Project Grant F31CA298728

DISULFATED POLYAMIDOSACCHARIDE NANOPARTICLES AS A P-SELECTIN TARGETING CHEMOTHERAPEUTIC DELIVERY SYSTEM - ABSTRACT CANCER IS ONE OF THE LEADING CAUSES OF DEATH WORLDWIDE, WITH METASTASIS BEING A PRIME CULPRIT. CANCERS OF THE BREAST AND LUNG ARE THE TWO MOST COMMON CANCERS TODAY, AND MOST FATAL CANCERS FOR WOMEN. NON-SMALL CELL LUNG CANCER (NSCLC) DIAGNOSES HAVE RISEN 84% FOR WOMEN OVER THE PAST 42 YEARS WHILE DROPPING 36% FOR MEN; 20% OF THESE FEMALE PATIENTS ARE LIFELONG NON-SMOKERS. THE INCREASE IN NON-SMOKER LUNG CANCER IS DUE IN LARGE PART TO GENETIC MUTATIONS SUCH AS ROS1 AND AKL FUSIONS AND EGFR MUTATIONS, ALL OF WHICH ARE SIGNIFICANTLY MORE PREVALENT IN WOMEN. THESE MUTATIONS ARE ALSO MORE PREVALENT IN LATE-STAGE NSCLC AND AFFECT PATIENT RESPONSE TO TREATMENTS, WHICH CAN RESULT IN A LONGER OPPORTUNITY FOR THE CANCER TO METASTASIZE. GENETIC MUTATIONS HAVE ALSO BEEN SHOWN TO LEAD TO UNCOMMON SITES OF METASTASIS, WHICH SUGGESTS ALTERNATIVE MECHANISMS OF DISSEMINATION. P-SELECTIN (CD62P) IS A PROTEIN UPREGULATED ON MANY TYPES OF TUMOR CELLS, INCLUDING BREAST AND LUNG, AND PLAYS A CRUCIAL ROLE IN THE DISSEMINATION OF THOSE CELLS AROUND THE BODY DUE TO ITS FUNCTION MEDIATING THE ROLLING OF CELLS AND FACILITATING ADHESION OF BLOOD CELLS TO THE ENDOTHELIUM OF OTHER ORGANS. IN HEALTHY CELLS THE EXPRESSION LEVEL OF CD62P IS CONSTITUTIVELY LOW, WHILE IN TUMOR MICROENVIRONMENTS SUCH AS KIDNEY, LUNG, AND BREAST CANCERS, THE PROTEIN IS HIGHLY EXPRESSED AND CAN BE FURTHER INDUCED VIA RADIATION TREATMENT, WHICH IS ABSCOPAL. FUCOIDAN EXHIBITS NANOMOLAR AFFINITY FOR CD62P, AND IT IS ACTIVELY INVESTIGATED AS A TARGETING MOIETY FOR DRUG DELIVERY PLATFORMS. UNFORTUNATELY, GIVEN THAT FUCOIDAN IS ISOLATED FROM THE CELL-WALL MATRIX OF SEAWEED, THERE IS HIGH DISPERSITY AND STRUCTURAL IRREGULARITY WITHIN BATCHES, ALONG WITH LARGE BATCH-TO- BATCH VARIABILITY BASED ON THE ENVIRONMENTAL CONDITIONS THE FUCOIDAN IS ISOLATED FROM. THUS, THERE ARE CHANGES IN SULFATION AND METHYLATION OF THE MONOSACCHARIDE UNITS, LEADING TO INCONSISTENT BINDING AFFINITY FOR CD62P. I PROPOSE THAT A 3,6-DISULFATED POLYAMIDOSACCHARIDE (DISULPAS) WILL SERVE AS A MUCH-NEEDED SYNTHETIC FUCOIDAN MIMETIC, RETAINING THE BIOCOMPATIBILITY OF NATURAL POLYSACCHARIDES BUT WITH A TUNABLE SULFATION DENSITY, MOLECULAR WEIGHT, AND NARROW DISPERSITY. FURTHER, BINDING STUDIES ON A LIBRARY OF DISULPAS VARYING IN MOLECULAR WEIGHT AND SULFATION DENSITY WILL GIVE INSIGHT INTO THE METASTASIS MECHANISMS OF GENETICALLY MUTATED NSCLC CELLS, AND NANOPARTICLES MADE FROM AMPHIPHILIC DISULPAS AND LOADED WITH PACLITAXEL WILL ACTIVELY TARGET METASTASIZING CANCER CELLS. IN THIS WORK I PROPOSE THAT DISULPAS WILL SERVE AS A SYNTHETIC FUCOIDAN MIMETIC, THE DISULPAS SYNTHESIS CAN BE OPTIMIZED IN MOLECULAR WEIGHT AND SULFATION DENSITY TO CREATE DISULPAS NANOPARTICLES FOR THE CD62P TARGETED DELIVERY OF CHEMOTHERAPEUTICS TO METASTASIZING CANCER CELLS, AND OPTIMAL DISULPAS FORMULATIONS MAY VARY BASED ON THE GENETIC MUTATIONS PRESENT IN THE CANCER, GIVING INSIGHT INTO THE MECHANISM OF METASTASIS IN MUTATION-BASED NSCLC.