Despite concerted efforts to improve therapy, 5-year survival rates for patients with advanced stage oral squamous cell carcinoma (SCC) remain discouragingly low. Clearly, early detection combined with strategies for local intervention, such as chemoprevention prior to SCC development, could dramatically improve clinical outcomes. The results of previously conducted oral cavity chemoprevention trials, however, have not been highly promising. Notably, the majority of previous oral chemoprevention trials administered agents systemically. For targeted disease management, local delivery methods have several advantages relative to systemic administration that include delivery of therapeutically relevant concentrations directly to the lesional site. Studies from our labs have shown that black raspberries possess cancer preventing properties at both the in vitro and in vivo levels. Dietary administration of freeze-dried black raspberries (FBR) successfully inhibited both esophageal and cheek pouch carcinoma in animal models. Our labs have recently shown that treatment of human oral SCC cells with the FBR ethanol extract (RO-ET) induces a wide array of chemopreventive effects that include growth suppression, reduction in pro-angiogenic cytokine release and induction of both apoptosis and differentiation. For persons with the premalignant condition, oral epithelial dysplasia, chemoprevention is likely to be necessary for the remainder of their lives. Therefore, identification of nontoxic, effective agents delivered in formulations that provide maximal concentrations at the lesional site, is necessary to improve patient prognosis. We propose that bioadhesive gel formulations, designed for topical intraoral application, will significantly advance treatment for oral epithelial dysplasia. Based on our results, we hypothesize that berry gels will attenuate pathways that accompany aberrant growth such as sustained proliferation and high production of proangiogenic molecules yet also stimulate growth regulatory mechanisms like apoptosis and terminal differentiation.
Aim 1 studies entail formulation and characterization of 2 bioadhesive berry gels that contain 10% RO-ET as their active component. The gel formulations will vary with respect to pH (3.5 or 5.5) in order to permit determination of which pH provides superior oral mucosal absorption.
In Aim 2, human pharmacokinetic analyses will be conducted on oral mucosa, saliva and peripheral blood samples in order to identify the clinical lead formulation i.e., the gel that is capable of achieving the highest levels of targeted compounds in oral mucosa. Public health relevance: Oral cancer remains a significant problem in the U.S. Even for those persons who can be cured, the necessary surgery is debilitating and often disfiguring. These studies will design and test bioadhesive gels that contain naturally derived cancer fighting compounds in human volunteers to determine the gels' abilities to effectively deliver the cancer preventing agents to the mouth tissues. ? ? ?
| Ling, Yonghua; Ren, Chen; Mallery, Susan R et al. (2009) A rapid and sensitive LC-MS/MS method for quantification of four anthocyanins and its application in a clinical pharmacology study of a bioadhesive black raspberry gel. J Chromatogr B Analyt Technol Biomed Life Sci 877:4027-34 |
| Ugalde, Carlos M; Liu, Zhongfa; Ren, Chen et al. (2009) Distribution of anthocyanins delivered from a bioadhesive black raspberry gel following topical intraoral application in normal healthy volunteers. Pharm Res 26:977-86 |
