Robinson Jonathan L, Miller Richard V, Brynildsen Mark P
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA.
Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
Metab Eng Commun. 2014 Sep 1;1:12-18. doi: 10.1016/j.meteno.2014.08.001. eCollection 2014 Dec.
The antimicrobial properties of nitric oxide (NO) have motivated the design of NO-releasing materials for the treatment and prevention of infection. The biological activity of NO is dependent on its delivery rate, suggesting that variable antimicrobial effects can result from identical NO payloads dosed at different rates. Using a kinetic model of the NO biochemical network, we investigated the relationship between NO delivery rate, payload, and cytotoxicity, as indicated by the duration of respiratory inhibition. At low NO payloads, the model predicted greater toxicity with rapid delivery, while slower delivery was more effective at higher payloads. These predictions were confirmed experimentally, and exhibited quantitative agreement with measured O and NO concentrations, and durations of respiratory inhibition. These results provide important information on key design parameters in the formulation of NO-based therapeutics, and highlight the utility of a model-based approach for the analysis of dosing regimens.
一氧化氮（NO）的抗菌特性推动了用于治疗和预防感染的NO释放材料的设计。NO的生物活性取决于其释放速率，这表明相同的NO有效载荷以不同速率给药可能会产生不同的抗菌效果。利用NO生化网络的动力学模型，我们研究了NO释放速率、有效载荷与细胞毒性之间的关系，细胞毒性以呼吸抑制持续时间表示。在低NO有效载荷下，模型预测快速释放时毒性更大，而在高有效载荷下较慢释放更有效。这些预测通过实验得到证实，并与测得的氧气和NO浓度以及呼吸抑制持续时间呈现出定量一致性。这些结果为基于NO的治疗药物配方中的关键设计参数提供了重要信息，并突出了基于模型的方法在分析给药方案方面的实用性。
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