗组（例如，nonoxynol-9）不同，在阴道和主要生殖器官上皮层中未观察到明显的组织学损伤和 CD45+ 细胞浸润。这可能是由于 MRP 生物相容性及其等渗浓度 (304.33 ± 0.58 mOsm/kg)。此外，与阴性对照相比，IL1α、ILβ、IL7、IP10 和 TNFα 等促炎细胞因子在统计学上没有显着增加。总的来说，这些数据表明 MRP 是一种相对安全的 HIV-1 gp120 刺激响应性阴道杀微生物剂递送系统纳米模板。