Poly(vinyl alcohol) boosting therapeutic potential of p-boronophenylalanine in neutron capture therapy by modulating metabolism.

Abstract

In the current clinical boron neutron capture therapy (BNCT), p-boronophenylalanine (BPA) has been the most powerful drug owing to its ability to accumulate selectively within cancers through cancer-related amino acid transporters including LAT1. However, the therapeutic success of BPA has been sometimes compromised by its unfavorable efflux from cytosol due to their antiport mechanism. Here, we report that poly(vinyl alcohol) (PVA) can form complexes with BPA through reversible boronate esters in aqueous solution, and the complex termed PVA-BPA can be internalized into cancer cells through LAT1-mediated endocytosis, thereby enhancing cellular uptake and slowing the untoward efflux. In in vivo study, compared with clinically used fructose-BPA complexes, PVA-BPA exhibited efficient tumor accumulation and prolonged tumor retention with quick clearance from bloodstream and normal organs. Ultimately, PVA-BPA showed critically enhanced antitumor activity in BNCT. The facile technique proposed in this study offers an approach for drug delivery focusing on drug metabolism.

• Authors: Takahiro Nomoto, Yukiya Inoue, Ying Yao, Minoru Suzuki, Kaito Kanamori, Hiroyasu Takemoto, Makoto Matsui, Keishiro Tomoda, Nobuhiro Nishiyama
• Journal: Science advances (Sci Adv) Vol. 6 Issue 4 Pg. eaaz1722 (01 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 32010792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Chemical References

• Boron Compounds
• Radiation-Sensitizing Agents
• Phenylalanine
• Polyvinyl Alcohol
• 4-boronophenylalanine

Topics

• Animals
• Boron Compounds (chemistry, pharmacokinetics, pharmacology)
• Boron Neutron Capture Therapy
• Cell Line, Tumor
• Disease Models, Animal
• Drug Synergism
• Energy Metabolism (drug effects)
• Humans
• Mass Spectrometry
• Mice
• Neoplasms (therapy)
• Phenylalanine (analogs & derivatives, chemistry, pharmacokinetics, pharmacology)
• Polyvinyl Alcohol (chemistry, pharmacokinetics, pharmacology)
• Radiation-Sensitizing Agents (chemistry, pharmacokinetics, pharmacology)
• Signal Transduction (drug effects)
• Tissue Distribution
• Xenograft Model Antitumor Assays