A research group led by Special Research Student Kakeru Konarita and Associate Professor Takahiro Nomoto at the Graduate School of Arts and Sciences of the University of Tokyo has announced that they successfully imparted properties of being accumulated and retained selectively in cancer more than clinical drugs to compounds previously considered ineffective for cancer treatment by simply adding poly(vinyl alcohol) (PVA), which is used in liquid glue. They applied this method to boron neutron capture therapy (BNCT) and virtually eradicated subcutaneous tumors in mice. They confirmed that the boron migration to normal tissues was far lower than that of conventional BNCT agents. The approach is expected to lead to indication expansion of BNCT. The results were published in the Journal of Controlled Release, an international journal, on December 3.
BNCT utilizes the nuclear reactions occurring when thermal neutrons collide with boron atoms to kill cancer cells. This treatment method has received regulatory approvals for treating unresectable locally advanced or locally recurrent head and neck cancer. Indications of expansion of BNCT to refractory malignancies that could not be treated with conventional methods have been awaited, but the development of agents with properties of being accumulated and retained selectively in cancer has been a challenge.
Currently, the boron agent L-boronophenylalanine (L-BPA) is used in clinical practice. It migrates into cells via LAT1 (amino acid transporter), which is highly expressed in cancer cells. Meanwhile, L-BPA also migrates into cells via the amino acid transporter expressed in other normal cells. The benefits of BNCT could not be fully exploited with L-BPA, and its indications were limited.
In this study, they focused on D-BPA, an enantiomer of L-BPA. Previous studies have reported that D-BPA did not accumulate in cancer cells as much as L-BPA, which was thus considered an inferior boron agent. In contrast, the research group found that in a mixture of D-BPA and PVA, the two substances form a chemical bond similar to the "chemistry of slime (a bond called boronate ester was formed between PVA and borax in laundry glue form to produce slime)," and the amount of D-BPA accumulated in cancer was much higher than that of the conventional compound (PVA-L-BPA).
BNCT in a mouse subcutaneous tumor model was conducted in cooperation with Professor Minoru Suzuki of the Institute for Integrated Radiation and Nuclear Science, Kyoto University. The results showed that PVA-D-BPA had a markedly more potent antitumor effect than L-BPA.
The research group investigated the mechanism and found that D-BPA had a higher selectivity for the LAT1 amino acid transporter than L-BPA but was less efficient in migration into cells. Meanwhile, PVA-D-BPA was taken up by cells through LAT1-mediated endocytosis, with an efficiency of more than twice that of L-BPA. PVA-D-BPA that entered cells was shown to be gradually degraded to D-BPA and was thereby prevented from externalization from cancer cells. PVA-D-BPA exhibited very high cancer-selective accumulation due to the effect of PVA on increasing the uptake efficiency combined with the prolonged intracellular retention of D-BPA. Moving forward, the research group will continue to collaborate on the practical application of PVA preparations of BNCT agents.
Nomoto said, "PVA and D-BPA used in this study are seemingly 'useless' as drugs on their own and have never attracted attention. However, when I took a fresh look at these substances, I found that they had an appeal that other substances never had, and they exerted a dramatic effect by simply mixing them. Through this study, I realized once again that the essence found by thinking deeply about what appears to be simple, without being influenced by trends, is what is truly 'useful'."
Journal Information
Publication: Journal of Controlled Release
Title: Poly(vinyl alcohol) potentiating an inert d-amino acid-based drug for boron neutron capture therapy
DOI: 10.1016/j.jconrel.2024.11.017
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