Enhanced eradication of intracellular and biofilm-residing methicillin-resistant Staphylococcus aureus (MRSA) reservoirs with hybrid nanoparticles delivering rifampicin.
Enhanced eradication of intracellular and biofilm-residing methicillin-resistant Staphylococcus aureus (MRSA) reservoirs with hybrid nanoparticles delivering rifampicin.
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DOI：
10.1016/j.ijpharm.2020.119784
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发表时间：
2020-11-15
影响因子：
5.8
通讯作者：
Wong HL
中科院分区：
文献类型：
--
作者：
Guo P;Xue HY;Buttaro BA;Tran NT;Wong HL
即使在延长，侵略性抗生素治疗后，骨髓炎也会出现高复发风险。关键挑战之一是消除抗甲氧西林的金黄色葡萄球菌（MRSA）的储层，内部宿主骨细胞及其生物膜内的储层。我们的目标是开发利福平加载的脂质聚合物杂交纳米载体（RF-LPN），并评估它们是否可以实现增强的利福平递送以消除这些细胞内和生物膜的MRSA。在优化成分后，RF-LPN的直径约为110 nm，在血清补充的培养基中保持稳定，药物有效载荷高达11.7％，持续利福平释放2周。当将RF-LPN与游离利福平进行比较时，观察到以浮游生物形式中等但显着（P <0.05）与三种导致骨髓炎的细菌（USA300-0114，CDC-587，RP-62A）相对于三种骨髓炎的细菌的显着改善（P <0.05）。相比之下，RF-LPN对生物膜和细胞内MRSA的活动的增强更为实质。针对USA300-0114，CDC-587和RP-62A的MBEC50值分别为42 vs 155、70 vs 388和265 ng/ml，而265 ng/ml vs超过400 ng/ml，最高为18.5倍，在细胞内MRSA MRSA计数中降低了Osteoblasts的细胞内MRSA计数。共聚焦显微镜图像证实了RF-LPN在生物膜基质内和MRSA感染的成骨细胞内的广泛积累。总体而言，在这项概念验证研究中，我们制定了并验证了利用纳米颗粒细胞和纳米颗粒 - 双膜相互作用的策略，该策略与新的利福平纳米成型以预防骨髓炎的复发和慢性。
Osteomyelitis carries a high risk of recurrence even after extended, aggressive antibiotic therapy. One of the key challenges is to eradicate the reservoirs of methicillin-resistant Staphylococcus aureus (MRSA) inside the host bone cells and their biofilms. Our goal is to develop rifampicin loaded lipid-polymer hybrid nanocarriers (Rf-LPN) and evaluate if they can achieve enhanced rifampicin delivery to eradicate these intracellular and biofilm-residing MRSA. After optimization of the composition, Rf-LPN demonstrated size around 110 nm in diameter that remained stable in serum-supplemented medium, drug payload up to 11.7% and sustained rifampicin release for 2 weeks. When comparing Rf-LPN with free rifampicin, moderate but significant (p<0.05) improvement of the activities against three osteomyelitis-causing bacteria (USA300-0114, CDC-587, RP-62A) in planktonic form were observed. In comparison, the enhancements in the activities against the biofilms and intracellular MRSA by Rf-LPN were even more substantial. The MBEC50 values against USA300-0114, CDC-587, and RP-62A were 42 vs 155, 70 vs 388, and 265 ng/ml vs over 400 ng/ml, respectively, and up to 18.5-fold reduction in the intracellular MRSA counts in osteoblasts was obtained. Confocal microscope images confirmed extensive accumulation of Rf-LPN inside the biofilm matrix and MRSA-infected osteoblasts. Overall, in this proof-of-concept study we have developed and validated the strategy to exploit the nanoparticle-cell and nanoparticle-biofilm interactions with a new rifampicin nanoformulation for prevention of osteomyelitis recurrence and chronicity caused by the elusive MRSA.
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