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BNCT has been hindered by the reliance on poorly soluble boronophenylalanine (BPA) for 10B delivery. For successful BNCT at least 20 μg of 10B needs to be delivered per gram of tumor and BPA often struggles to achieve this despite being approved for the treatment of head and neck cancer in Japan. We aim to overcome these limitations by developing new boron-carrying entities including unnatural amino acids and dipeptides that are more soluble than BPA making them more suitable as drugs. Boronated compounds were designed based on known LAT-1 substrates, synthesized using boronation techniques and purified using preparative HPLC. The compounds were formulated to achieve high concentrations when compared to BPA-fructose (BPA-F). Boronated compounds were tested for boron uptake and retention in multiple cell lines expressing either LAT1 and/or PEPT1. Compounds were further tested in multiple human xenograft models representing the cancer indication currently treatable by BNCT as well as in one syngeneic colon tumor model that may have high PEPT1 expression. Intracellular and intra tumor boron concentration were measured by ICP OES and compared to boron in normal organs. We also synthesized 2 dipeptides and tested them in BNCT experiments with our collaborators at Kyoto University in Japan. They were tested in a CT26 mouse syngeneic model using neutrons from KURR1. All test articles were compared with BPA using 12 and 6 minutes neutron exposure. We synthesized multiple boronated compounds with better solubility than BPA (100mg/ml v 30mg/ml in fructose). They were readily taken up in multiple cell lines and one of these compounds had longer retention than others. In competition experiments we 12- and 6-minutes were able to show that this compound was a superior substrate for LAT1. These new molecules could be dosed up to 1000mg/kg in vivo (v 200-300mg/kg for BPA). In doing this we could consistently observed 2-3 x more boron in the tumor compared to BPA. One compound had longer tumor retention in vivo confirming the observations made in vitro. This enhanced retention and rapid clearance from the blood meant that we could achieve tumor to blood ratios of 25:1 compared to 7:1 with BPA. In several BNCT experiments at KURR1 where we showed that our dipeptides were able to cause complete tumor eradication after 6 minutes irradiation while tumors treated with BPA grew as normal. BPA works for BNCT but it has limitations such as poor solubility. We made several new boronated compounds with better solubility than BPA and showed that we could deliver 2-3 x more boron in vitro and in vivo with one of these compounds having improved retention given better T:B ratio. We made 5 boronated dipeptides and showed that they are transported by PEPT1 as well as LAT1 which could translate to better boron uptake in the clinic. 2 dipeptides tested by BNCT could completely eradicate CT26 tumors while those treated with BPA, or irradiation alone, grew as normal. These new compounds will be developed for next gen BNCT. [ABSTRACT FROM AUTHOR]