Boron neutron capture therapy (BNCT) is a therapeutic modality for tumors utilizing nuclear reaction of <sup>10</sup>B atoms and neutrons, which generates α particles that can efficiently kill cells. Since the range of the α particle is about 10 µm, selective delivery of <sup>10</sup>B to target tumor cells is critical for successful BNCT. Up to now, boronophenylalanine (BPA) has been extensively investigated as a boron drug in clinical studies, because BPA offers selective accumulation within tumors owing to its structure resembling phenylalanine, which facilitates cellular internalization through LAT1 transporters overexpressed on many tumor cells. However, upon decrease of extracellular BPA concentration, exchange transport mechanism of LAT1 might cause efflux of intracellular BPA. Such efflux may decrease intratumoral boron concentration during irradiation of neutrons, thereby compromising therapeutic efficiency of BPA. Here, to improve the intracellular retention of BPA and maintain high intratumoral boron concentration, we have developed biocompatible polymers possessing polyol structures that can form reversible bonds with boronic acids. The polymers and BPA could form complexes by simple mixing of these components in aqueous solution, and the complex exposes the phenylalanine structure that is critical for recognition by LAT1. The polymer-BPA complex was internalized into cancer cells through LAT1-mediated endocytosis, and localized in endo-/lysosomes, whereas conventional BPA was localized in cytosol. The polymer-BPA also exhibited prolonged intracellular retention, which may be owing to the alteration of subcellular localization and avoidance of the efflux by LAT1. Importantly, the polymer-BPA revealed significantly enhanced tumor accumulation and retention, and exerted drastic antitumor activity upon irradiation of neutrons (Figure 1). Our polymer-BPA complex should offer great promise in clinical application.

Metabolism-controlled boron delivery systems composed of biocompatible polymers and boronophenylalanine for neutron capture therapy

2019 Spring National Meeting

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