Development and evaluation of a thermosensitive vaginal gel containing raltegravir plus efavirenz loaded nanoparticles for HIV prophylaxis
Development and evaluation of a thermosensitive vaginal gel containing raltegravir plus efavirenz loaded nanoparticles for HIV prophylaxis
复制标题
DOI：
10.1016/j.antiviral.2012.09.015
复制
发表时间：
2012-12-01
影响因子：
7.6
通讯作者：
Destache, Christopher J.
中科院分区：
文献类型：
--
作者：
Date, Abhijit A.;Shibata, Annemarie;Destache, Christopher J.
本研究的目的是研制一种用于HIV暴露前预防的含有雷替格列韦+依沙韦林的PLGA纳米粒(Ral+EFV-NPs)的温敏阴道凝胶。采用改进的乳液-溶剂挥发法制备了Ral+EFV-NPs，并对其尺寸和Zeta电位进行了表征。平均粒径和表面电荷分别为81.8+/-6.4 nm和-23.18+/-7.18 mV。Raltegravir和efavirenz的平均包封率分别为55.5%和98.2%。将Pluronic F127(20%w/v)和Pluronic F68(1%w/v)混合使用，成功地制备了含有Ral+EFV-NPs的温敏阴道凝胶。在凝胶中掺入Ral+EFV-NPs不会导致纳米粒子聚集，而含有凝胶的Ral+EFV-NPs在32.5℃下表现出热凝胶作用，用TZM-bl指示细胞评价Ral+EFV-NPs对HIV-1(NL4-3)的抑制作用。Ral+EFV-NPs的EC90低于Raltegravir+EFV(Ral+EFV)溶液，但差异无统计学意义。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天内无细胞毒作用。Ral+EFV-NPs处理的HeLa细胞内药物浓度在14天内一直高于EC90，而雷替格雷在6天内消除。纳米粒子在凝胶中的Transwell实验表明，荧光纳米粒子在30分钟内从凝胶中快速转移并被HeLa细胞摄取。这些数据证明了抗逆转录病毒NP包埋阴道凝胶用于长期阴道暴露前预防异性HIV-1传播的潜力。(C)2012爱思唯尔B.V.保留所有权利。
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 degrees C. The RAL+EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC90 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 EC90 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. (C) 2012 Elsevier B.V. All rights reserved.