Project Grant R21CA286235

TARGETED NANOTHERAPIES FOR THE TREATMENT OF PROSTATE CANCER - PROJECT SUMMARY THE PROPOSED PROJECT ADDRESSES THE CRITICAL NEED FOR THE TREATMENT OF ADVANCED PROSTATE CANCER (PCA), A SECOND LEADING CAUSE OF CANCER-RELATED DEATHS AMONG MEN IN THE UNITED STATES. PROSTATE-SPECIFIC MEMBRANE ANTIGEN (PSMA) IS HIGHLY EXPRESSED ON PCA CELLS. TARGETING PSMA IS USED CLINICALLY FOR IMAGING AND RADIO-LIGAND THERAPY. DESPITE ADVANCES IN CANCER CARE, TREATMENT OPTIONS FOR ADVANCED PCA PATIENTS REMAIN LIMITED DUE TO CHALLENGES ASSOCIATED WITH EFFECTIVE AND SELECTIVE DRUG DELIVERY TO PCA CELLS. COMBINING PSMA TARGETING WITH NANOTECHNOLOGY-BASED APPROACH, WE PROPOSE TO DEVELOP NOVEL SYSTEMIC PSMA-TARGETED GLYCODENDRIMER NANOPLATFORMS (TGDNS) CAPABLE OF SELECTIVE INTRACELLULAR DELIVERY OF HIGH PAYLOADS OF POTENT CHEMOTHERAPEUTICS TO TUMOR CELLS, ALSO ENABLING COMBINATION THERAPIES THROUGH MULTIFUNCTIONAL SURFACE OF DENDRIMERS. OUR PRIOR RESEARCH ON HYDROXYL DENDRIMERS SHOWED THE POTENTIAL OF TARGETED INTRACELLULAR DELIVERY, WITH EARLY CLINICAL PROMISE. THIS NEW TGDN TECHNOLOGY IS DESIGNED TO SIMULTANEOUSLY ACHIEVE SELECTIVE TARGETING OF HIGH PAYLOADS TO PCA CELLS WITH REDUCED SIDE-EFFECTS, LOW IMMUNOGENICITY, IN VIVO STABILITY, WATER SOLUBILITY, EASE OF SCALABILITY, AND FLEXIBILITY IN SINGLE OR MULTIPLE DRUGS DELIVERY. WE WILL USE CABOZANTINIB (CAB), A MULTI TYROSINE KINASE INHIBITOR AS A PROOF OF CONCEPT. CAB IS APPROVED FOR RENAL CELL CARCINOMA AND HEPATOCELLULAR CARCINOMA IN USA AND EUROPE, BUT ITS PCA CLINICAL TRIAL WAS TERMINATED DUE TO ITS NEGATIVE SIDE EFFECTS AT A TOLERATED DOSE. TGDN-BASED TARGETED DELIVERY OF CAB SELECTIVELY TO PCA CELLS CAN BE HIGHLY BENEFICIAL TO ENHANCE ITS EFFICACY AND REDUCE OFF-TARGET TOXICITY. WE WILL ACHIEVE OUR GOALS THROUGH THE FOLLOWING AIMS. 1) WE WILL SYNTHESIZE TGDNS WITH VARIABLE PSMA LIGAND LOADING AND DETERMINE THEIR IN VITRO CANCER TARGETING IN PCA PATIENT-DERIVED XENOGRAFT (PDX) PRIMARY CULTURES, ORGANOIDS AND PSMA+ PCA CELLS. 2) WE WILL SYNTHESIZE PSMA TARGETED TGDN-CAB CONJUGATE; INVESTIGATE THE MAXIMUM TOLERABLE DOSE IN HEALTHY MICE, IN VIVO EFFICACY IN PCA PDX ANIMAL MODEL; AND EVALUATE POTENTIAL OFF-TARGET CYTOTOXICITY. OUR LONG-TERM OBJECTIVE IS TO DEVELOP SCALABLE, SYSTEMIC DENDRIMER-DRUGS CHEMOTHERAPIES WITH IMPROVED EFFICACY AND REDUCED SYSTEMIC SIDE-EFFECTS THAT CAN BE USED NOT ONLY FOR PCA BUT OTHER CANCERS AS WELL. OUR TEAM HAS A SIGNIFICANT EXPERIENCE IN SYNTHESIS, IN VIVO STUDIES, AND CLINICAL TRANSLATION OF DENDRIMER NANOMEDICINES. IF SUCCESSFUL, OUR TECHNOLOGY SHALL FILL IN THE LONG-STANDING TECHNOLOGY GAP FOR THE TREATMENT OF PCA AND PROVIDE AN URGENTLY NEEDED EFFICIENT, ECONOMIC, AND SAFE DRUG DELIVERY FOR CLINICAL TRANSLATION.