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/或抑制自发产生的肠道肿瘤的能力。可生物降解的微球是专门配制的，以实现肠上皮的强粘附。在用舒林酸（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）加载微球后，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作用的功效。在小鼠模型中，由于人类腺瘤性大肠息肉病（APC）的小鼠同源基因突变而自发产生多种肠道肿瘤。基因。将生物黏附微球的递送效果与游离药物和/或细胞因子的大剂量递送效果进行比较。该疗法的抗肿瘤功效被评估为：a)在预防环境中，年轻小鼠在肿瘤形成之前使用含有舒林达克的微球治疗；b)在肿瘤形成后使用含有舒林达克和/或il -12的微球治疗。通过微球将药物局部持续递送至肠上皮有望提高舒林达的抗肿瘤活性并阻止肿瘤生长，同时靶向IL-12到肿瘤环境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依据。建议的商业应用：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有望增强药物和细胞因子的抗肿瘤活性，并减少它们在全身给药时对正常组织的毒性作用。受专利保护的微球为细胞因子的传递提供了一种简单而便宜得多的替代基因疗法，它们可以同时在局部传递药物和细胞因子。这些可生物降解的无毒微球如果在预防或治疗结肠癌方面被证明是有效的，将具有巨大的市场潜力，因为结直肠癌是美国癌症相关死亡的第三大常见原因。预计这种新型给药系统将有更多的潜在市场，包括将该技术应用于其他肿瘤，以及局部和持续给药其他药物，这些药物在全身注射时是有毒的。

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.