用 1,3-β-葡聚糖对 PLGA 纳米颗粒进行功能化可增强巨噬细胞内利福平的细胞内药代动力学。
Functionalization of PLGA Nanoparticles with 1,3-β-glucan Enhances the Intracellular Pharmacokinetics of Rifampicin in Macrophages.
机构信息
Department of Chemistry, Tshwane University of Technology, Pretoria, South Africa.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa,, Lisbon, Portugal.
出版信息
Pharm Res. 2018 Mar 29;35(6):111. doi: 10.1007/s11095-018-2391-8.
PURPOSE
Mycobacterium tuberculosis which causes tuberculosis, is primarily resident within macrophages. 1,3-β-glucan has been proposed as a ligand to target drug loaded nanoparticles (NPs) to macrophages. In this study we characterized the intracellular pharmacokinetics of the anti-tubercular drug rifampicin delivered by 1,3-β-glucan functionalized PLGA NPs (Glu-PLGA). We hypothesized that Glu-PLGA NPs would be taken up at a faster rate than PLGA NPs, and consequently deliver higher amounts of rifampicin into the macrophages.
METHODS
Carbodiimide chemistry was employed to conjugate 1,3-β-glucan and rhodamine to PLGA. Rifampicin loaded PLGA and Glu-PLGA NPs as well as rhodamine functionalized PLGA and Glu-PLGA NPs were synthesized using an emulsion solvent evaporation technique. Intracellular pharmacokinetics of rifampicin and NPs were evaluated in THP-1 derived macrophages. A pharmacokinetic model was developed to describe uptake, and modelling was performed using ADAPT 5 software.
RESULTS
The NPs increased the rate of uptake of rifampicin by a factor of 17 and 62 in case of PLGA and Glu-PLGA, respectively. Expulsion of NPs from the macrophages was also observed, which was 3 fold greater for Glu-PLGA NPs than for PLGA NPs. However, the ratio of uptake to expulsion was similar for both NPs. After 24 h, the amount of rifampicin delivered by the PLGA and Glu-PLGA NPs was similar. The NPs resulted in at least a 10-fold increase in the uptake of rifampicin.
CONCLUSIONS
Functionalization of PLGA NPs with 1,3-β-glucan resulted in faster uptake of rifampicin into macrophages. These NPs may be useful to achieve rapid intracellular eradication of Mycobacterium tuberculosis.
目的
结核分枝杆菌是导致肺结核的主要病原体，它主要存在于巨噬细胞内。1,3-β-葡聚糖已被提议作为一种配体，将载药纳米颗粒（NPs）靶向巨噬细胞。在这项研究中，我们对 1,3-β-葡聚糖功能化 PLGA NPs（Glu-PLGA）递送的抗结核药物利福平的细胞内药代动力学进行了表征。我们假设 Glu-PLGA NPs 的摄取速度会比 PLGA NPs 更快，因此会将更多的利福平递送到巨噬细胞内。
方法
采用碳化二亚胺化学将 1,3-β-葡聚糖和罗丹明偶联到 PLGA 上。使用乳化溶剂蒸发技术合成利福平负载的 PLGA 和 Glu-PLGA NPs 以及罗丹明功能化的 PLGA 和 Glu-PLGA NPs。在 THP-1 衍生的巨噬细胞中评估了利福平和 NPs 的细胞内药代动力学。建立了一个药代动力学模型来描述摄取，使用 ADAPT 5 软件进行建模。
结果
与 PLGA 相比，NPs 将利福平的摄取速度分别提高了 17 倍和 62 倍。也观察到了 NPs 从巨噬细胞中排出，Glu-PLGA NPs 的排出速度是 PLGA NPs 的 3 倍。然而，两种 NPs 的摄取与排出的比例相似。24 小时后，PLGA 和 Glu-PLGA NPs 递送的利福平量相似。NPs 使利福平的摄取量至少增加了 10 倍。
结论
用 1,3-β-葡聚糖对 PLGA NPs 进行功能化可使利福平更快地进入巨噬细胞。这些 NPs 可能有助于实现对结核分枝杆菌的快速细胞内根除。
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