Rechargeable Infection-responsive 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、复发的疾病，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，特别是对于经常在免疫和/或医学上受到损害的老年退伍军人群体。该项目将开发一种可充电的、“点击/关闭”的防伪技术来管理CAD。我们建议将甲基丙烯酸(MAA)部分结合到义齿材料中，作为“充电电池”，结合并缓释抗真菌药物。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，如咪康唑和洗必泰二葡萄糖酸盐，可以被带入新的义齿材料中，并在较长的一段时间内(几周或几个月)缓慢释放。药物可以用EDTA等猝灭剂处理义齿材料，然后用相同或不同的抗真菌试剂重新充电。在目前的方案中，我们将验证这一假设，即该技术既可以应用于氨基甲酸酯基义齿材料，也可以应用于含有三种不同化学和生化结构的抗真菌药物的氨基甲酸酯基义齿材料，即咪康唑(咪康唑)、多烯(制霉菌素)和唾液抗菌多肽(合成组蛋白5)。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。新系统的生物相容性和抗真菌效果的评估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。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。该项目开发的可充电、“点击/点击关闭”的抗真菌义齿材料可以根据临床念珠菌感染的存在或不存在而激活和终止抗真菌药物治疗。可充电功能可能会允许切换到更有效/更有效的试剂，以增强抗真菌效力和/或将真菌耐药性的风险降至最低，从而为冠心病和其他相关疾病提供个性化的治疗策略。此外，这项新技术可能被广泛用于治疗其他口腔或全身疾病的药物输送系统和/或牙科/医疗器械的感染控制。

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.