Medical Device to Enhance Colorectal Cancer Screening via More Efficient Applicat

DESCRIPTION (provided by applicant): Following systemic administration, most anticancer drugs exhibit very limited uptake into the brain. The blood- brain barrier (BBB) is the single most important factor for restricting drug delivery to the brain. The BBB is formed by a continuous monolayer of cerebrovascular endothelial cells joined together by tight junctions and lacks fenestrations. To cross the BBB, solutes must diffuse across the lipid endothelial cell membrane or be carried across either by receptor-mediated transport or by membrane transport. The capillary endothelial cells of the BBB express an array of uptake and efflux transporters. Regulated expression and function of these transporters govern access of essential nutrients and therapeutic drugsto the central nervous system (CNS). Successful drug delivery to brain tumors includes not only penetration of the BBB, but also delivery to and uptake into tumor cells. The Large Amino Acid Transporter 1 (LAT1) fulfills all necessary requirements - expression at both sides of the BBB, high expression in almost all tumor cells regardless of the tissue of origin, and very low endogenous expression in non-proliferative cells. Furthermore, it is characterized by an appreciable capacity, which can be exploitedto deliver therapeutically meaningful amounts of chemotherapeutic agents. LAT1 activity correlates with cell proliferation, tumor growth, and is inversely related to disease prognosis and patient survival. Quadriga BioSciences will use NIH/NCI funding to engineer novel anti-cancer agents by combining the properties of cytotoxic agents with LAT1-mediated delivery to cancerous cells. The aims of Phase 1 of the proposed SBIR research are geared to determine whether LAT1-transported anticancer agents are a viable option for the development of chemotherapeutics to treat brain tumors. Success of our strategy is defined as activity and high specificity for LAT1. In Aim 1 a set of compounds will be synthesized that are hybrid compounds in which a known cytotoxic moiety is chemically fused to a LAT1- specific recognition element. These compounds will be tested for LAT1 activity and specificity in Aim 2. LAT1 transport will be determined in vitro using [3H]-gabapentin uptake competition in HEK cells and direct uptake coupled with LC/MS/MS detection. The specificity for LAT1 vs. other amino acid transporters will be tested by [3H]-phenylalanine uptake competition in cells expressing those transporters. Possible BBB transport of the compounds will be assessed by and invitro transwell transport assay. In Aim 3, cytotoxicity (LD50 and LD100) of compounds toward cancer cell lines and bone marrow progenitor cells is evaluated. To exclude that test compounds enter the cell via means other than LAT1, the effect of LAT1 inhibitors on the cytotoxicity will be determined. A successful compound will be cytotoxic to LAT1-expressing cancer cell lines through selective accumulation and exhibit no cytotoxicity to bone marrow progenitor cells. In projected Phase 2 studies, successfulcompounds will be tested in vivo in validated xenograft models for various brain tumors. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: This SBIR Phase 1 grant application is relevant to the mission of the National Institute of Health. The main objective is to develop novel anti-cancer agents for patients with primary or metastatic brain tumors. Small polar nutrients can cross the blood brain barrier (BBB) and reach brain cancer cells through specific influx transporters with expression at boththe BBB and the tumor. Our strategy is to exploit these up-take mechanisms for an increased and targeted drug delivery. Engineered chemotherapeutics, mimicking endogenous nutrients are taken up from the circulation into the brain and the tumor. Key to ourapproach is the promise of high efficacy and low systemic toxicity. Transporter targeted chemotherapy provides a novel effective armamentarium against brain tumors with potential utility for treatment of other cancers.