Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.
J Control Release. 2017 Dec 10;267:133-143. doi: 10.1016/j.jconrel.2017.08.007. Epub 2017 Aug 7.
Methicillin-resistant Staphylococcus aureus (MRSA) infection is a serious threat to the public health. MRSA is particularly difficult to treat when it invades host cells and survive inside the cells. Although vancomycin is active against MRSA, it does not effectively kill intracellular MRSA due to the molecular size and polarity that limit its cellular uptake. To overcome poor intracellular delivery of vancomycin, we developed a particle formulation (PpZEV) based on a blend of polymers with distinct functions: (i) poly(lactic-co-glycolic acid) (PLGA, P) serving as the main delivery platform, (ii) polyethylene glycol-PLGA conjugate (PEG-PLGA, p) to help maintain an appropriate level of polarity for timely release of vancomycin, (iii) Eudragit E100 (a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, E) to enhance vancomycin encapsulation, and (iv) a chitosan derivative called ZWC (Z) to trigger pH-sensitive drug release. PpZEV NPs were preferentially taken up by the macrophages due to its size (500-1000nm) and facilitated vancomycin delivery to the intracellular pathogens. Accordingly, PpZEV NPs showed better antimicrobial activity than free vancomycin against intracellular MRSA and other intracellular pathogens. When administered intravenously, PpZEV NPs rapidly accumulated in the liver and spleen, the target organs of intracellular infection. Therefore, PpZEV NPs is a promising carrier of vancomycin for the treatment of intracellular MRSA infection.
耐甲氧西林金黄色葡萄球菌（MRSA）感染对公众健康构成严重威胁。当 MRSA 侵入宿主细胞并在细胞内存活时，治疗尤其困难。虽然万古霉素对 MRSA 有效，但由于分子大小和极性限制了其细胞摄取，因此不能有效杀死细胞内的 MRSA。为了克服万古霉素细胞内递送效果差的问题，我们开发了一种基于具有不同功能的聚合物混合物的颗粒制剂（PpZEV）：（i）聚（乳酸-共-羟基乙酸）（PLGA，P）作为主要的递送平台，（ii）聚乙二醇-PLGA 缀合物（PEG-PLGA，p）有助于维持适当的极性水平，以便及时释放万古霉素，（iii）Eudragit E100（基于二甲基氨基乙基甲基丙烯酸酯、丁基甲基丙烯酸酯和甲基丙烯酸甲酯的共聚物，E）增强万古霉素包封，（iv）壳聚糖衍生物 ZWC（Z）触发 pH 敏感的药物释放。PpZEV NPs 由于其大小（500-1000nm）而被巨噬细胞优先摄取，并促进了万古霉素向细胞内病原体的递送。因此，与游离万古霉素相比，PpZEV NPs 对细胞内 MRSA 和其他细胞内病原体具有更好的抗菌活性。静脉给药时，PpZEV NPs 迅速在肝脏和脾脏积聚，这是细胞内感染的靶器官。因此，PpZEV NPs 是治疗细胞内 MRSA 感染的万古霉素有前途的载体。
