title: pH-activated nanoparticles for controlled topical delivery of farnesol to disrupt oral biofilm virulence.
abstract: Development of effective therapies to control oral biofilms is challenging, as topically introduced agents must avoid rapid clearance from biofilm-tooth interfaces while targeting biofilm microenvironments. Additionally, exopolysaccharides-matrix and acidification of biofilm microenvironments are associated with cariogenic (caries-producing) biofilm virulence. Thus, nanoparticle carriers capable of binding to hydroxyapatite (HA), saliva-coated HA (sHA), and exopolysaccharides with enhanced drug release at acidic pH were developed. Nanoparticles are formed from diblock copolymers composed of 2-(dimethylamino)ethyl methacrylate (DMAEMA), butyl methacrylate (BMA), and 2-propylacrylic acid (PAA) (p(DMAEMA)-b-p(DMAEMA-co-BMA-co-PAA)) that self-assemble into ∼21 nm cationic nanoparticles. Nanoparticles exhibit outstanding adsorption affinities (∼244 L-mmol(-1)) to negatively charged HA, sHA, and exopolysaccharide-coated sHA due to strong electrostatic interactions via multivalent tertiary amines of p(DMAEMA). Owing to hydrophobic cores, nanoparticles load farnesol, a hydrophobic antibacterial drug, at ∼22 wt %. Farnesol release is pH-dependent with t1/2 = 7 and 15 h for release at pH 4.5 and 7.2, as nanoparticles undergo core destabilization at acidic pH, characteristic of cariogenic biofilm microenvironments. Importantly, topical applications of farnesol-loaded nanoparticles disrupted Streptococcus mutans biofilms 4-fold more effectively than free farnesol. Mechanical stability of biofilms treated with drug-loaded nanoparticles was compromised, resulting in >2-fold enhancement in biofilm removal under shear stress compared to free farnesol and controls. Farnesol-loaded nanoparticles effectively attenuated biofilm virulence in vivo using a clinically relevant topical treatment regimen (2×/day) in a rodent dental caries disease model. Strikingly, treatment with farnesol-loaded nanoparticles reduced both the number and severity of carious lesions, while free farnesol had no effect. Nanoparticle carriers have great potential to enhance the efficacy of antibiofilm agents through multitargeted binding and pH-responsive drug release due to microenvironmental triggers.
authors: †Department of Biomedical Engineering, ‡Center for Oral Biology, ⊥Department of Chemical Engineering, and #Center of Musculoskeletal Research, University of Rochester, Rochester, New York 14627, United States.|§Biofilm Research Lab, Levy Center for Oral Health, and ∥Department of Orthodontics and Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors: Benjamin
authors: B
authors: Horev
authors: †Department of Biomedical Engineering, ‡Center for Oral Biology, ⊥Department of Chemical Engineering, and #Center of Musculoskeletal Research, University of Rochester, Rochester, New York 14627, United States.|§Biofilm Research Lab, Levy Center for Oral Health, and ∥Department of Orthodontics and Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors: Marlise I
authors: MI
authors: Klein
authors: †Department of Biomedical Engineering, ‡Center for Oral Biology, ⊥Department of Chemical Engineering, and #Center of Musculoskeletal Research, University of Rochester, Rochester, New York 14627, United States.|§Biofilm Research Lab, Levy Center for Oral Health, and ∥Department of Orthodontics and Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors: Geelsu
authors: G
authors: Hwang
authors: †Department of Biomedical Engineering, ‡Center for Oral Biology, ⊥Department of Chemical Engineering, and #Center of Musculoskeletal Research, University of Rochester, Rochester, New York 14627, United States.|§Biofilm Research Lab, Levy Center for Oral Health, and ∥Department of Orthodontics and Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors: Yong
authors: Y
authors: Li
authors: †Department of Biomedical Engineering, ‡Center for Oral Biology, ⊥Department of Chemical Engineering, and #Center of Musculoskeletal Research, University of Rochester, Rochester, New York 14627, United States.|§Biofilm Research Lab, Levy Center for Oral Health, and ∥Department of Orthodontics and Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors: Dongyeop
authors: D
authors: Kim
authors: †Department of Biomedical Engineering, ‡Center for Oral Biology, ⊥Department of Chemical Engineering, and #Center of Musculoskeletal Research, University of Rochester, Rochester, New York 14627, United States.|§Biofilm Research Lab, Levy Center for Oral Health, and ∥Department of Orthodontics and Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors: Hyun
authors: H
authors: Koo
authors: †Department of Biomedical Engineering, ‡Center for Oral Biology, ⊥Department of Chemical Engineering, and #Center of Musculoskeletal Research, University of Rochester, Rochester, New York 14627, United States.|§Biofilm Research Lab, Levy Center for Oral Health, and ∥Department of Orthodontics and Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors: Danielle S W
authors: DS
authors: Benoit
mesh_terms: D000287:Administration, Topical; D018441:Biofilms / Q000187:drug effects*; D003692:Delayed-Action Preparations; D044622:Dental Pellicle / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry*; D017886:Durapatite / Q000378:metabolism; D005204:Farnesol / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009055:Mouth / Q000187:drug effects / Q000382:microbiology*; D011135:Polysaccharides, Bacterial / Q000378:metabolism; D013295:Streptococcus mutans / Q000378:metabolism / Q000472:pathogenicity* / Q000502:physiology*; D013499:Surface Properties; D014774:Virulence / Q000187:drug effects
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011135:Polysaccharides, Bacterial; D005204:Farnesol; D017886:Durapatite
keywords: Streptococcus mutans biofilms; dental caries; dental pellicle; exopolysaccharides; farnesol; matrix; nanoparticles; pH-responsive; polymeric micelles