The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL+EFV-NPs) for pre-exposure prophylaxis of HIV. RAL+EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL+EFV-NP were 81.8±6.4 nm and -23.18±7.18 mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL+EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL+EFV-NPs in the gel did not result in nanoparticle aggregation and RAL+EFV-NPs containing gel showed thermogelation at 32.5°C. The RAL+EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL+EFV-NPs was lower than raltegravir+efavirenz (RAL+EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL+EFV-NPs or blank gel were not cytotoxic for 14 days in vitro. The intracellular levels of efavirenz in RAL+EFV-NPs treated HeLa cells were above the EC(90) for 14 days whereas raltegravir intracellular concentrations were eliminated within 6 days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30 min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission.

译文

这项研究的目的是开发一种热敏性阴道凝胶,该凝胶包含雷特格拉韦依非韦伦负载的PLGA纳米颗粒 (RAL efv-nps),用于预防HIV暴露前。使用改进的乳液-溶剂蒸发方法制备RAL efv-nps,并对尺寸和zeta电位进行了表征。RAL + EFV-NP的平均尺寸和表面电荷分别为81.8 ± 6.4 nm和-23.18 ± 7.18 mV。raltegravir和efavirenz的平均包封效率分别为55.5% 和98.2%。使用Pluronic F127 (20% w/v) 和Pluronic F68 (1% w/v) 的组合成功地制备了含有RAL + EFV-NPs的热敏阴道凝胶。在凝胶中掺入RAL + efv-nps不会导致纳米颗粒聚集,并且含RAL + efv-nps的凝胶在32.5 °C下显示出热凝胶化。使用TZM-bl指示剂细胞评估RAL + EFV-NPs对HIV-1(NL4-3) 的抑制作用。RAL + EFV-NPs的EC(90) 低于雷替格拉韦 + 依非韦伦 (RAL + EFV) 溶液,但没有达到显著性。与未经任何处理的对照HeLa细胞相比,RAL + EFV-NPs或空白凝胶在体外14天内无细胞毒性。RAL + EFV-NPs处理的HeLa细胞中依非韦仑的细胞内水平在14天内高于EC(90),而raltegravir细胞内浓度在6天内被消除。凝胶中NPs的Transwell实验表明,荧光纳米颗粒在30分钟内从凝胶中快速转移并在HeLa细胞中吸收。这些数据证明了抗逆转录病毒NP包埋的阴道凝胶对长期阴道暴露前预防异性HIV-1传播的潜力。

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