Experimental design and multivariate analysis for optimizing poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle synthesis using molecular micelles
Experimental design and multivariate analysis for optimizing poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle synthesis using molecular micelles
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DOI：
10.1166/jnn.2008.011
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发表时间：
2008-01-01
影响因子：
--
通讯作者：
Warner, Isiah M.
中科院分区：
文献类型：
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作者：
Ganea, Gabriela M.;Sabilov, Cristina M.;Warner, Isiah M.
聚合物纳米粒子作为药物递送系统的效用取决于对其物理化学特性具有显著影响的合成参数的有效控制。本研究采用化学计量学中心组合实验设计（CCD）优化聚通过使用阴离子分子胶束的乳化溶剂蒸发制备（D，L-丙交酯-共-乙交酯）（PLGA）纳米颗粒，例如聚（N-十一碳烯酸硫酸钠）（聚SUS），聚（N-十一酰基甘氨酸钠）（聚SUG）和聚（N-十一酰-L-亮氨酰-缬氨酸钠）乳化剂可以是聚-L-SULV（聚-L-SULV）以及常规乳化剂，如阴离子十二烷基硫酸钠（SDS）和非离子聚（乙烯醇）（PVA）。使用多变量分析研究了PLGA浓度、乳化剂浓度、均质化速度和超声处理时间（设计变量）对粒度和多分散指数（响应）的单独和组合影响。与其他设计变量相比，影响纳米颗粒尺寸和尺寸分布的最显著的设计变量是PLGA浓度和乳化剂浓度（p < 0.05）。二次模型表现出最高的预测能力时，分子胶束用作乳化剂。根据CCD最佳合成的PLGA纳米颗粒通过透析进一步纯化，然后冷冻干燥。与发生纳米颗粒聚集的SIDS相比，用分子胶束和PVA合成的干燥纳米颗粒容易重新悬浮在水中。使用分子胶束合成的PLGA纳米颗粒的尺寸增加冷冻干燥后，但保持小于100 nm时，使用聚-L-SULV作为乳化剂。对于所有研究的分子胶束，PDI值表明在纯化和冷冻干燥后的单分散纳米颗粒悬浮液（PDI < 0.100）。使用分子胶束合成的纳米颗粒悬浮液在透析和冷冻干燥后是最稳定的，具有低的负ζ电位值，范围从聚-L-SULV的-54 +/-1.6 mV到聚-SUS的-63.2 +/-0.4 mV。透射电子显微镜（TEM）显微照片显示，使用分子胶束合成的PLGA纳米粒子的球形和光滑的表面。
The utility of polymeric nanoparticles as drug delivery systems depends on effective control of synthetic parameters with a significant impact on their physico-chemical characteristics. In this study, a chemometric central composite experimental design (CCD) was used to optimize the synthesis of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles by emulsification solvent evaporation using anionic molecular micelles, such as poly(sodium N-unclecylenic sulfate) (poly-SUS), poly(sodium N-undecanoyl-glycinate) (poly-SUG) and poly(sodium N-undecanoyl-L-leucyl-valinate) (poly-L-SULV) as well as conventional emulsifiers, such as anionic sodium dodecyl sulfate (SDS) and non-ionic poly(vinyl alcohol) (PVA). The individual and combined effects of PLGA concentration, emulsifier concentration, homogenization speed, and sonication time (design variables) on particle size and polydispersity index (responses) were investigated using multivariate analysis. The most significant design variables influencing the nanoparticle size and size distribution were PLGA concentration and emulsifier concentration (p < 0.05) in comparison to the other design variables. The quadratic model demonstrated the highest predictive ability when the molecular micelles were used as emulsifiers. The PLGA nanoparticles optimally synthesized according to the CCD were further purified by dialysis and then freeze-dried. Dried nanoparticles synthesized with molecular micelles and PVA were readily re-suspended in water, as compared with SIDS for which nanoparticle aggregation occurred. The size of PLGA nanoparticles synthesized using molecular micelles increased after freeze-drying, but remained smaller than 100 nm when poly-L-SULV was used as emulsifier. The PDI values indicated monodisperse nanoparticle suspensions after purification and freeze-drying for all investigated molecular micelles (PDI < 0.100). The nanoparticle suspensions synthesized using molecular micelles were the most stable after dialysis and freeze-drying, having low negative zeta potential values ranging from -54 +/- 1.6 mV for poly-L-SULV to -63.2 +/- 0.4 mV for poly-SUS. Transmission electron microscopy (TEM) micrographs showed spherical shape and smooth surface for the PLGA nanoparticles synthesized using molecular micelles.