Cross-Kingdom Assemblage Clearance via Anionic Chondroitin Sulfate Nanohybrid Aggregates

About This Grant

PROJECT SUMMARY/ABSTRACT Early childhood caries (ECC) preferentially affects nearly 25% of American children of the pre-school age. The impact of ECC to both the child and family is devasting both emotionally and financially - as the cost of restorative treatment is both substantial and time consuming. ECC preferentially affects those of low socioeconomic status and specifically, those with poor oral hygiene leading, a high sugar diet and chronic tooth-borne biofilms comprising Streptococcus mutans and Candida albicans. Current ECC prevention protocols include fluoride treatment combined with various antimicrobial regimens, however, evidence supporting the currently available antimicrobial agents in long term success is lacking potentially attributed to microbial resistance and/or poor efficacy against S. mutans-C. albicans assemblages. We have developed anionic, nanohybrid aggregate formulations comprised of chondroitin sulfate A (CSA) and cerium oxide nanoparticles (CeO2-NP) that achieve plaque reduction via selective clearance of S. mutans (and assembled C. albicans) reducing their contribution to adherent plaque formation with minimal toxicity. In contrast, single metal oxide nanoparticles (MxOy-NP) often researched for anti-biofilm activity are often plagued with poor selectivity and enhanced toxicity. The central hypothesis is based on the fluid nanohybrid aggregate structure where both CSA and CeO2-NP are surface exposed, such that i) CSA aids in the targeting of cationic protein(s) on the S. mutans surface over random salivary proteins and the ii) nanoceria aggregate structure facilitates extended aggregation reducing penetration of soft tissues. This proposal tests the above hypotheses with the development of two independent Aims and the benefit of an interdisciplinary team of investigators. In Aim 1, we utilize literature based pull down assays and antibody labeling experiments to identify the key protein (or proteins) on the S. mutans surface mediating the phenotypic effects resulting from CeO2-NP-CSA(-B) treatment. In Aim-2, 3D oral soft tissue models will be repeatedly dosed with CeO2-NP-CSA(-B) along with CeO2-NP to establish their effects on barrier integrity, inflammation and toxicity over time. Completion of the above aims will define a new area of selective, non-toxic and inexpensive topical therapeutics that can achieve targeted removal of pathogens associated with the incidence and severity of ECC. Long term goals involve testing the nanohybrid aggregates in advanced in vivo studies relevant to patient care of this at-risk population.