Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts 02139, USA.
ACS Nano. 2012 May 22;6(5):4279-87. doi: 10.1021/nn3008383. Epub 2012 Apr 12.
Bacteria have shown a remarkable ability to overcome drug therapy if there is a failure to achieve sustained bactericidal concentration or if there is a reduction in activity in situ. The latter can be caused by localized acidity, a phenomenon that can occur as a result of the combined actions of bacterial metabolism and the host immune response. Nanoparticles (NP) have shown promise in treating bacterial infections, but a significant challenge has been to develop antibacterial NPs that may be suitable for systemic administration. Herein we develop drug-encapsulated, pH-responsive, surface charge-switching poly(D,L-lactic-co-glycolic acid)-b-poly(L-histidine)-b-poly(ethylene glycol) (PLGA-PLH-PEG) nanoparticles for treating bacterial infections. These NP drug carriers are designed to shield nontarget interactions at pH 7.4 but bind avidly to bacteria in acidity, delivering drugs and mitigating in part the loss of drug activity with declining pH. The mechanism involves pH-sensitive NP surface charge switching, which is achieved by selective protonation of the imidazole groups of PLH at low pH. NP binding studies demonstrate pH-sensitive NP binding to bacteria with a 3.5 ± 0.2- to 5.8 ± 0.1-fold increase in binding to bacteria at pH 6.0 compared to 7.4. Further, PLGA-PLH-PEG-encapsulated vancomycin demonstrates reduced loss of efficacy at low pH, with an increase in minimum inhibitory concentration of 1.3-fold as compared to 2.0-fold and 2.3-fold for free and PLGA-PEG-encapsulated vancomycin, respectively. The PLGA-PLH-PEG NPs described herein are a first step toward developing systemically administered drug carriers that can target and potentially treat Gram-positive, Gram-negative, or polymicrobial infections associated with acidity.
如果未能达到持续杀菌浓度或局部活性降低，细菌已经表现出克服药物治疗的显著能力。后一种情况可能是由局部酸度引起的，这是由于细菌代谢和宿主免疫反应的联合作用而发生的现象。纳米颗粒 (NP) 在治疗细菌感染方面显示出了前景，但一个重大挑战是开发可能适合全身给药的抗菌 NP。在此，我们开发了载药的、pH 响应的、表面电荷转换的聚（D，L-乳酸-共-乙醇酸）-b-聚（L-组氨酸）-b-聚（乙二醇）（PLGA-PLH-PEG）纳米粒子用于治疗细菌感染。这些 NP 药物载体旨在在 pH 7.4 时屏蔽非靶向相互作用，但在酸度下与细菌紧密结合，递送药物并部分减轻随着 pH 下降药物活性丧失的问题。该机制涉及 pH 敏感的 NP 表面电荷转换，这是通过在低 pH 下选择性质子化 PLH 的咪唑基团来实现的。NP 结合研究表明，与 pH 7.4 相比，NP 在 pH 6.0 时对细菌的 pH 敏感结合增加了 3.5±0.2-至 5.8±0.1 倍。此外，与游离和 PLGA-PEG 包封的万古霉素相比，PLGA-PLH-PEG 包封的万古霉素在低 pH 下的疗效丧失减少，最低抑菌浓度增加了 1.3 倍、2.0 倍和 2.3 倍。本文所述的 PLGA-PLH-PEG NPs 是开发可靶向并可能治疗与酸度相关的革兰氏阳性、革兰氏阴性或混合感染的系统给药药物载体的第一步。
