Surface charge-switching polymeric nanoparticles for bacterial cell wall-targeted delivery of antibiotics.
Surface charge-switching polymeric nanoparticles for bacterial cell wall-targeted delivery of antibiotics.
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DOI：
10.1021/nn3008383
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发表时间：
2012-05-22
期刊：
影响因子：
17.1
通讯作者：
Farokhzad OC
中科院分区：
文献类型：
--
作者：
Radovic-Moreno AF;Lu TK;Puscasu VA;Yoon CJ;Langer R;Farokhzad OC
如果未能达到持续的杀菌浓度，或者原位活性降低，细菌就会表现出强大的克服药物治疗的能力。后者可能是由局部酸性引起的，这种现象可能是细菌代谢和宿主免疫反应共同作用的结果。纳米粒子（NP）在治疗细菌感染方面已显示出前景，但一个重大挑战是开发可能适合全身给药的抗菌纳米粒子。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。这些纳米粒子药物载体被设计为在pH 7.4时屏蔽非靶标相互作用，但在酸性环境中与细菌紧密结合，递送药物并部分减轻因pH降低而导致的药物活性损失。其机制涉及pH敏感的纳米粒子表面电荷转换，这是通过在低pH下PLH的咪唑基团选择性质子化实现的。纳米粒子结合研究表明，纳米粒子与细菌的结合具有pH敏感性，在pH 6.0时与细菌的结合比在pH 7.4时增加了3.5±0.2到5.8±0.1倍。此外，PLGA - PLH - PEG包裹的万古霉素在低pH下表现出药效损失降低，其最小抑菌浓度的增加倍数为1.3倍，而游离的和PLGA - PEG包裹的万古霉素分别为2.0倍和2.3倍。本文所述的PLGA - PLH - PEG纳米粒子是开发可全身给药的药物载体的第一步，这种载体能够靶向并可能治疗与酸性相关的革兰氏阳性、革兰氏阴性或混合微生物感染。
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 towards developing systemically administered drug carriers that can target and potentially treat Gram-positive, Gram-negative, or polymicrobial infections associated with acidity.
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影响因子：
16
作者：
Kohanski MA;DePristo MA;Collins JJ
通讯作者：
Collins JJ
影响因子：
4
作者：
Lambert, RJW;Pearson, J
通讯作者：
Pearson, J
影响因子：
38.3
作者：
Liu, Lihong;Xu, Kaijin;Yang, Yi-Yan
通讯作者：
Yang, Yi-Yan
影响因子：
5.5
作者：
Misra, Ranjita;Acharya, Sarbari;Sahoo, Sanjeeb K.
通讯作者：
Sahoo, Sanjeeb K.
影响因子：
5.2
作者：
Mercier, RC;Stumpo, C;Rybak, MJ
通讯作者：
Rybak, MJ