Formulation & Evaluation of Bioadhesive Gels for Oral Cancer Chemoprevention

描述（由申请人提供）：尽管共同努力改善治疗，晚期口腔鳞状细胞癌（SCC）患者的5年生存率仍然低得令人沮丧。显然，早期发现与局部干预策略相结合，如在SCC发展之前进行化学预防，可以显著改善临床结果。然而，先前进行的口腔化学预防试验的结果并不是很有希望。值得注意的是，以前的大多数口服化学预防试验都是系统地给药。对于靶向疾病管理，局部给药方法相对于全身给药有几个优点，包括将治疗相关浓度直接递送到病变部位。我们实验室的研究表明，黑树莓在体内和体外都有防癌作用。冻干黑覆盆子（FBR）在动物模型中成功抑制食管癌和颊袋癌。我们的实验室最近表明，用FBR乙醇提取物（RO-ET）处理人口腔SCC细胞可诱导一系列化学预防作用，包括生长抑制、减少促血管生成细胞因子释放和诱导细胞凋亡和分化。对于患有癌前病变的人，口腔上皮发育不良，在他们的余生中，化学预防可能是必要的。因此，鉴别出在病变部位提供最大浓度的配方中无毒、有效的药物，对于改善患者预后是必要的。我们建议，设计用于局部口腔内应用的生物粘合剂凝胶制剂将显著推进口腔上皮发育不良的治疗。基于我们的研究结果，我们假设浆果凝胶会减弱伴随异常生长的途径，如持续增殖和促血管生成分子的高产量，同时也会刺激细胞凋亡和终末分化等生长调节机制。目的1研究需要配方和表征2生物胶浆果凝胶，含有10%的RO-ET作为其活性成分。凝胶制剂将随pH值（3.5或5.5）而变化，以便确定哪种pH值提供更好的口腔黏膜吸收。在Aim 2中，将对口腔黏膜、唾液和外周血样本进行人体药代动力学分析，以确定临床先导制剂，即能够在口腔黏膜中达到最高水平的靶向化合物的凝胶。公共卫生相关性：口腔癌在美国仍然是一个重大问题，即使对那些可以治愈的人来说，必要的手术也会使人虚弱，而且往往会毁容。这些研究将在人类志愿者身上设计和测试含有天然抗癌化合物的生物粘附凝胶，以确定这种凝胶有效地将防癌剂输送到口腔组织的能力。

DESCRIPTION (provided by applicant): 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.