Rechargeable Long-term Anticandidal Denture Materials

描述（由申请人提供）：牙列相关性义齿性口炎（CADS）是义齿佩戴者常见的复发性疾病，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CADS，并且再感染率很高，特别是在老年人和那些医学或免疫功能低下的人中。该项目建立在我们由NIDCR（可充电的长期抗真菌药物材料，R 03 DE 018735）赞助的试点研究基础上，将使用可充电的“点击/点击关闭”anticandidal技术来控制CADS。我们已经证明，少量（10%）的甲基丙烯酸（MAA）可以在固化步骤中与聚氨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部分充当“可充电电池”，以结合然后长时间（数周至数月）缓慢释放阳离子抗真菌药物，如咪康唑和葡萄糖酸氯己定。药物可以通过用乙二胺四乙酸（EDTA）处理而被“淬灭”（洗掉），并且树脂再填充相同或不同的抗真菌药物。在目前的项目中，我们将使用各种局部抗念珠菌药物，包括唑类（克霉唑和咪康唑），多烯（制霉菌素）和唾液抗微生物多肽（合成组胺素5），将这种技术应用于以明胶为基础的和以丙烯酸为基础的义齿材料。将在体外使用人口腔上皮-念珠菌和重组人上皮（RHE）-念珠菌共培养模型评价新系统的生物相容性和抗念珠菌功效。还将测试产生微生物耐药性的风险。拟议研究的具体目标是：（1）制备新型丙烯酸酯和聚氨酯可充式抗龋义齿材料，并表征新材料的物理/机械性能，（2）配制含抗龋药物的义齿材料，建立药物结合/释放动力学，并评价新型义齿材料的“click-on/click-off”抗龋技术，体外评价新型义齿材料的生物相容性、抗龋活性及微生物对材料的耐药性风险。拟议的可充电、“点击/点击”抗牙床假牙材料可以根据临床需求启动或终止抗真菌药物治疗。可充电的功能将允许切换到更强效/有效的药物，以增强抗念珠菌效力和/或最大限度地减少真菌耐药性的风险，从而为CADS和相关疾病提供个性化的治疗策略。 公共卫生相关性：义齿相关性口炎（CADS）是一种常见的复发性疾病，严重影响患者的口腔健康和福祉。CADS的管理和预防是一个重大的临床挑战。该项目将开发新的义齿材料，提供持续和可充电的抗牙床活动，具有基于临床感染状态的“点击/点击”药物输送的独特功能。该技术可以提供个性化的CADS治疗和预防，也可能需要开发下一代抗菌导管，气管内导管和相关设备，以对抗感染并开发更安全的医疗环境。

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. PUBLIC HEALTH RELEVANCE: Candida-associated denture stomatitis (CADS) is a common, recurring disease that seriously affects patients' oral health and wellbeing. Management and prevention of CADS is a significant clinical challenge. This project will develop new denture materials that provide sustained and rechargeable anticandidal activity with the unique features of "click-on/click-off" drug delivery based on clinical infection status. The technology can provide personalized CADS treatment and prevention, and may also be needed to develop next generation antimicrobial catheters, endotracheal tubes, and related devices to fight infection and develop safer healthcare environment.