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.
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.
