Rechargeable Long-term Antifungal Denture Materials

描述（由申请人提供）：项目摘要：使用抗真菌义齿是治疗牙周炎相关义齿性口炎（CADS）的一种有吸引力的方法，CADS是义齿佩戴者中常见的复发性疾病，特别是在免疫功能低下或医学上有缺陷的人群中。这种方法的有效性已在短期研究中得到证实。然而，目前的抗真菌义齿并不适合长期使用。数天至数周后，释放的抗真菌剂不能达到必要的浓度，抑制作用丧失。我们建议使用可充电技术，以创造长期应用的感染响应性抗真菌义齿材料。聚丙烯酸（PAA，玻璃离子水门汀的主要成分）和<$-环糊精（<$-CD，一种广泛使用的FDA批准的药物载体）将共价结合到义齿表面。带负电荷的PAA将通过离子络合物结合并缓慢释放阳离子抗真菌剂。预期释放速率是感染响应性的，因为念珠菌属的定殖将降低pH值，这将破坏离子复合物，从而增加抗真菌剂释放速率。<$-CD的疏水空腔将通过包合复合物结合并释放抗真菌剂。这种双重结合机制预计将显着增加义齿的抗真菌结合能力。此外，各种类型的抗真菌剂可以通过离子和/或包合复合物组合成一个义齿系统，这有望显着提高抑制效力，降低微生物耐药性的风险。在一定时间段之后（例如，周），释放的抗真菌剂的浓度将降低到次优水平。然而，当这种情况发生时，假牙将被清洁并再次注入抗真菌剂。由于PAA和<$-CD通过共价键永久附着在假牙上，因此它们不会从假牙上扩散。因此，“新”抗真菌剂将通过形成离子和/或包合物结合到义齿表面。重新充电的假牙将再次提供足够量的抗真菌药物的感染响应释放，以抑制念珠菌定植。因此，新的假牙将充当抗真菌药物的“可充电电池”，可以反复充电，提供长期保护。在再充电时，可以更换/旋转抗真菌剂，以进一步增强抑制活性并最大限度地降低微生物耐药性的风险。如果成功，这项技术将为控制CADS和其他牙科和医疗器械相关感染提供一种创新方法。拟议的研究旨在确定新方法的可行性，有效性和安全性。具体目标是：（1）创建可充电的感染响应性抗真菌义齿材料;（2）表征所开发义齿材料的机械性能、抗定植和抗生物膜活性、耐久性、可充电性、生物相容性和安全性。 项目叙述：新方法的独特功能包括释放的抗真菌剂的可再充电性以实现长期保护，感染响应释放模式以增加最需要药物时释放的抗真菌剂的数量，以及在初始结合和随后的再充电处理中使用和轮换多种抗真菌剂以提高抑制效力并最大限度地降低微生物耐药性的风险。这些优点使得可再充电的感染响应性抗真菌方法成为用于控制念珠菌定殖/生物膜形成和降低在高风险患者中长期应用的CADS发生率的有吸引力的候选物。此外，可充电感染响应方法可能会刺激其他长期抗感染牙科/医疗器械的开发，这些器械将为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.