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MICROSPHERE-BASED FORMULATION OF DOLCANATIDE TO PREVENT COLON CARCINOGENESIS - ABSTRACT COLORECTAL CANCER (CRC) RANKS THIRD AMONG NEWLY DIAGNOSED CANCERS IN THE UNITED STATES, AND IT IS THE SECOND MOST COMMON CAUSE OF CANCER MORTALITY. INDIVIDUALS WITH INFLAMMATORY BOWEL DISEASE (IBD) ARE AT SEVERAL FOLD HIGH-RISK OF DEVELOPING CRC. GUANYLYL CYCLASE-C (GC-C) IS ACTIVATED UPON BINDING OF GUANYLIN (GN) OR UROGUANYLIN (UG), RESULTING IN STIMULATION IN CYCLIC GMP (CGMP) PRODUCTION LEADING TO FLUID SECRETION IN PROXIMAL INTESTINE TO NORMALIZE BOWEL MOVEMENT. TWO ORALLY ADMINISTERED GC-C AGONISTS TRULANCE® AND LINZESS® ARE APPROVED FOR TREATMENT OF CHRONIC IDIOPATHIC CONSTIPATION (CIC) AND IRRITABLE BOWEL SYNDROME-CONSTIPATION (IBS-C). BEYOND FLUID SECRETION IN PROXIMAL INTESTINE, ACTIVATION OF GC-C SIGNALING BY UG OR GN ALSO REGULATES COLONIC EPITHELIAL HOMEOSTASIS AND TUMOR SUSCEPTIBILITY. PIONEERING RESULTS FROM PI'S LAB SHOWED THAT TRANSCRIPT LEVELS OF BOTH UG AND GN ARE REDUCED DRAMATICALLY IN HUMAN COLON POLYPS AND ADENOCARCINOMAS, AND THAT THE DIETARY SUPPLEMENTATION WITH HUMAN UG NOT ONLY INHIBITED POLYP FORMATION BUT ALSO DELAYED THEIR PROGRESSION TO ADENOCARCINOMAS IN APC+/MIN MICE. SUBSEQUENTLY, SEVERAL OTHER RESEARCHERS HAVE SHOWN THAT DISRUPTION IN GC-C SIGNALING, DUE TO NEAR UNIVERSAL LOSS OF GN AND UG, DISRUPTS THE INTESTINAL EPITHELIAL CELL HOMEOSTASIS IN EARLY STAGES OF CRC. THUS, ORAL TREATMENT WITH GC-C AGONIST TO OVERCOME THIS DEFICIENCY MAY REPRESENT A PROMISING NOVEL APPROACH FOR TREATMENT AND/OR PREVENTION OF ALL TYPES OF CRC. IN THIS CONTEXT, ORALLY ADMINISTERED PLECANATIDE OR DOLCANATIDE (DOL), ANALOGUES OF UG, EFFECTIVELY AMELIORATED GI INFLAMMATION IN ACUTE AND CHRONIC MODELS OF EXPERIMENTAL COLITIS IN MICE. IN ADDITION, DIETARY SUPPLEMENTATION WITH PLECANATIDE SUPPRESSED GENERATION OF COLONIC TUMORS IN MICE. HOWEVER, IT WAS OBSERVED THAT ORALLY ADMINISTERED GC-C AGONIST SHOWED INVERTED U (BELL SHAPED) THERAPEUTIC RESPONSES IN THESE ANIMAL STUDIES. THESE RESULTS RAISED THE POSSIBILITY THAT THE HIGHER DOSES MIGHT LEAD TO EXCESSIVE FLUID SECRETION IN THE PROXIMAL INTESTINE, WHICH MIGHT WASH OUT THE DRUG PRIOR TO REACHING COLON, AND THEREBY, RESULTING IN THE REDUCED THERAPEUTIC EFFECT. IN ADDITION, GC-C SIGNALING IS ALSO DISRUPTED BY OVEREXPRESSION OF CGMP-PHOSPHODIESTERASE 5 (PDE5) IN GI INFLAMMATORY DISEASES AND CRC. THUS, COMBINATION OF A GC-C AGONIST WITH A PDE5 INHIBITOR (SILDENAFIL; SIL) MIGHT PRODUCE ADDITIVE OR SYNERGISTIC EFFECT. PI DEVELOPED AN ORAL FORMULATION OF DRUG-LOADED MICROPARTICLES THAT WERE SEQUENTIALLY COATED WITH TIME- AND PH-DEPENDENT POLYMERS TO BYPASS STOMACH AND PROXIMAL INTESTINE REGIONS, AND TO RELEASE DRUG IN DISTAL INTESTINE AND COLON. THIS SBIR PHASE 1 GRANT PROPOSAL IS TO EVALUATE MICROSPHERES-LOADED FORMULATION OF DOL EITHER ALONE OR IN COMBINATION WITH SIL TO PREVENT COLITIS ASSOCIATED CRC IN MICE. SPECIFIC AIMS ARE: AIM 1, TO DEVELOP AND OPTIMIZE DRUG-LOADED MICROSPHERES FORMULATIONS OF PLACEBO (INACTIVE PEPTIDE SP-300), DOL AND SIL. IN SPECIFIC AIM 2, THE OPTIMIZED FORMULATIONS OF DOL AND SIL, EITHER ALONE OR IN COMBINATION, WILL BE EVALUATED TO PREVENT AOM-DSS INDUCED CRC IN B6 MICE. COLON TISSUE (PROXIMAL, MIDDLE AND DISTAL SEGMENTS) WILL BE COLLECTED FOR EVALUATION FOR STIMULATION GC-C AND PDE5 SIGNALING. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES IS EXPECTED TO IDENTIFY A SUITABLE MICROSPHERE-LOADED FORMULATION OF DOL EITHER ALONE OR IN COMBINATION WITH SIL FOR FURTHER NON-CLINICAL AND CLINICAL DEVELOPMENT TO PREVENT CRC IN HUMANS.
$308.7k 6/12/24