BIOADHESIVE MICROSPHERES FOR COLON CANCER THERAPY

一种新的药物和细胞因子递送系统正在测试其预防和/或抑制自发发生的肠道肿瘤的能力。可生物降解的微球是专门研制的，以实现对肠道上皮的强烈黏附。在负载了舒林酸(一种具有抗肿瘤活性的非类固醇抗炎药物)和/或白介素12(一种强大的免疫刺激细胞因子)后，在小鼠模型(C57BL/6J-Min)中评估了微球将药物或细胞因子输送到肿瘤发生部位并促进抗肿瘤效果的有效性。将生物黏附微球与团注游离药物和/或细胞因子的效果进行比较。该疗法的抗肿瘤效果是：a)在预防环境中，幼鼠在肿瘤发生之前使用舒林酸微球进行治疗，以及b)在小鼠建立肿瘤后，使用舒林酸和/或IL-12微球进行治疗。通过微球将药物局部和持续地输送到肠上皮细胞，有望提高舒林酸的抗肿瘤活性，防止肿瘤生长，而靶向肿瘤环境的IL-12的能力有望抑制肿瘤生长，延长生存期，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理由。拟议的商业应用：在肿瘤部位局部和持续释放细胞毒性药物和生物活性分子，如JL-12，有望增强药物和细胞因子的抗肿瘤活性，并减少其全身给药时对正常组织的毒性影响。受专利保护的微球为细胞因子输送的基因治疗提供了一种简单且便宜得多的替代方案，并且它们可以同时在局部输送药物和细胞因子。这些可生物降解、无毒的微球如果在这里被证明对预防或治疗结肠癌有效，将具有巨大的市场潜力，因为结直肠癌是美国与癌症相关的死亡的第三大常见原因。这种新型递送系统在将这项技术应用于其他肿瘤以及局部和持续递送其他系统注射时有毒的药物方面，预计会有更多的潜在市场。

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.