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.

Public Health Relevance

Candida-associated denture stomatitis (CADS) is a common and recurrent problem for denture wearers. The elderly veterans are especially susceptible to CADS due to a high incidence of tooth loss commonly leading to the need for dentures and other risk factors for Candida infections associated with compromised medical and immunological conditions. Recent studies further suggest that oral infections can be linked to a patient's overall health. Therefore, the prevention and management of CADS are vital to the veterans'well-being but currently still pose a clinical challenge. This project will develop new and innovative denture materials that can provide sustained and rechargeable anticandidal activity with the unique features of a click-on/click-off (activated or inactivated) drug delivery system based on the clinical infection statuses of patients. The technology developed here could provide personalized CADS treatment/prevention that will reduce CADS and unnecessary oral microorganism burdens to denture wearers in both the veterans and general populations.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001103-02
Application #
8597913
Study Section
Infectious Diseases B (INFB)
Project Start
2012-10-01
Project End
2016-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
South Texas Veterans Health Care System
Department
Type
DUNS #
078493228
City
San Antonio
State
TX
Country
United States
Zip Code
78229