Combined Chemoprevention Using a Nanotechnology-based Therapeutic System

描述(由申请人提供)： 结直肠癌(CRC)是美国第二大癌症死亡原因，每年报告的死亡人数超过56,000人。虽然手术和化疗一直是主要的疾病干预方法，但随着有证据表明化学预防药物能够预防结直肠癌，化学预防已成为诊断和治疗的替代方案。在使用临床前和临床模型进行测试的药物中，阿司匹林、钙和叶酸受到了极大的关注。当单独使用时，所有这些药物都显示出减少CRC的效果。然而，一些研究报告了严重的副作用，特别是阿司匹林，包括与高剂量化学预防相关的胃肠道出血和血小板功能障碍。人们对联合治疗的兴趣越来越大，因为其他有希望的化学预防药物已经显示出协同疗效和最小的毒性。联合疗法的研究仍处于初级阶段；因此，有必要在这一领域做出更多努力。选择适当的药物输送系统对于确保药物到达其预定的作用部位也很重要。使用靶向系统将化学预防药物的组合直接输送到局部结肠环境中，将导致较低剂量和较小的毒性影响机会，同时保持疗效。使用这种载体系统的潜在好处是显而易见的，但其在化学预防中的应用从未被研究过，这表明需要在这一领域进行研究。因此，这项初步研究的总体目标是开发一种有效的新型化学预防药物组合，使用独特的基于纳米技术的结肠靶向递送系统来预防结直肠癌。我们应用的具体目标是：(1)设计并制备一种新型基于纳米技术的药物输送系统，能够将预定组合的阿司匹林、钙和叶酸直接包裹并输送到结肠；(2)从药物靶向、结肠壁的生物黏附和药物释放方面评价制备的纳米制剂；(3)使用动物模型评估阿司匹林、钙和叶酸联合使用对结直肠癌的协同化学预防作用，同时将毒副作用降至最低。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most common cause of cancer death in the United States with more than 56,000 deaths reported each year. While surgery and chemotherapy have been the major disease intervention methods, chemoprevention has emerged as an alternative to diagnosis and treatment, as evidence of the ability of chemopreventive agents to prevent CRC becomes available. Among agents being tested using preclinical and clinical models, aspirin, calcium and folic acid have received significant attention. All of these agents have shown effects in reducing CRC, when used individually. However, several studies have reported severe side effects, especially for aspirin, including gastrointestinal bleeding and platelet dysfunction associated with high doses needed for chemoprevention. The interest in combination therapy has been increasing, as other promising chemopreventive agents have shown synergistic efficacy with minimized toxicity. Research in combination therapy is still in its infancy; hence more efforts in this area are warranted. The selection of an appropriate drug delivery system is also of importance to ensure that drug reaches its intended site of action. Delivering combinations of chemopreventive agents using a targeted system directly into the local colonic environment would result in lower doses with lesser chances of toxic effects, while maintaining efficacy. The potential benefits of using such carrier systems is apparent, however its application in chemoprevention has never been studied, demonstrating a need for research in this area. Thus, the overall goal of this pilot study is to develop an effective novel combination of chemopreventive agents delivered using a unique nanotechnology- based colon-targeting delivery system to prevent CRC. The specific aims of our application are : (1) to design and prepare a novel nanotechnology-based drug delivery system capable of encapsulating and delivering predetermined combinations of aspirin, calcium and folic acid directly into the colon; (2) to evaluate the prepared nanoparticle formulations in terms of drug targeting to the colon, bioadhesion to the colonic wall and drug release; (3) to assess the synergistic chemopreventive effects of a combination of aspirin, calcium and folic acid against CRC while minimizing toxic side effects, using an animal model.