The potent anticancer agent NSC 278214 carbamic acid, (1-methylethyl)-, (5-(3,4-dichlorophenyl)-2,3-dihydro-lH-pyrrolizine-6,7-diyl) bis (methylene) ester is selected as a model compound for study to develop a novel drug formulation and delivery system. This compound, which exhibits both poor water solubility and severe stability problems, cannot be formulated by classical solubilizing techniques. Tegeris Laboratories proposes to combine both prodrug modification and suitable formulation vehicles to solve the solubility and stability problems. The principal investigator has synthesized many water soluble prodrugs of NSC 278214. These prodrugs increase the solubility dramatically to 104-fold, but they lack the stablity in aqueous media. In Phase I, four lipophilic ester prodrugs of NSC 278214 will be synthesized to enhance the stability. Both water soluble and more stable prodrugs will be incorporated into suitable formulations such as emulsion, microencapsulation and liposomes to achieve the intravenous delivery. We propose to develop the work as a series of five tasks: 1. Study the physical and chemical properties of anticancer agents, 2. Synthesize the prodrug to enhance the water solubility and/or stability, 3. Incorporate the prodrug into suitable formulation and delivery system, 4. Develop analytical procedures to assess the stability of test dosage form, and 5. Evaluate the suitability and toxicity of the formulation.National Cancer Institute (NCI)
