Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec, Canada H3C 3J7.
J Microencapsul. 2013;30(3):205-17. doi: 10.3109/02652048.2012.714410. Epub 2012 Aug 15.
Poly(ethylene glycol)/polylactic acid (PEG/PLA) nanoparticles (NPs) containing the hydrophobic antifungal itraconazole (ITZ) were developed to provide a controlled release pattern of ITZ as well as to improve its aqueous dispersibility and hence enhance its antifungal action. Two PEG/PLA copolymers (PEGylated PLA polymers) were used in this study; branched PEGylated polymer in which PEG was grafted on PLA backbone at 7% (mol/mol of lactic acid monomer), PEG7%-g-PLA, and multiblock copolymer of PLA and PEG, (PLA-PEG-PLA)n with nearly similar PEG insertion ratio and similar PEG chain length. ITZ-loaded PLA NPs were also prepared and included in this study as a control. ITZ-NPs were prepared from a 1 : 1 w/w blend of PLA and each PEGylated polymer either PEG7%-g-PLA or (PLA-PEG-PLA)n using an oil-in-water emulsion evaporation method. The NPs morphology, size and size distribution, zeta potential, loading efficiency, release profile and antifungal activity were characterized. All ITZ-NPs were nearly spherical with smooth surface and showed less aggregating tendency with a size range of 185-285 nm. All ITZ-NPs measured nearly neutral zeta potential values close to 0 mV. The % LE of ITZ was ∼94% for PEG7%-g-PLA NPs and ∼83% for (PLA-PEG-PLA)n at 15.3% w/w theoretical loading. PEG/PLA NPs were stable over time regarding size and size distribution and % ITZ loading efficiency (% LE). ITZ release showed an initial burst followed by a gradual release profile for ITZ-NPs over 5 days. (PLA-PEG-PLA)n NPs exhibited faster release rates than PEG7%-g-PLA NPs particularly at the last 2 days. Differential scanning calorimetry and powder X-ray diffractometry data confirmed that ITZ exists in an amorphous state or a solid solution state into the NPs matrix. Fourier transform infrared revealed the possibility of chemical interaction between ITZ and the NPs matrix polymer indicating the successful entrapment of ITZ inside the particles. In haemolysis test, ITZ-NPs caused mild haemolysis over the concentration range (5-20 µg/mL) compared to free ITZ, indicating better safety profile of ITZ-NPs. ITZ-loaded PEG/PLA NPs inhibited fungal growth more efficiently than either free ITZ or ITZ-loaded PLA NPs. Our results suggest that PEG/PLA-ITZ could be used efficiently as a nanocarrier to improve the aqueous dispersibility of ITZ, control its release over time and, thereby, enhance its antifungal efficacy.
聚乙二醇/聚乳酸（PEG/PLA）纳米颗粒（NPs）中含有疏水性抗真菌药物伊曲康唑（ITZ），旨在提供 ITZ 的控制释放模式，提高其在水中的分散性，从而增强其抗真菌作用。本研究使用了两种 PEG/PLA 共聚物（PEG 化 PLA 聚合物）；一种是在 PLA 主链上以 7%（摩尔比乳酸单体）接枝 PEG 的支化 PEG 化聚合物，PEG7%-g-PLA，另一种是 PLA 和 PEG 的多嵌段共聚物（PLA-PEG-PLA）n，其 PEG 插入率和 PEG 链长相似。也制备了载有 ITZ 的 PLA NPs 并将其包括在本研究中作为对照。使用油包水乳状液蒸发法，将 PLA 和每种 PEG 化聚合物（PEG7%-g-PLA 或（PLA-PEG-PLA）n）以 1：1 的 1：1 w/w 比例混合制备 ITZ-NPs。对 NPs 的形态、大小和粒径分布、Zeta 电位、载药量、释放曲线和抗真菌活性进行了表征。所有 ITZ-NPs 均为近球形，表面光滑，粒径范围为 185-285nm，聚集倾向较小。所有 ITZ-NPs 的 Zeta 电位值均接近 0mV，接近中性。PEG7%-g-PLA NPs 的 ITZ 载药量（%LE）约为 94%，（PLA-PEG-PLA）n 的 ITZ 载药量（%LE）约为 83%，理论载药量为 15.3%w/w。PEG/PLA NPs 在粒径和粒径分布以及 ITZ 载药量效率（%LE）方面随时间保持稳定。ITZ-NPs 在 5 天内表现出初始突释，随后呈现出逐渐释放的曲线。（PLA-PEG-PLA）n NPs 的释放速度比 PEG7%-g-PLA NPs 快，特别是在最后 2 天。差示扫描量热法和粉末 X 射线衍射数据证实 ITZ 以无定形或固溶体状态存在于 NPs 基质中。傅里叶变换红外光谱表明 ITZ 与 NPs 基质聚合物之间存在化学相互作用的可能性，表明 ITZ 成功地被包埋在颗粒内部。在溶血试验中，与游离 ITZ 相比，ITZ-NPs 在（5-20μg/mL）浓度范围内引起轻度溶血，表明 ITZ-NPs 的安全性更好。载有 ITZ 的 PEG/PLA NPs 比游离 ITZ 或载有 ITZ 的 PLA NPs 更有效地抑制真菌生长。我们的结果表明，PEG/PLA-ITZ 可作为纳米载体有效提高 ITZ 在水中的分散性，控制其随时间释放，从而增强其抗真菌功效。
