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Particle engineering for intracellular delivery of vancomycin to methicillin-resistant Staphylococcus aureus (MRSA)-infected macrophages
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2017-08-07 , DOI: 10.1016/j.jconrel.2017.08.007
Yihua Pei , Mohamed F. Mohamed , Mohamed N. Seleem , Yoon Yeo

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 (500–1000 nm) 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.



中文翻译:

用于万古霉素向耐甲氧西林金黄色葡萄球菌(MRSA)感染的巨噬细胞内细胞内递送万古霉素的颗粒工程

耐甲氧西林金黄色葡萄球菌(MRSA)感染严重威胁公共健康。当MRSA侵入宿主细胞并在细胞内存活时,它特别难以治疗。尽管万古霉素具有抗MRSA的活性,但由于分子大小和极性限制了其对细胞的吸收,因此无法有效杀死细胞内MRSA。(ⅰ)的聚(乳酸- :为了克服万古霉素的差的细胞内递送,我们基于共混物具有不同官能团的聚合物的开发了一种微粒制剂(PpZEV)-乙醇酸(PLGA,P)作为主要递送平台,(ii)聚乙二醇-PLGA共轭物(PEG-PLGA,p)有助于维持适当的极性水平,以适时释放万古霉素,(iii)Eudragit E100 (基于甲基丙烯酸二甲基氨基乙基酯,甲基丙烯酸丁酯和甲基丙烯酸甲酯的共聚物,E)增强万古霉素的包封,以及(iv)称为ZWC(Z)的壳聚糖衍生物,可触发pH敏感药物的释放。由于PpZEV NPs的大小(500-1000 nm),其优先被巨噬细胞吸收,并促进万古霉素向细胞内病原体的递送。因此,PpZEV NP对细胞内MRSA和其他细胞内病原体显示出比游离万古霉素更好的抗菌活性。静脉内给药时,PpZEV NP在肝脏和脾脏中迅速积聚,细胞内感染的靶器官。因此,PpZEV NP是万古霉素有望用于治疗细胞内MRSA感染的载体。

更新日期:2017-08-07
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