Discipline of Pharmaceutical Sciences, College of Health Sciences , University of KwaZulu-Natal , Durban , South Africa.
School of Pharmacy and Health Sciences , United States International University of Africa , Nairobi , Kenya.
Mol Pharm. 2019 Nov 4;16(11):4594-4609. doi: 10.1021/acs.molpharmaceut.9b00713. Epub 2019 Oct 16.
pH-responsive drug delivery systems are yielding opportunities to directly deliver antibiotics to the site of infection. Therefore, this study aimed to develop and evaluate novel pH-responsive lipid-dendrimer hybrid nanoparticles (LDH-NPs) for the delivery of vancomycin (VCM) to the site of infection, by intracellular bacterial pathogens. The LDH-NPs were formulated using the emulsification solvent evaporation method and were characterized by various and molecular dynamic (MD) simulation techniques. LDH-NPs were 124.4 ± 2.01 nm in size, with a zeta-potential of -7.15 ± 2.98 mV and drug entrapment efficiency of 82.70 ± 4.09%, which exhibited pH-responsive behavior by shifting the surface charge from negative at physiological pH to positive in acidic pHs, with a size increase from 124.4 ± 2.01 to 173.9 ± 13.38 nm, and 252.7 ± 3.98 nm at pHs of 7.4, 6.0, and 4.5, respectively. Results indicated that the drug release of VCM from LDH-NPs occurred faster at pH 6.0 than at pH 7.4. The antibacterial activity of LDH-NPs against methicillin-resistance (MRSA) showed 8-fold lower MICs at pH 6.0 and 7.4, compared to treatment with VCM only. A bacterial cell viability study showed LDH-NPs had an 84.19% killing of MRSA, compared to VCM (49.26%) at the same MIC, further confirming its efficacy. Cell uptake studies showed that LDH-NPs intracellularly accumulated in HEK 293 cells, confirming significant clearance ( < 0.0001) of intracellular bacteria. MD simulation showed that interaction between the dendrimer and oleylamine was predominantly governed by van der Waals (VdW) interactions; whereas the interaction between the dendrimer and VCM was governed by both VdW and electrostatic interactions. Therefore, this study concludes that the pH-responsive release of VCM enhanced antibacterial efficacy against MRSA and intracellular delivery of an antibiotic. Thus, LDH-NPs is a promising nanocarrier system for antibiotics with the potential to improve the treatment outcomes of bacterial infections in patients with antibiotic resistant strains.
pH 响应型药物递送系统为将抗生素直接递送到感染部位提供了机会。因此，本研究旨在开发和评估新型 pH 响应性脂质-树枝状大分子杂化纳米粒子（LDH-NPs），通过细胞内细菌病原体将万古霉素（VCM）递送到感染部位。LDH-NPs 采用乳化溶剂蒸发法制备，并通过各种和分子动力学（MD）模拟技术进行了表征。LDH-NPs 的粒径为 124.4±2.01nm，Zeta 电位为-7.15±2.98mV，药物包封效率为 82.70±4.09%，在生理 pH 下带负电荷，在酸性 pH 下带正电荷，粒径从 124.4±2.01nm 增加到 173.9±13.38nm 和 252.7±3.98nm，分别在 pH 为 7.4、6.0 和 4.5。结果表明，VCM 从 LDH-NPs 的释放速度在 pH 6.0 时比在 pH 7.4 时更快。与单独使用 VCM 相比，LDH-NPs 对耐甲氧西林 （MRSA）的 药物释放显示出在 pH 6.0 和 7.4 时 MIC 降低了 8 倍。细菌细胞活力研究表明，与相同 MIC 下的 VCM（49.26%）相比，LDH-NPs 对 MRSA 的杀伤率为 84.19%，进一步证实了其疗效。细胞摄取研究表明，LDH-NPs 在 HEK 293 细胞内积累，证实了对细胞内细菌的显著清除（<0.0001）。MD 模拟表明，树枝状大分子与油胺之间的相互作用主要受范德华（VdW）相互作用控制; 而树枝状大分子与 VCM 之间的相互作用受范德华和静电相互作用共同控制。因此，本研究得出结论，VCM 的 pH 响应性释放增强了对 MRSA 的抗菌功效，并实现了抗生素的细胞内递送。因此，LDH-NPs 是一种有前途的抗生素纳米载体系统，具有改善对具有抗生素耐药性菌株的患者的细菌感染治疗效果的潜力。
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