Aguilar-Colomer Anna, Colilla Montserrat, Izquierdo-Barba Isabel, Jiménez-Jiménez Carla, Mahillo Ignacio, Esteband Jaime, Vallet-Regí María
Dpto. Química en Ciencias Farmacéuticas, U.D Química Inorgánica y Bioinorgánica. Universidad Complutense de Madrid. Instituto de Investigación Sanitaria Hospital 12 de Octubre i+12. Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
Centro de Investigación Biomédica en Red. CIBER-BBN, Madrid, Spain.
Microporous Mesoporous Mater. 2020 Oct 7;311:110681. doi: 10.1016/j.micromeso.2020.110681. eCollection 2021 Feb.
Mesoporous silica nanoparticles (MSNs) are promising drug nanocarriers for infection treatment. Many investigations have focused on evaluating the capacity of MSNs to encapsulate antibiotics and release them in a controlled fashion. However, little attention has been paid to determine the antibiotic doses released from these nanosystems that are effective against biofilm during the entire release time. Herein, we report a systematic and quantitative study of the direct effect of the antibiotic-cargo released from MSNs on Gram-positive and Gram-negative bacterial biofilms. Levofloxacin (LVX), gentamicin (GM) and rifampin (RIF) were separately loaded into pure-silica and amino-modified MSNs. This accounts for the versatility of these nanosystems since they were able to load and release different antibiotic molecules of diverse chemical nature. Biological activity curves of the released antibiotic were determined for both bacterial strains, which allowed to calculate the active doses that are effective against bacterial biofilms. Furthermore, in vitro biocompatibility assays on osteoblast-like cells were carried out at different periods of times. Albeit a slight decrease in cell viability was observed at the very initial stage, due to the initial burst antibiotic release, the biocompatibility of these nanosystems is evidenced since a recovery of cell viability was achieved after 72 h of assay. Biological activity curves for GM released from MSNs exhibited sustained patterns and antibiotic doses in the 2-6 μg/mL range up to 100 h, which were not enough to eradicate biofilm. In the case of LVX and RIF first-order kinetics featuring an initial burst effect followed by a sustained release above the MIC up to 96 h were observed. Such doses reduced by 99.9% bacterial biofilm and remained active up to 72 h with no emergence of bacterial resistance. This pioneering research opens up promising expectations in the design of personalized MSNs-based nanotherapies to treat chronic bone infection.
介孔二氧化硅纳米颗粒（MSNs）是用于感染治疗的很有前景的药物纳米载体。许多研究都集中在评估MSNs包封抗生素并以可控方式释放它们的能力。然而，很少有人关注确定从这些纳米系统中释放出的在整个释放时间内对生物膜有效的抗生素剂量。在此，我们报告了一项关于从MSNs释放的载药抗生素对革兰氏阳性和革兰氏阴性细菌生物膜直接作用的系统定量研究。左氧氟沙星（LVX）、庆大霉素（GM）和利福平（RIF）分别被载入纯硅和氨基修饰的MSNs中。这说明了这些纳米系统的多功能性，因为它们能够载入和释放不同化学性质的抗生素分子。测定了两种细菌菌株释放的抗生素的生物活性曲线，从而能够计算出对细菌生物膜有效的活性剂量。此外，在不同时间段对成骨样细胞进行了体外生物相容性测定。尽管在最初阶段由于抗生素的初始爆发释放观察到细胞活力略有下降，但这些纳米系统的生物相容性得到了证明，因为在测定72小时后细胞活力得以恢复。从MSNs释放的GM的生物活性曲线呈现持续模式，在长达100小时内抗生素剂量在2 - 6μg/mL范围内，这不足以根除生物膜。对于LVX和RIF，观察到一级动力学特征，即初始爆发效应后接着在高于最低抑菌浓度（MIC）的情况下持续释放长达96小时。这样的剂量使细菌生物膜减少了99.9%，并且在长达72小时内保持活性，没有出现细菌耐药性。这项开创性的研究为设计基于MSNs的个性化纳米疗法治疗慢性骨感染带来了充满希望的预期。
