Rechargeable Infection-responsive Anticandidal Denture Materials

描述（由申请人提供）： 义齿相关性口炎（CADS）是义齿佩戴者中常见的复发性疾病，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，特别是对于经常免疫和/或医学受损的老年退伍军人群体。该项目将开发一种可充电的“点击/点击关闭”anticandidal技术来管理CADS。我们建议，甲基丙烯酸（MAA）部分可以被纳入义齿材料，并作为一个“充电电池”结合，然后缓慢释放抗真菌药物。我们的初步研究表明，MAA（高达10%）可以在固化步骤中与义齿树脂单体共聚，而不会对所得树脂的物理/机械性能产生负面影响。抗真菌药物，如咪康唑和氯己定二葡萄糖酸盐，可以装入新的义齿材料，并缓慢释放一段时间（数周或数月）。药物可以通过用淬灭剂如EDTA处理义齿材料而被“淬灭”（洗掉或“点击”掉），并且淬灭的义齿材料可以用相同或不同的抗真菌剂再填充。在当前的提案中，我们将测试这一假设，即该技术可以应用于具有不同化学和生物化学结构的三种抗牙床药物的树脂基和丙烯酸基义齿材料，即，唑（咪康唑）、多烯（制霉菌素）和唾液抗微生物多肽（合成组胺素5）。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。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有效性。还将测试产生微生物耐药性的潜在风险，以确定新方法的安全性。本项目中开发的可充电的“点击/点击关闭”抗牙床义齿材料可以根据临床念珠菌感染的存在或不存在激活和终止抗真菌药物治疗。可再充电的特征将可能允许切换到更强效/有效的试剂，以增强抗念珠菌效力和/或最小化真菌耐药性的风险，从而为CADS和其他相关疾病提供个性化的治疗策略。此外，这种新技术可能用于其他口腔或全身性疾病和/或牙科/医疗器械感染控制的广泛药物递送系统。

DESCRIPTION (provided by applicant): Candida-associated denture stomatitis (CADS) is a common, recurring disease among 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, particularly for the elderly veteran population who are often immunologically and/or medically compromised. This project will develop a rechargeable, "click-on/click-off" anticandidal technology to manage CADS. We propose that methacrylic acid (MAA) moieties can be incorporated into denture materials and act as a "rechargeable battery" to bind and then slowly release antifungal drugs. Our preliminary studies have demonstrated that MAA (up to 10%) can be copolymerized with denture resin monomers in the curing step without negatively affecting the physical/mechanical properties of the resulting resins. Antifungal drugs such as miconazole and chlorhexidine digluconate can be charged into the new denture materials and slowly released for a prolonged period of time (weeks or months). The drugs could be "quenched" (washed out or "clicked" off) by treating the denture materials with a quenching agent such as EDTA, and the quenched denture materials can be recharged with the same or different antifungal reagents. In the current proposal, we will test the hypothesis that this technique can be applied to both urethane-based and acrylic-based denture materials with three anticandidal drugs of different chemical and biochemical structures, i.e., a azole (miconazole), a polyene (nystatin) and a salivary antimicrobial polypeptide (synthetic histatin 5). 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 evaluation of biocompatibility and anticandidal efficacy of the new systems will be performed in vitro with human oral epithelium-Candida and reconstituted human epithelium (RHE)-Candida co-culture models. The potential risk of developing microbial resistance will also be tested to determine the safety of the new approach. The rechargeable, "click-on/click-off" anticandidal denture materials developed in this project can activate and terminate antifungal drug treatment depending on the presence or absence of clinical Candida infection. The rechargeable feature will likely allow switching to more potent/effective reagents to enhance anticandidal potency and/or minimize the risk of fungal resistance, leading to a personalized therapeutic strategy for CADS and other related diseases. Furthermore, this new technology could be potentially used in a broad range of drug delivery systems for other oral or systemic diseases and/or infection control of dental/medical devices.