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Curcumin-Loaded Liquid Crystalline Systems for Controlled Drug Release and Improved Treatment of Vulvovaginal Candidiasis
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-05 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00507 Camila Fernanda Rodero 1 , Giovana Maria Fioramonti Calixto 1 , Karen Cristina dos Santos 1 , Mariana Rillo Sato 1 , Matheus Aparecido dos Santos Ramos 2 , Maria Soledad Miró 3 , Emilse Rodríguez 3 , Cecilia Vigezzi 3 , Tais Maria Bauab 2 , Claudia Elena Sotomayor 3 , Marlus Chorilli 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-05 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00507 Camila Fernanda Rodero 1 , Giovana Maria Fioramonti Calixto 1 , Karen Cristina dos Santos 1 , Mariana Rillo Sato 1 , Matheus Aparecido dos Santos Ramos 2 , Maria Soledad Miró 3 , Emilse Rodríguez 3 , Cecilia Vigezzi 3 , Tais Maria Bauab 2 , Claudia Elena Sotomayor 3 , Marlus Chorilli 1
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Vulvovaginal candidiasis (VVC) is the most common infection caused by Candida albicans and greatly reduces the quality of life of women affected by it. Due to the ineffectiveness of conventional treatments, there is growing interest in research involving compounds of natural origin. One such compound is curcumin (CUR), which has been proven to be effective against this microorganism. However, some of CUR’s physicochemical properties, especially its low aqueous solubility, make the therapeutic application of this compound difficult. Thus, the incorporation of CUR in mucoadhesive liquid crystalline systems (MLCSs) for vaginal administration may be an efficient strategy for the treatment of VVC. MLCSs are capable of potentiating the compound’s action, releasing it in a controlled manner, and can enable longer exposure at the site of infection. In this study, MLCSs consisting of oleic acid and ergosterol 5:1 (w/w) as the oily phase, PPG-5-CETETH-20 as the surfactant, and a polymer dispersion of 1% chitosan as the aqueous phase, were developed for the application of CUR (MLCS-CUR) in VVC treatment. The formulations were characterized by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), oscillatory rheometry, continuous shear rheometry, texture profile analysis, and in vitro mucoadhesion. In addition, the antimicrobial activity was evaluated in vitro, and the effects on local fungal burden and cytokine profiles were investigated in a murine model of VVC. PLM and SAXS showed that the developed formulations presented a characteristic of a microemulsion. However, after the addition of artificial vaginal mucus (AVM), PLM showed that the formulations had structures similar to the “Maltese cross” characteristic of lamellar MLCS. Mucoadhesive test results showed an increase in the mucoadhesive strength of these formulations. Rheology analyses suggested long-lasting action of the formulation at the infected site. The in vitro antimicrobial activity assays suggested that CUR possesses antifungal activity against Candida albicans, determined after its incorporation into the MLCS. Further, MLCS-CUR was also more effective in vivo in the control of vaginal infection than treatment with fluconazole. Immunological assays showed that the ratio of pro-inflammatory (IL-1β) to anti-inflammatory (TGF-β) cytokines has decreased and that there is a reduction in the number of polymorphonuclear neutrophils recruited to the vaginal lumen, showing that treatment with MLCS-CUR was effective in modulating the inflammatory reaction associated with the infection. The results suggest that MLCSs could potentially be used in the treatment of VVC with CUR.
