Evaluation of a Mucoadhesive Fenretinide Patch for Local Intraoral Delivery: A Strategy to Re-introduce Fenretinide for Oral Cancer Chemoprevention
Menée sur des lapins et à l'aide de kératinocytes humains de la cavité buccale, cette étude évalue la pharmacocinétique et l'efficacité du fenrétinide (un rétinoïde synthétique), administré au moyen d'un patch mucoadhésif, dans la chimioprévention des cancers de la cavité buccale
Systemic delivery of fenretinide in oral cancer chemoprevention trials has been largely unsuccessful due to dose-limiting toxicities and sub-therapeutic intra-oral 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 8 rabbits (30 minutes, 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: 5.65μM; 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 <5μM, reduced Ki-67 indices >5μM) 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 inter-donor 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 re-introduce a compound known to induce keratinocyte differentiation to human oral cancer chemoprevention trials.
http://carcin.oxfordjournals.org/content/early/2012/03/15/carcin.bgs122.abstract