Next-Generation Boron Drugs and Rational Translational Studies Driving the Revival of BNCT

Abstract

BNCT is a high-linear-energy transfer therapy that facilitates tumor-directed radiation delivery while largely sparing adjacent normal tissues through the biological targeting of boron compounds to tumor cells. Tumor-specific accumulation of boron with limited accretion in normal cells is the crux of successful BNCT delivery. Given this, developing novel boronated compounds with high selectivity, ease of delivery, and large boron payloads remains an area of active investigation. Furthermore, there is growing interest in exploring the immunogenic potential of BNCT. In this review, we discuss the basic radiobiological and physical aspects of BNCT, traditional and next-generation boron compounds, as well as translational studies exploring the clinical applicability of BNCT. Additionally, we delve into the immunomodulatory potential of BNCT in the era of novel boron agents and examine innovative avenues for exploiting the immunogenicity of BNCT to improve outcomes in difficult-to-treat malignancies.

Keywords: BNCT; High-LET; immunomodulation; novel boron compounds.

Figure 1

A schematic overview of BNCT. BNCT involves the selective delivery of boronated compounds into tumor cells, followed by exposure of the tumor to epithermal neutron irradiation. Epithermal neutrons maybe generated through the interaction of protons with a lithium or beryllium target, a linear accelerator, or via nuclear reactors. Boron-10 atoms then react with neutrons via a nuclear capture and fission reaction, leading to the production of a high-LET, low-energy, alpha particle and a recoil lithium-7 atom (¹⁰B + ¹n → [¹¹B]* → ⁴He + ⁷Li) [1,2,3]. The high-LET alpha particles form dense ionization tracks along cellular macromolecules, leading to tumor cell death. As there is limited boron accumulation in normal cells, they are spared from the impacts of high-LET radiation.

Figure 2

Examples of novel boron carriers and their mechanisms of boron delivery. Several novel classes of boron compounds have been developed and tested in preclinical studies. Panel (A) demonstrates liposome and antibody-based boron carriers. Boron may be encapsulated within the lipid bilayer or conjugated to the lipid membrane. For tumor-targeting purposes, a receptor-targeting antibody may be coupled to the boron-containing liposome, or boron may be directly attached to tumor-directed antibodies via peptide linkers. Panel (B) demonstrates the mechanism of liposome engulfment and boron delivery to the tumor cells. Panel (C) demonstrates nanoparticle-based boron delivery in which boron may be linked to nanoparticles carrying tumor-specific targeting moieties.

Figure 3

The immunogenic potential of BNCT through cGAS-STING pathway activation. High-LET alpha particles generated through BNCT may cause extensive direct and irreparable DNA damage and the formation of cytoplasmic micronuclei. The presence of cytoplasmic DNA is detected by cGAS, leading to synthesis of the second messenger, cGAMP, which binds to STING, an endoplastic reticulum adapter. STING complex translocates to the Golgi apparatus and recruits TBK1. This leads to phosphorylation of IRF3, which then moves into the nucleus and directs the transcription of type I interferons. Type I interferons facilitate multiple immunomodulatory effects, including the maturation of dendritic cells, migration of dendritic cells to regional lymph nodes, and clonal expansion of cytotoxic T-lymphocytes in regional lymph nodes, ultimately converting an immunologically “cold” tumor into a “hot” entity.