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Review
. 2023 Nov 23;15(12):2663.
doi: 10.3390/pharmaceutics15122663.

Amino Acid-Based Boron Carriers in Boron Neutron Capture Therapy (BNCT)

Juulia Järvinen  1 , Herkko Pulkkinen  2 , Jarkko Rautio  1 , Juri M Timonen  1   3
Affiliations
Review

Amino Acid-Based Boron Carriers in Boron Neutron Capture Therapy (BNCT)

Juulia Järvinen et al. Pharmaceutics. .

Abstract

Interest in the design of boronated amino acids has emerged, partly due to the utilization of boronophenylalanine (BPA), one of the two agents employed in clinical Boron Neutron Capture Therapy (BNCT). The boronated amino acids synthesized thus far for BNCT investigations can be classified into two categories based on the source of boron: boronic acids or carboranes. Amino acid-based boron carriers, employed in the context of BNCT treatment, demonstrate significant potential in the treatment of challenging tumors, such as those located in the brain. This review aims to shed light on the developmental journey and challenges encountered over the years in the field of amino acid-based boron delivery compound development. The primary focus centers on the utilization of the large amino acid transporter 1 (LAT1) as a target for boron carriers in BNCT. The development of efficient carriers remains a critical objective, addressing challenges related to tumor specificity, effective boron delivery, and rapid clearance from normal tissue and blood. LAT1 presents an intriguing and promising target for boron delivery, given its numerous characteristics that make it well suited for drug delivery into tumor tissues, particularly in the case of brain tumors.

Keywords: BNCT; LAT1; amino acids; boron carriers; boron neutron capture therapy; glioma; tumor targeting.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Structures of the two clinically used boron delivery agents, l-4-boronophenylalanine, l-BPA (l-1), and BSH (2), in which grey dots represent boron atoms.
Figure 1
Figure 1
Principle of BNCT. (A) First, the patient is injected with 10B-enriched amino acid-based boron carriers, which are (B) selectively taken up by cancer cells. When the tumor site is radiated with thermal neutrons, 10B atoms within the carriers capture neutrons, forming unstable 11B atoms. They undergo nuclear fission, producing a fast-moving 4He-nucleus and 7Li+ ion with an effective range of 10 μm. Produced particles damage the DNA strands of cancer cells, resulting in (C) their death. Created with BioRender.com.
Scheme 2
Scheme 2
Boronophenylalanine derivatives BPA (1), m-BPA (3) and o-BPA (4).
Scheme 3
Scheme 3
Fluorinated BPA derivatives for non-invasive detection by PET and MRI.
Scheme 4
Scheme 4
Polyhedral boron cage-containing amino acid-based boron carriers.
Scheme 5
Scheme 5
Examples of amino acid-based boron carriers with increased water-solubility.
Scheme 6
Scheme 6
Examples of enantiopure boron carriers synthesized via asymmetric synthesis rather than enzymatic resolution.
Scheme 7
Scheme 7
Amino acid-based boron carriers with different unnatural scaffolds.
Figure 2
Figure 2
The structure of the LAT1 and 10 (yellow)/Tyr (green)/BPA (pink) complex, as predicted and presented by Li et al. 2019 [72]. LAT1 is represented in solid gray ribbon. Dotted sky-blue lines highlight hydrogen bonds between the ligands and LAT1, involving residues Trp202, Ser26, Gly27, Ile205, and Ile23. This depiction is derived from the research conducted by Li et al.
Scheme 8
Scheme 8
Most recent structures of amino acid-based boron carriers.
Scheme 9
Scheme 9
Fluorescent sensors for detection of boronic acids in aqueous solutions.
See this image and copyright information in PMC

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