title: Topical delivery of low-cost protein drug candidates made in chloroplasts for biofilm disruption and uptake by oral epithelial cells.
abstract: Protein drugs (PD) are minimally utilized in dental medicine due to high cost and invasive surgical delivery. There is limited clinical advancement in disrupting virulent oral biofilms, despite their high prevalence in causing dental caries. Poor efficacy of antimicrobials following topical treatments or to penetrate and disrupt formed biofilms is a major challenge. We report an exciting low-cost approach using plant-made antimicrobial peptides (PMAMPs) retrocyclin or protegrin with complex secondary structures (cyclic/hairpin) for topical use to control biofilms. The PMAMPs rapidly killed the pathogen Streptococcus mutans and impaired biofilm formation following a single topical application of tooth-mimetic surface. Furthermore, we developed a synergistic approach using PMAMPs combined with matrix-degrading enzymes to facilitate their access into biofilms and kill the embedded bacteria. In addition, we identified a novel role for PMAMPs in delivering drugs to periodontal and gingival cells, 13-48 folds more efficiently than any other tested cell penetrating peptides. Therefore, PDs fused with protegrin expressed in plant cells could potentially play a dual role in delivering therapeutic proteins to gum tissues while killing pathogenic bacteria when delivered as topical oral formulations or in chewing gums. Recent FDA approval of plant-produced PDs augurs well for clinical advancement of this novel concept.
authors: Department of Orthodontics, Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA.
authors: Yuan
authors: Y
authors: Liu
authors: Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA.
authors: Aditya C
authors: AC
authors: Kamesh
authors: Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA.
authors: Yuhong
authors: Y
authors: Xiao
authors: Department of Orthodontics, Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA.
authors: Victor
authors: V
authors: Sun
authors: Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA.
authors: Michael
authors: M
authors: Hayes
authors: Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA. Electronic address: hdaniell@upenn.edu.
authors: Henry
authors: H
authors: Daniell
authors: Department of Orthodontics, Divisions of Pediatric Dentistry and Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA. Electronic address: koohy@upenn.edu.
authors: Hyun
authors: H
authors: Koo
mesh_terms: D000287:Administration, Topical; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development*; D002460:Cell Line; D002478:Cells, Cultured; D002736:Chloroplasts / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D009061:Mouth Mucosa / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D010936:Plant Extracts
keywords: Antimicrobial peptide; Dental caries; Drug delivery; Plant biopharmaceuticals; Therapeutic enzymes