Condition responsive nanoparticles for managing infection and inflammation in keratitis
Condition responsive nanoparticles for managing infection and inflammation in keratitis
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DOI：
10.1039/c7nr00922d
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发表时间：
2017-07-28
期刊：
影响因子：
6.7
通讯作者：
Rao, Ch. Mohan
中科院分区：
文献类型：
--
作者：
Ahsan, Saad M.;Rao, Ch. Mohan
角膜炎是可避免的视力损害的主要原因。在发展中国家，大约30%的真菌性角膜炎患者最终会永久失明。由病原体和宿主分泌的蛋白酶在感染消除之前就会破坏角膜。治疗角膜炎是一项挑战，因为感染和炎症都需要解决。另一个挑战是，在眨眼和泪膜冲洗掉药物时，在角膜表面保持治疗剂量，以滴眼液的形式给药。我们已经开发了一种基于纳米颗粒的药物输送系统，通过在角膜上锚定来延长药物停留时间，降低炎症并释放抗真菌药物：所有这些都是以一种条件响应的方式进行的。角膜上皮细胞上toll样受体（TLR4）的表达随着感染的增加而增加。我们在酮康唑包封的明胶纳米颗粒表面偶联了抗tlr4抗体。抗tlr4抗体不仅可以促进纳米颗粒与角膜的结合，延长其停留时间，还可以降低炎症细胞因子的水平。宿主和真菌蛋白酶降解明胶纳米颗粒（蛋白酶的替代底物），从而减少角膜损伤并释放与感染严重程度成正比的包封药物酮康唑。在用人类角膜上皮细胞测试了该系统的功效后，我们将研究扩展到角膜炎大鼠模型。结果显示，明显增加角膜保留，抑制炎症和感染的解决在感染的眼睛。我们相信这将是一个很好的方法来管理角膜炎以及其他局部眼部感染。
Keratitis is a major cause of avoidable visual impairment. About 30% of patients with fungal keratitis eventually become permanently blind in the developing world. Proteases, secreted by the pathogen and the host, damage the cornea before the infection is resolved. Treating keratitis is a challenge because both infection and inflammation need to be addressed. An additional challenge is to maintain a therapeutic dose at the corneal surface as blinking and tear film wash away the drugs, administered as eye drops. We have developed a nanoparticle-based drug delivery system that enhances the drug residence time by anchoring to the cornea, down-regulates inflammation and releases the antifungal drug: all in a condition-responsive manner. The expression of Toll-Like Receptors (TLR4) on the corneal epithelial cells increases in response to infection. We have conjugated anti-TLR4 antibodies on the surface of ketoconazole-encapsulated gelatin nanoparticles. The anti-TLR4 antibody not only facilitates binding of nanoparticles to the cornea, enhancing their residence time, but also reduces the levels of inflammatory cytokines. Host and fungal proteases degrade the gelatin nanoparticle, an alternative substrate for proteases, thereby reducing corneal damage and releasing the encapsulated drug, ketoconazole, proportional to the severity of infection. After testing the efficacy of the system with human corneal epithelial cells, we have extended our studies to a rat model of keratitis. The results show a significantly increased corneal retention, suppressed inflammation and resolution of infection in the infected eyes. We believe that this will be an excellent approach to manage keratitis as well as other topical ocular infections.