HEAT-ACTIVATED MICROPARTICLE DRUG DELIVERY SYSTEMS

THE OVERALL OBJECTIVE OF THE PROJECT IS TO DEVELOP HEAT-ACTIVATED MICROPARTICLE DRUG DELIVERY SYSTEMS FOR DELIVERY OF CHEMOTHERAPEUTIC AGENTS THAT COULD BE USED IN CONJUNCTION WITH THERAPEUTIC HYPERTHERMIA OR HYPERTHERMIA PLUS RADIATION. DURING PHASE I, MICROPARTICLES WILL BE PREPARED FROM RIBOFLAVIN AND TRIGLYCERIDE ESTERS OF HIGHER FATTY ACIDS THAT MELT AT 40 DEGREES CENTIGRADE TO 45 DEGREESCENTIGRADE. RIBOFLAVIN WAS SELECTED AS A MODEL COMPOUND BECAUSE IT IS SIGNIFICANTLY LESS COSTLY THAN ANTITUMOR AGENTS. MICROSPHERES WILL BE PREPARED BY A SOLVENT EVAPORATION PROCESS THAT PRODUCES A MONOLITHIC DRUG POLYMER MATRIX. A NEW MICROFLUIDIZED BED PROCESS DEVELOPED BY BIOTEK, INC., WILL BE USED TO PRODUCE TRUE WALL/RESERVOIR MICROCAPSULES IN WHICH THE DRUG IS COMPLETELY SURROUNDED BY A TRIGLYCERIDE ESTER WALL MATERIAL. PRELIMINARY STUDIES INDICATE THAT MICROPARTICLES CAN BE EFFECTIVELY COATED WITH TRIGLYCERIDE ESTERS. THE MICROPARTICLES WILL BE EVALUATED FOR IN VITRO RELEASE OF THE DRUG AT INCREMENTAL TEMPERATURES FROM 37 DEGREES CENTIGRADE TO 45 DEGREES CENTIGRADE. IN ADDITION, THEY WILL BE CHARACTERIZED AS TO DRUG CONTENT, SIZE DISTRIBUTION,AND SURFACE MORPHOLOGY. THE MOST PROMISING FORMULATION WILLBE EVALUATED IN VIVO IN MICE. THE PHASE I STUDIES WILL PROVIDE THE BASIS FOR FURTHER DEVELOPMENT OF THE PROCESS IN PHASE II AND THE MICROENCAPSULATION OF CHEMOTHERAPEUTIC AGENTS THAT WOULD BENEFIT FROM ACTIVATION BY THERAPEUTIC HYPERTHERMIA.