BIOADHESIVE MICROSPHERES FOR COLON CANCER THERAPY

用于结肠癌治疗的生物粘附微球

• 批准号: 6630858
• 负责人: NEJAT K EGILMEZ
• 金额: $ 1.56万
• 依托单位: T AND B BIOCLONE, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630858
• 关键词: adhesions; antineoplastics; colon neoplasms; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; interleukin 12; laboratory mouse; microcapsule; neoplasm /cancer therapy

A novel drug and cytokine delivery system is being tested for its ability to prevent and/or suppress spontaneously arising intestinal tumors. Biodegradable microspheres are specifically formulated to achieve a strong adhesion to intestinal epithelium. Following their loading with either sulindac (a nonsteroidal anti-inflammatory drug with antitumor activity) and/or Interleukin-12 (a potent immunostimulatory cytokine) the efficacy of the microspheres to deliver a drug or cytokine to the site of tumor development and to promote an antitumor effect is evaluated in a murine model (C57Bl/6J-Min) in which multiple intestinal tumors arise spontaneously as a result of a mutation in the murine homolog of the human adenomatous polyposis coli (APC) gene. The effectiveness of delivery with bioadhesive microspheres is compared to that obtained with bolus delivery of the free drug and/or cytokine. The antitumor efficacy of the therapy is evaluated a) in a prophylactic setting where young mice are treated with sulindac-loaded microspheres prior to tumor development, and b) at a later stage with sulindac and/or IL-12-loaded microspheres when they have established tumors. Local and sustained delivery of the drug by the microspheres to the intestinal epithelium is expected to improve the antitumor activity of sulindac and to prevent the growth of tumors while the ability to target IL-12 to the tumor milieu is expected to suppress tumor growth, prolong survival and induce antitumor immunity. If successful, these data will provide the requisite rationale for initiating a phase I clinical trial. PROPOSED COMMERCIAL APPLICATIONS: The local and sustained release of cytotoxic drugs and biologically active molecules such as JL-12 at the tumor site is expected to enhance the anti- tumor activity of drugs and cytokines and decrease their toxic effects upon normal tissues that occur when given systemically. The microspheres, that are protected by patents, provide a simple and much less expensive alternative to gene therapy for cytokine delivery and they can locally deliver drugs and cytokines simultaneously. These biodegradable, non-toxic microspheres if proven effective here for either prevention or treatment of colon cancer would have a significant market potential since colorectal cancer is the third most common cause of cancer related deaths in the United States. Additional potential markets are anticipated for this novel delivery system in the application of this technology to other tumors and for the local and sustained delivery of other drugs that are toxic when delivered systemically as bolus injections.

一种新的药物和细胞因子传递系统正在测试其预防和/或抑制自发产生的肠道肿瘤的能力。生物可降解微球是专门配制的，以实现对肠上皮的强粘附。在服用舒林酸后（一种具有抗肿瘤活性的非甾体抗炎药）和/或白细胞介素-12（一种有效的免疫刺激细胞因子）在鼠模型中评价微球将药物或细胞因子递送至肿瘤发展部位和促进抗肿瘤作用的功效（C57 B1/6 J-Min），其中由于人腺瘤性结肠息肉病（APC）基因的鼠同源物中的突变而自发产生多个肠肿瘤。将用生物粘附性微球递送的有效性与用游离药物和/或细胞因子的推注递送获得的有效性进行比较。评估该疗法的抗肿瘤功效a）在预防性环境中，其中在肿瘤发展之前用舒林酸加载的微球治疗年幼小鼠，和B）在后期阶段，当它们已经建立肿瘤时，用舒林酸和/或IL-12加载的微球治疗。通过微球将药物局部和持续递送至肠上皮预期改善舒林酸的抗肿瘤活性并防止肿瘤生长，而将IL-12靶向至肿瘤环境的能力预期抑制肿瘤生长、延长存活并诱导抗肿瘤免疫。 如果成功，这些数据将为启动I期临床试验提供必要的依据。拟议的商业应用：细胞毒性药物和生物活性分子如JL-12在肿瘤部位的局部和持续释放预期增强药物和细胞因子的抗肿瘤活性并降低它们在全身给予时对正常组织发生的毒性作用。受专利保护的微球为细胞因子递送的基因治疗提供了一种简单且便宜得多的替代方案，并且它们可以同时局部递送药物和细胞因子。这些可生物降解的无毒微球如果在此被证明对预防或治疗结肠癌有效，将具有显著的市场潜力，因为结肠直肠癌是美国癌症相关死亡的第三大常见原因。在将该技术应用于其他肿瘤以及用于局部和持续递送其他药物（当作为团注全身递送时是有毒的）方面，预期这种新型递送系统具有额外的潜在市场。