Project Grant R15CA271365

PHARMACEUTICAL NANOFACTORIES: INTRACELLULAR SYNTHESIS OF BIOACTIVE DRUG MOLECULES - PROJECT SUMMARY: SINCE THE DISCOVERY OF ANTICANCER AND CHEMOTHERAPEUTIC PHARMACEUTICALS, SOCIETY HAS BEEN CHALLENGED BY DETRIMENTAL AND LIFE ALTERING SIDE EFFECTS, DRUG RESISTANCE VIA CELLULAR MUTATIONS, AND DISTRIBUTED NON- METABOLIZED PHARMACEUTICALS BACK INTO THE ENVIRONMENT, WHICH HAS LONG-TERM EFFECTS ON WILDLIFE AND WATER SUPPLIES. THE SYNTHETIC CONTROL MY TEAM HAS ON THE PORE ENVIRONMENT OF MESOPOROUS SILICA NANOPARTICLES (MSN) OFFERS A UNIQUE PERSPECTIVE OF DELIVERING ACTIVE, HETEROGENOUS CATALYTIC SPECIES TO CELLS. USING THE VAST KNOWLEDGE BASE ALREADY KNOWN ON INTERNALIZING MSN VIA ENDOCYTOSIS FOR DRUG DELIVERY, WE WILL DESIGN BIOCOMPATIBLE POROUS NANOMATERIALS THAT WILL ENTER CELLS WITH INORGANIC AND BIOLOGICAL CATALYSTS ENTRAPPED INSIDE THE PORES. PROTECTED MOLECULES THAT ARE NOT BIOLOGICALLY ACTIVE WILL BECOME ACTIVATED ONCE THEY ENCOUNTER THE CATALYTIC ACTIVE SITES. THE CONFINED SPACE OFFERED BY THE MESOPORES WILL PROTECT THE CATALYTIC SPECIES (TETHERED MOLECULAR CATALYSTS AND EXOGENOUS ENZYMES) FROM THE REDUCTIVE ENVIRONMENT OF THE CELLS. WE CAN SELECTIVELY FUNCTIONALIZE THE EXTERNAL AND INTERNAL PORE ENVIRONMENTS, ALLOWING US TO CONTROL THE INTERNALIZATION AND STABILIZATION INTRACELLULARLY ALONG WITH CATALYTIC PROPERTIES. CURRENT TECHNOLOGY TO DELIVER BIOLOGICALLY ACTIVE MOLECULES CONTAINS NUMEROUS DISADVANTAGES THE SITE-SPECIFIC SYNTHESIS COULD ELIMINATE. THE SCIENTIFIC INNOVATION INCLUDES A SYSTEMATIC INVESTIGATION OF NOVEL POROUS, BIOMATERIALS ENTRAPPING METAL CATALYSTS AND ENZYMES TO INVESTIGATE THE SYNTHESIS AND ACTIVATION OF PRODRUG AND PROFLUOROPHORE MOLECULES INTRACELLULARLY. THE HYPOTHESIS IS THAT IF CATALYSTS CAN BE SUPPORTED AND PROTECTED IN THE PORE STRUCTURE OF MSN AND THE NANOMATERIAL WILL BE INTERNALIZED BY CELLS, THEN BIOORTHOGONAL CHEMICAL REACTIONS CAN BE CONDUCTED INTRACELLULARLY TO PRODUCE BIOLOGICALLY ACTIVE MOLECULES ON SITE ELIMINATING THE NEED FOR DELIVERY OF DRUG MOLECULES THAT HAVE DETRIMENTAL SIDE EFFECTS AND LEAD TO RESISTANCE. THE TEACHING INNOVATION OF THIS PROJECT IS IN THE COOPERATIVE AND TEAM-ORIENTED RESEARCH ACTIVITIES INVOLVING PARTICIPANTS FROM HIGH SCHOOL THROUGH THE PI. STUDENTS WILL RECEIVE HANDS-ON TRAINING ON NUMEROUS STATE-OF-THE-ART INSTRUMENTATIONS ALONG WITH CHEMICAL SYNTHESES, CHARACTERIZATION, AND BIOCHEMICAL TECHNIQUES. THIS RESEARCH WILL ALSO BE USED TO GUIDE WEEKLY UNDERGRADUATE BIOCHEMISTRY LABORATORY EXPERIMENTS, FOCUSED ON IMPORTANT INTERACTIONS BETWEEN BIOMOLECULES AND INORGANIC SUBSTRATES FOR ENZYME STABILIZATION AND AS PART OF THE CURRICULUM IN LECTURE COURSES. THE IMPACT TO STUDENTS IS FIRST-HAND EXPERIENCE IN WORKING COOPERATIVELY AND ESSENTIAL SKILLS THAT GO INTO SCIENTIFIC RESEARCH AND UNDERSTANDING, SUCH AS THE IMPORTANCE OF PROPER CONTROLS, STATISTICAL ANALYSIS, AND COMMUNICATION SKILLS THAT ARE REQUIRED IN SCIENCE AND ENGINEERING.