title: Evaluation of a mucoadhesive fenretinide patch for local intraoral delivery: a strategy to reintroduce fenretinide for oral cancer chemoprevention.
abstract: Systemic delivery of fenretinide in oral cancer chemoprevention trials has been largely unsuccessful due to dose-limiting toxicities and subtherapeutic intraoral drug levels. Local drug delivery, however, provides site-specific therapeutically relevant levels while minimizing systemic exposure. These studies evaluated the pharmacokinetic and growth-modulatory parameters of fenretinide mucoadhesive patch application on rabbit buccal mucosa. Fenretinide and blank-control patches were placed on right/left buccal mucosa, respectively, in eight rabbits (30 min, q.d., 10 days). No clinical or histological deleterious effects occurred. LC-MS/MS analyses of post-treatment samples revealed a delivery gradient with highest fenretinide levels achieved at the patch-mucosal interface (no metabolites), pharmacologically active levels in fenretinide-treated oral mucosa (mean: 5.65 μM; trace amounts of 4-oxo-4-HPR) and undetectable sera levels. Epithelial markers for cell proliferation (Ki-67), terminal differentiation (transglutaminase 1-TGase1) and glucuronidation (UDP-glucuronosyltransferase1A1-UGT1A1) exhibited fenretinide concentration-specific relationships (elevated TGase1 and UGT1A1 levels <5 μM, reduced Ki-67 indices >5 μM) relative to blank-treated epithelium. All fenretinide-treated tissues showed significantly increased intraepithelial apoptosis (TUNEL) positivity, implying activation of intersecting apoptotic and differentiation pathways. Human oral mucosal correlative studies showed substantial interdonor variations in levels of the enzyme (cytochrome P450 3A4-CYP3A4) responsible for conversion of fenretinide to its highly active metabolite, 4-oxo-4-HPR. Complementary in vitro assays in human oral keratinocytes revealed fenretinide and 4-oxo-4-HPR's preferential suppression of DNA synthesis in dysplastic as opposed to normal oral keratinocytes. Collectively, these data showed that mucoadhesive patch-mediated fenretinide delivery is a viable strategy to reintroduce a compound known to induce keratinocyte differentiation to human oral cancer chemoprevention trials.
authors.affiliation: Division of Oral Maxillofacial Surgery, Pathology and Anesthesiology, College of Dentistry, The Ohio State University, 2205 Postle Hall, 305 W. 12th Avenue, Columbus, OH 43210-1241, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Holpuch
authors.forename: Maynard P
authors.initials: MP
authors.lastname: Phelps
authors.forename: Kashappa-Goud H
authors.initials: KG
authors.lastname: Desai
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: George M
authors.initials: GM
authors.lastname: Koutras
authors.forename: Byungdo B
authors.initials: BB
authors.lastname: Han
authors.forename: Blake M
authors.initials: BM
authors.lastname: Warner
authors.forename: Ping
authors.initials: P
authors.lastname: Pei
authors.forename: Garrett A
authors.initials: GA
authors.lastname: Seghi
authors.forename: Meng
authors.initials: M
authors.lastname: Tong
authors.forename: Michael B
authors.initials: MB
authors.lastname: Border
authors.forename: Henry W
authors.initials: HW
authors.lastname: Fields
authors.forename: Gary D
authors.initials: GD
authors.lastname: Stoner
authors.forename: Peter E
authors.initials: PE
authors.lastname: Larsen
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Liu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Schwendeman
authors.forename: Susan R
authors.initials: SR
authors.lastname: Mallery
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism; D009062:Mouth Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D011817:Rabbits
chemical_list: C494898:4-oxofenretinide; D014408:Biomarkers, Tumor; D017313:Fenretinide; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014453:Glucuronosyltransferase