Rechargeable Long-term Anticandidal Denture Materials

描述(由申请人提供)：假丝酵母菌相关性义齿口炎(CADS)是假牙佩戴者的一种常见、反复发作的疾病，可导致其他口腔健康问题、全身感染、生活质量下降，甚至死亡。到目前为止，还没有有效的治疗策略来控制冠心病，再感染率很高，特别是在老年人和那些药物或免疫功能受损的人中。该项目以我们由NIDCR(可充电长期抗真菌义齿材料，R03 DE018735)赞助的试点研究为基础，将使用可充电的“点击/点击”防腐技术来控制牙冠。我们已经证明，在固化步骤中，少量(10%)的甲基丙烯酸(MAA)可以与氨基甲酸酯义齿树脂单体共聚，而不会对所得树脂的物理/机械性能产生负面影响。义齿树脂中的阴离子MAA部分起到“充电电池”的作用，长时间(几周到几个月)结合并缓慢释放咪康唑和葡萄糖酸洗必泰等阳离子抗真菌药物。这些药物可以用乙二胺四乙酸(EDTA)处理，然后用相同或不同的抗真菌药物重新充电。在目前的项目中，我们将把这项技术应用于氨基甲酸酯基义齿材料和丙烯酸基义齿材料，使用不同类别的局部抗真菌药物，包括唑类(克霉唑和咪康唑)、多烯(制霉菌素)和唾液抗菌多肽(合成组蛋白5)。新系统的生物相容性和抗真菌效果将在体外用人口腔上皮-念珠菌和重组人上皮-念珠菌共培养模型进行评估。还将测试产生微生物耐药性的风险。本研究的具体目的是：(1)制备新型丙烯酸和氨基甲酸酯可充电义齿材料，并对其物理力学性能进行表征；(2)研制含药物义齿材料，建立药物结合/释放动力学，评价新型义齿材料的“点击/点击”防牙技术；(3)体外评价新型义齿材料的生物相容性、抗真菌活性及微生物耐药性风险。建议使用的可充电、“点击/点击”的抗真菌义齿材料可根据临床需要启动或终止抗真菌药物治疗。可充电功能将允许切换到更有效/更有效的药物，以增强抗真菌效力和/或将真菌耐药性的风险降至最低，从而为冠心病和相关疾病带来个性化的治疗策略。

DESCRIPTION (provided by applicant): Candida-associated denture stomatitis (CADS) is a common, recurrent disease in denture wearers and can lead to other oral health problems, systemic infections, compromised quality of life, and even death. Thus far, there are no effective treatment strategies to control CADS, and the reinfection rate is high, particularly in the elderly and those who are medically or immunocompromised. This project, building on our pilot studies sponsored by NIDCR (Rechargeable Long-term Antifungal Denture Materials, R03 DE018735) will use rechargeable, "click-on/click-off" anticandidal technology to control CADS. We have demonstrated that a small amount (10%) of methylacrylic acid (MAA) could be copolymerized with urethane denture resin monomers in the curing step without negatively affecting the physical/mechanical properties of the resulting resins. The anionic MAA moieties in the denture resins acted as a "rechargeable battery" to bind and then slowly release cationic antifungal drugs such as miconazole and chlorhexidine gluconate for a long period of time (weeks to months). The drugs could be "quenched" (washed out) by treating with ethylenediaminetetraacetic acid (EDTA) and the resins recharged with the same or different antifungal drugs. In the current project, we will apply this technique to both urethane-based and acrylic-based denture materials using various classes of topical anticandidal drugs, including azoles (clotrimazole and miconazole), polyene (nystatin) and salivary antimicrobial polypeptides (synthetic histatin 5). The biocompatibility and anticandidal efficacy of the new systems will be evaluated in vitro with human oral epithelium-Candida and reconstituted human epithelium (RHE)-Candida co-culture models. The risk of developing microbial resistance will also be tested. The specific aims of the proposed research are to: (1) fabricate new acrylic and urethane rechargeable anticandidal denture materials, and characterize the physical/mechanical properties of the new materials, (2) formulate the anticandidal drug-containing denture materials, establish drug binding/releasing kinetics, and evaluate the "click-on/click-off" anticandidal technology of the new denture materials, and (3) evaluate in vitro the biocompatibility and anticandidal activity of the new denture materials and the risk of microbial resistance to the materials. The proposed rechargeable, "click-on/click-off" anticandidal denture materials can activate or terminate antifungal drug treatment based on clinical needs. The rechargeable feature will allow switching to more potent/effective drugs to enhance anticandidal potency and/or minimize the risk of fungal resistance, leading to a personalized therapeutic strategy for CADS and related diseases.