SMART PHOTODYNAMIC THERAPY FOR ACNE BY REVERSIBLY SWITCHABLE INTERSYSTEM CROSSING IN PURE ORGANIC MATERIALS - ABSTRACT - ACNE VULGARIS IS THE MOST COMMON SKIN CONDITION IN THE UNITED STATES, AFFECTING UP TO 50 MILLION AMERICANS ANNUALLY. WHILE ACNE IS COMMON IN YOUNG PEOPLE, THIS CONDITION BECOMES INCREASINGLY WIDESPREAD IN ADULTS, ESPECIALLY IN FEMALES- CHRONIC POST-ADOLESCENT ACNE AFFECTS ABOUT 15 PERCENT OF WOMEN IN THE USA. MODERATE TO SEVERE ACNE CONFERS A TREMENDOUS MEDICAL, PSYCHOLOGICAL, AND ECONOMIC HEALTH CARE BURDEN ON THE US POPULATION. THE DEVELOPMENT OF ACNE IS MULTIFACTORIAL, BUT CENTERS AROUND THE SEBACEOUS GLANDS (SG), WHICH ARE THE MICROSCOPIC HOLOCRINE GLANDS WITHIN THE SKIN DERMIS. SGS COMPRISE SPECIALIZED CELLS-SEBOCYTES-THAT SECRETE A VARIETY OF LIPIDS COMPOSING THE SEBUM. CONVENTIONAL CLINICAL TREATMENT OF SEVERE INFLAMMATORY ACNE INVOLVES A COMBINATION OF TOPICAL AND SYSTEMIC DRUGS, ADMINISTERED OVER THE COURSE OF SEVERAL MONTHS OR EVEN YEARS. THESE INCLUDE TOPICAL AND ORAL RETINOIDS, ANTIBIOTICS, AND IN SOME INSTANCES, HORMONAL THERAPY. TREATMENT IS OFTEN INEFFECTIVE AND CARRIES THE RISK OF ADVERSE SIDE EFFECTS. REMARKABLY, PHOTODYNAMIC THERAPY (PDT) HAS SHOWN BREAKTHROUGH POTENTIAL FOR DERMATOLOGY. PDT INVOLVES TOPICAL APPLICATION OF AGENTS CALLED PHOTOSENSITIZERS (PS) TO THE AFFECTED SKIN AREA. WHEN EXPOSED TO SPECIFIC WAVELENGTHS OF LIGHT, THESE AGENTS GENERATE HIGHLY CYTOTOXIC SINGLET OXYGEN (1O2 ) THAT DAMAGES SEBOCYTES, REDUCING BOTH THE SIZE AND ACTIVITY OF SGS, AND LOCALLY ELIMINATES BACTERIAL INFECTIONS. HOWEVER, USE OF CONVENTIONAL PDT INCLUDES A SIGNIFICANT RISK OF SKIN DAMAGE AS THE 1O2 INHERENTLY DAMAGES FIBROBLASTS, EPITHELIUM, AND OTHER SKIN COMPONENTS OUTSIDE THE SG IN THE ENTIRE IRRADIATED SKIN AREA. THE UNINTENDED PHOTODAMAGE HAS AN ADVERSE EFFECT ON SKIN STRUCTURE AND FUNCTION AND CAN POTENTIALLY LEAD TO CANCER. THUS, THE UTILITY OF CONVENTIONAL PDT IS LIMITED BECAUSE OF THESE SIGNIFICANT SIDE EFFECTS. TO ADDRESS THIS LIMITATION, ACIS IS DEVELOPING A SMART PDT (S-PDT) PLATFORM WILL ENABLE TARGETED AND TUNABLE TREATMENT TO CELLS OF THE SGS, WHILE SPARING OTHER CELL TYPES. AS PART OF THIS, ACIS IS DEVELOPING A NEXT GENERATION PS AGENT THAT IS DESIGNED TO BE ACTIVE SELECTIVELY IN THE SEBUM PRODUCING CELLS OF SGS AND BACTERIA-INFECTED SITES, WHILE CAUSING NO DAMAGE TO THE SURROUNDING HEALTHY TISSUE. THIS APPROACH ALLEVIATES THE COMMON PHOTODYNAMIC THERAPY LIMITATIONS VIA REVERSIBLE ON/OFF SWITCHING OF INTERSYSTEM CROSSING IN SMALL ORGANIC MOLECULES, THEREBY BOOSTING (IN "ON" MODE) OR SUPPRESSING (IN "OFF" MODE) SINGLET OXYGEN PRODUCTION. THE SPECIFIC AIMS OF THIS PHASE I PROJECT ARE AS FOLLOWS : 1) DESIGN AND SYNTHESIZE A REVERSIBLY SWITCHABLE PH-SENSITIVE PS WITH TUNABLE ISOELECTRIC POINT AND TUNABLE ABSORPTION MAXIMUM TO PENETRATE THE SKIN AT THE OPTIMAL DEPTH; AND 2) DEMONSTRATE THE VIABILITY OF THE S-PDT APPROACH VIA IN VITRO AND EX VIVO TESTS, INCLUDING CELLULAR UPTAKE, CYTOTOXICITY, AND PDT ACTION OF NEWLY SYNTHESIZED MATERIALS IN HUMAN SKIN MODELS. SUCCESSFUL COMPLETIONS OF THESE AIMS WILL DEMONSTRATE THE VIABILITY OF THE S-PDT PLATFORM AND SUPPORT FURTHER DEVELOPMENT IN PHASE II.