INSOLUBLE ANTINEOPLASTICS. PARTICLES FOR IV INJECTION

NUMEROUS COMPOUNDS WITH KNOWN OR SUSPECTED ANTINEOPLASTIC ACTIVITY HAVE BEEN SYNTHESIZED, WHICH FREQUENTLY ARE TOO INSOLUBLE OR UNSTABLE IN AQUEOUS MEDIA FOR PARENTERAL ADMINISTRATION. SOME OF THESE COMPOUNDS ARE NOT SUFFICIENTLY SOLUBLE EVEN WITH PH ADJUSTMENT OR MINOR SOLVENT REFORMULATIONS, AND REQUIRE A MORE COMPLICATED APPROACH. THE OBJECTIVE OF THIS PROPOSAL IS TO DEMONSTRATE THAT INSOLUBLE ANTINEOPLASTIC COMPOUNDS CAN BE PREPARED IN THE FORM OF STABLE SUSPENSIONS OF PARTICLES OF (A) ONE MICRON DIAMETER, FOR INTRAVENOUS ADMINISTRATION AND DEPOSITION IN THE RETICULOENDOTHELIAL SYSTEM WITH SUBSEQUENT SLOW SOLUBILIZATION AND RELEASE TO MALIGNANT TISSUES (PRIMARILY LIVER METASTASES AND SPLENIC LYMPHOMAS); AND (B) 150-300 MICRON DIAMETER, FOR INTRARTERIAL DELIVERY VIA SELECTIVE CATHETERIZATION OF A TUMOR-FEEDING ARTERY. THESE PARTICLES WOULD PARTIALLY EMBOLIZE THE VESSEL ALLOWING SUBSEQUENT SLOW SOLUBILIZATION AND SELECTIVE DELIVERY OF THE CHEMOTHERAPEUTIC AGENT DIRECTLY TO THE MALIGNANT TISSUE. THE PROPOSED RESEARCH IS AN EXTENSION OF STUDIES WITH RADIOPAQUE MATERIALS BY THE PRINCIPAL INVESTIGATOR FOR TUMOR IMAGING. DURING THE COURSE OF THESE PHS-SUPPORTED INVESTIGATIONS, THE FOLLOWING TECHNICAL DIFFICULTIES WERE RESOLVED: (1) CONTROL OF PARTICLE SIZE DISTRIBUTION; (2) STABILIZATION OF SUSPENSIONS IN VITRO AND IN VIVO; (3) SELECTIVE DELIVERY TO LIVER AND SPLEEN (NOT BONE MARROW) FOLLOWING INTRAVENOUS ADMINISTRATION OF PARTICULATE CONTRAST MATERIAL. THE METHODOLOGY PROPOSED IN THIS PHASE I APPLICATION IS ANALOGOUS TO THE ABOVE-CITED RESEARCH AND COULD, THEREFORE, BE INITIATED IMMEDIATELY. SPECIFIC GOALS OF THIS PROPOSAL ARE: (1) DETERMINATION OF SOLUBILITIES FOR SELECTED COMPOUNDS IN PSS, PLASMA AND SEVERAL ORGANIC SOLVENTS; (2) PREPARATION OF PARTICLES WITH DESIRED SIZE DISTRIBUTIONS: (3) DETERMINATION OF THE TENDENCY FOR PARTICLE AGGREGATION IN BLOOD; (4) EVALUATION OF THE USE OF ALBUMIN IN PREVENTING PARTICLE AGGREGATION. THE PURPOSE OF THIS PHASE I RESEARCH IS TO DEMONSTRATE THAT STABLE SUSPENSIONS OF APPROPRIATELY-SIZED PARTICLES CAN BE FORMULATED WITH ONE OR MORE ANTINEOPLASTIC COMPOUNDS. IMPORTANT QUESTIONS OF EFFICACY AND TOXICITY IN EXPERIMENTAL ANIMALS WILL BE ADDRESSED IN THE SUBSEQUENT PHASE II APPLICATION. THE ATTAINMENT OF THESE GOALS COULD RESULT IN THE THERAPEUTIC UTILIZATION OF INSOLUBLE ANTINEOPLASTIC COMPOUNDS WHICH OTHERWISE MIGHT NOT BECOME AVAILABLE IN THE CLINIC. ALSO, THE POSSIBILITY OF SELECTIVE DELIVERY AND/OR A DEPOT MECHANISM FOR THESE COMPOUNDS WILL BE EVALUATED.