The success of intraoral local drug delivery strategies is mainly dependent on the ability of polymeric carriers to provide: i) increased apparent solubility and stability in physiological fluids, e.g., saliva, ii) appropriate rate of drug release for an optimized effect, iii) facilitated penetration and local distribution of chemopreventive compounds, and iv) flexibility to allow controlled drug delivery to various oral mucosal sites. Furthermore, due to the risk factors associated with oral cancer (i.e., tobacco and/or alcohol use), the entire oral mucosa is hypothesized to have undergone field cancerization.[74
] Therefore, optimal therapeutic efficacy for oral cancer chemoprevention would likely entail both lesion-specific (topical agent) and field coverage (rinse) components. Hence, our laboratories have developed optimal intraoral drug delivery strategies for numerous chemopreventive agents by manipulating the properties of drugs (e.g., improving the apparent solubility, stability, and tissue distribution of drugs), utilizing polymeric carriers (e.g., developing mucoadhesive gels and patches, millicylindrical implants for long-term delivery, and nanoparticles), and using various delivery approaches (e.g., short- and sustained-duration drug release formulations).[13
Lesion-specific, targeted therapies are currently under evaluation in our labs, and include strategies for the delivery of black raspberry extract, fenretinide, and the matrix metalloproteinase inhibitor, N
] In addition to the 10% BRB gel currently under Phase III evaluation, sustained release poly(dl-lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) implant formulations have been developed for the sustained delivery of black raspberry anthocyanins (PLA), fenretinide (PLGA), and N
] Notably, these injectable implants demonstrated sustained release for 4–5 weeks in vitro
(black raspberry extract, N
salts, and fenretinide) and 4 weeks in vivo
(black raspberry extract), thus providing a potential local chemoprevention delivery method independent of daily patient compliance.[75
] Furthermore, preliminary in vitro
and in vivo
studies on the development and evaluation of a novel mucoadhesive fenretinide patch demonstrate both burst and sustained release patterns imparting therapeutically relevant levels in rabbit oral mucosa.[55
] In addition, our lab has demonstrated the feasibility of patch-mediated nanoparticle delivery to the basal epithelial cells and underlying connective tissue of human oral mucosal explants.[78
] This nanoparticle study provides yet another mechanism for drug stabilization and subsequent local delivery to the oral epithelium.
Recent studies in our labs have also demonstrated long-term sustainability of a black raspberry oral rinse formulation designed to provide a field coverage effect.[73
] Notably, rinse administration exhibited greater sustained salivary levels of anthocyanins relative to corresponding levels in pharmacokinetic studies of the 10% BRB gel.[56
Based on the collective results of the local delivery chemoprevention trials, which demonstrated a pharmacologic advantage over systemic strategies by minimizing systemic toxicities while obtaining therapeutically relevant local levels, these local intraoral delivery strategies developed in our laboratories warrant further evaluation for clinical efficacy in oral cancer chemoprevention. In addition, future oral cancer chemoprevention trials should focus on similar local delivery strategies and utilize the recommended study design parameters outlined within this review.