Rechargeable Long-term Antifungal Denture Materials

描述(由申请人提供)：项目摘要：使用抗真菌义齿是一种有吸引力的方法来管理假丝酵母菌相关性义齿口炎(CADS)，这是假牙佩戴者中一种常见的复发性疾病，特别是在那些免疫功能低下或医学上不佳的人中。这种方法的有效性已经在短期研究中得到了证明。然而，目前的抗真菌义齿长期使用效果不佳。几天到几周后，释放的抗真菌药物不能达到必要的浓度，抑制作用就会消失。我们建议使用可充电技术来创造长期应用的感染敏感抗真菌义齿材料。聚丙烯酸(PAA，玻璃离子粘固剂的主要成分)和环糊精(CD，FDA批准的广泛使用的药物载体)将共价结合到义齿表面。带负电荷的PAA会通过离子络合物结合并缓慢释放阳离子抗真菌药物。由于假丝酵母菌的定植会降低pH值，从而破坏离子络合物，从而增加抗真菌的释放速度，因此释放速度预计是对感染敏感的。CD的疏水空腔将通过包合物结合和释放抗真菌药物。这种双重结合机制有望显著提高义齿的抗真菌结合能力。此外，不同类别的抗真菌药物可以通过离子和/或包合物结合到一个义齿系统中，这有望显著增强抑制效力，降低微生物耐药性的风险。在一段时间后(例如，几周)，释放的抗真菌药物的浓度将下降到次优水平。然而，当这种情况发生时，假牙将被清洁并再次补充抗真菌药物。由于PAA和CD通过共价键永久地附着在义齿上，它们不会从义齿上扩散出去。因此，新的抗真菌药物将通过形成离子和/或包合物结合到义齿表面。充填的假牙将再次提供感染反应释放足够数量的抗真菌药物，以抑制念珠菌的定植。因此，这种新型假牙将充当抗真菌药物的“可充电电池”，可反复充电以提供长期保护。在充电过程中，可以更换/轮换抗真菌药物，以进一步增强抑制活性，并将微生物耐药性的风险降至最低。如果成功，这项技术将提供一种创新的方法来控制冠心病和其他与牙科和医疗器械相关的感染。拟议的研究旨在确定新方法的可行性、有效性和安全性。其具体目标是：(1)开发可充电的感染敏感抗真菌义齿材料；(2)表征所开发的义齿材料的力学性能、抗定植和抗生物膜活性、耐用性、可充电性、生物相容性和安全性。 项目说明：新方法的独特之处包括：释放的抗真菌药物的可充电性，以实现长期保护；感染反应释放模式，在最需要药物时增加抗真菌药物的释放数量；以及在最初的结合和随后的再充电治疗中使用和轮换多种抗真菌药物，以提高抑制效力并将微生物耐药性的风险降至最低。这些优点使可充电的感染反应性抗真菌方法成为控制念珠菌定植/生物被膜形成和减少高危患者长期应用中的冠心病发生率的有吸引力的候选方法。此外，可充电的感染反应方法可能会刺激其他长期抗感染的牙科/医疗设备的开发，这些设备将对改善医疗保健做出重大贡献。

DESCRIPTION (provided by applicant): Project Summary: Using antifungal dentures is an attractive approach to manage Candida-associated denture stomatitis (CADS), a common recurring disease among denture wearers, particularly in those who are immunocompromised or medically compromised. The effectiveness of this approach has been demonstrated in short-term studies. However, the current antifungal dentures are not effective for long-term use. After days to weeks, the antifungals released cannot reach the necessary concentrations, and inhibitory effects are lost. We propose to use rechargeable technology to create infection-responsive antifungal denture materials for long-term applications. Poly acrylic acid (PAA, a major component of glass-ionomer cements) and ¿-cyclodextrin (¿-CD, a widely used FDA approved drug carrier) will be covalently bound onto denture surfaces. The negatively charged PAA will bind and slowly release cationic antifungals through ionic complexes. The release rate is expected to be infection-responsive since the colonization of Candida species will decrease pH values, which will break the ionic complexes and thereby increase the rate of antifungal release. The hydrophobic cavities of ¿-CD will bind and release antifungals through inclusion complexes. This dual binding mechanism is anticipated to significantly increase the antifungal-binding capacity of the dentures. Moreover, various classes of antifungals can then be combined into one denture system through ionic and/or inclusion complexes, which is expected to markedly enhance inhibitory potency and reduce the risk of microbial resistance. After a certain period of time (e.g., weeks), the concentration of the antifungals released will decrease to suboptimal levels. However, when this happens, the dentures will be cleaned and recharged with antifungals again. Because the PAA and ¿-CD are permanently attached to the dentures through covalent bonds, they will not diffuse away from the dentures. Therefore, the "new" antifungals will be bound onto the denture surfaces by forming ionic and/or inclusion complexes. The recharged dentures will again provide infection-responsive release of a sufficient amount of antifungals to inhibit Candida colonization. Thus, the new dentures will act as a "rechargeable battery" of antifungals that can be repeatedly recharged to provide long- term protection. In recharging, the antifungals can be changed/rotated to further enhance inhibitory activity and minimize the risk of microbial resistance. If successful, this technology will provide an innovative approach to controlling CADS and other dental and medical device-related infections. The proposed research is designed to establish the feasibility, effectiveness, and safety of the new approach. The specific aims are to: (1) create rechargeable infection-responsive antifungal denture materials; and (2) characterize the mechanical properties, anti-colonization and anti-biofilm activity, durability, rechargeability, biocompatibility and safety of the denture materials developed. Project Narrative: The unique features of the new approach include the rechargeability of the released antifungals to achieve long-term protection, the infection-responsive release pattern to increase the quantity of antifungals released when the drugs are most needed, and the use and rotation of multiple antifungal agents in the initial binding and subsequent recharging treatments to improve inhibitory potency and minimize the risk of microbial resistance. These advantages make the rechargeable infection-responsive antifungal approach an attractive candidate for controlling Candida colonization/biofilm formation and reducing the incidence of CADS in long- term applications among high-risk patients. In addition, the rechargeable infection-responsive approach may stimulate the development of other long-term infection-resistant dental/medical devices that will make significant contributions to improving healthcare.