中文翻译：
姜黄素负载液晶系统可控制药物释放并改善念珠菌性外阴念珠菌病
外阴念珠菌病（VVC）是由白色念珠菌引起的最常见感染并大大降低了受其影响的女性的生活质量。由于常规治疗的无效性，对涉及天然来源化合物的研究越来越感兴趣。一种这样的化合物是姜黄素（CUR），已被证明对这种微生物有效。但是，CUR的某些物理化学性质，尤其是其低的水溶性，使该化合物的治疗应用变得困难。因此，将CUR掺入用于阴道给药的粘膜粘附液晶系统（MLCS）中可能是治疗VVC的有效策略。MLCS能够增强化合物的作用，以受控的方式释放它，并且可以在感染部位更长的暴露时间。在这项研究中，由油酸和麦角固醇5：1（w / w）组成的MLCS为油相，开发了PPG-5-CETETH-20作为表面活性剂，以及1％壳聚糖的聚合物分散体作为水相，用于CUR（MLCS-CUR）在VVC处理中的应用。通过偏光显微镜（PLM），小角X射线散射（SAXS），振荡流变，连续剪切流变，结构轮廓分析和体外粘膜粘附来表征制剂。另外，在体外评估抗微生物活性，并在鼠VVC模型中研究了其对局部真菌负荷和细胞因子谱的影响。PLM和SAXS表明，开发的配方具有微乳液的特征。但是，在添加人工阴道粘液（AVM）之后，PLM显示该制剂的结构类似于层状MLCS的“马耳他十字”特征。粘膜粘附测试结果显示这些制剂的粘膜粘附强度增加。流变学分析表明该制剂在受感染部位具有持久作用。体外抗菌活性测定表明，CUR具有抗真菌活性白色念珠菌，掺入MLCS后测定。此外，MLCS-CUR在体内在控制阴道感染方面也比氟康唑治疗更有效。免疫学分析表明促炎（IL-1β）与消炎（TGF-β）细胞因子的比例降低，募集到阴道腔的多形核中性粒细胞减少，这表明采用MLCS治疗-CUR在调节与感染有关的炎症反应方面有效。结果表明，MLCSs可以潜在地用于CUR治疗VVC。
更新日期：2018-09-05
中文翻译：
姜黄素负载液晶系统可控制药物释放并改善念珠菌性外阴念珠菌病
外阴念珠菌病（VVC）是由白色念珠菌引起的最常见感染并大大降低了受其影响的女性的生活质量。由于常规治疗的无效性，对涉及天然来源化合物的研究越来越感兴趣。一种这样的化合物是姜黄素（CUR），已被证明对这种微生物有效。但是，CUR的某些物理化学性质，尤其是其低的水溶性，使该化合物的治疗应用变得困难。因此，将CUR掺入用于阴道给药的粘膜粘附液晶系统（MLCS）中可能是治疗VVC的有效策略。MLCS能够增强化合物的作用，以受控的方式释放它，并且可以在感染部位更长的暴露时间。在这项研究中，由油酸和麦角固醇5：1（w / w）组成的MLCS为油相，开发了PPG-5-CETETH-20作为表面活性剂，以及1％壳聚糖的聚合物分散体作为水相，用于CUR（MLCS-CUR）在VVC处理中的应用。通过偏光显微镜（PLM），小角X射线散射（SAXS），振荡流变，连续剪切流变，结构轮廓分析和体外粘膜粘附来表征制剂。另外，在体外评估抗微生物活性，并在鼠VVC模型中研究了其对局部真菌负荷和细胞因子谱的影响。PLM和SAXS表明，开发的配方具有微乳液的特征。但是，在添加人工阴道粘液（AVM）之后，PLM显示该制剂的结构类似于层状MLCS的“马耳他十字”特征。粘膜粘附测试结果显示这些制剂的粘膜粘附强度增加。流变学分析表明该制剂在受感染部位具有持久作用。体外抗菌活性测定表明，CUR具有抗真菌活性白色念珠菌，掺入MLCS后测定。此外，MLCS-CUR在体内在控制阴道感染方面也比氟康唑治疗更有效。免疫学分析表明促炎（IL-1β）与消炎（TGF-β）细胞因子的比例降低，募集到阴道腔的多形核中性粒细胞减少，这表明采用MLCS治疗-CUR在调节与感染有关的炎症反应方面有效。结果表明，MLCSs可以潜在地用于CUR治疗VVC。
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