Letters to the Editor

TREATMENT OF MALIGNANT MELANOMA BY SINGLE THERMAL NEUTRON CAPTURE THERAPY WITH MELANOMA-SEEKING ¹⁰B-COMPOUND

p-boronophenylalanine (BPA) is so far the most promising drug in clinical boron neutron capture therapy (BNCT) due to its safety and selective targeting of numerous cancer cells through amino acid transporters, such as LAT1. However, the therapeutic effectiveness of BPA is limited to its low water solubility and poor accumulation in tumor tissues caused by antiport mechanism. Herein, we take advantage of BPA ability to form boronate ester complexes with diols and we report on the coupling of BPA to phase-change ultrasound contrast agents, namely superheated decafluorobutane nanodroplets (NDs) stabilized by a crosslinked shell of poly(vinyl-alcohol) (PVA). The NDs will serve, from one side, to boost the targeting of the cancer cells by enhancing the cellular uptake of BPA through LAT1-mediated endocytosis and by slowing the untoward efflux. From the other side, the high linear energy transfer (LET) particles emitted as a result of nuclear reaction between 10-boron and thermal neutrons will induce the liquid-to-gas transition of the NDs core converting them into echogenic microbubbles detectable by ultrasound imaging (US). The evaluation of US contrast enhancement will allow for in-situ radiation dosimetry. This study demonstrates the effective functionalization of BPA to the NDs and their interactions with the cells and reports on the early-stage in vitro proof-of-concept of neutron-induced NDs-BPA vaporization. The suggested facile technique offers in perspective an innovative approach for both drug delivery and real-time radiation dosimetry with US imaging.

Boron neutron capture therapy (BNCT) is a highly targeted, selective and effective technique to cure various types of cancers, with less harms to the healthy cells. In principle, BNCT treatment needs to selectively and homogeneously distribute the ¹⁰boron (¹⁰B) atoms inside the tumor tissues as well as capturing of sufficient neutrons to initiate a nuclear fission reaction with release of the high linear energy particles to kill the tumor cells. Similar to chemotherapy and other radiotherapy for tumor treatment, emerging theranostics are vital in BNCT. Particularly, the in vivo localization and quantification of ¹⁰B concentrations are critical for the success of BNCT. However, the current scenarios, including both instrumentation and technology, do not fulfill the accurate measurement and time requirements. Therefore, more effective strategies are in demand in BNCT treatment. This review summarizes and outlooks on the emerging imaging techniques that are currently or potentially used in BNCT, such as magnetic resonance imaging (MRI), positron emission tomography (PET), and fluorescence imaging (FI).

Triple-negative breast cancer (TNBC) is characterized by highly proliferative cancer cells and is the only subtype of breast cancer that lacks a targeted therapy. Boron neutron capture therapy (BNCT) is an approach that combines chemotherapy with radiotherapy and can potentially offer beneficial targeted treatment for TNBC patients owing to its unique ability to eradicate cancer cells selectively while minimizing damage to the surrounding healthy cells. Since BNCT relies on specific delivery of a high loading of B10 to the tumor site, there is growing research interest to develop more potent boron-based drugs for BNCT that can overcome the limitations of small-molecule boron compounds. In this study, polyethylene-glycol-coated boron carbon oxynitride nanoparticles (PEG@BCNO) of size $134.2\pm 23.6\mathrm{nm}$ were prepared as a promising drug for BNCT owing to their high boron content and enhanced biocompatibility. The therapeutic efficiency of PEG@BCNO was compared with a state-of-the-art ¹⁰BPA boron drug in mice bearing MDA-MB-231 tumor. In the orthotopic mouse model, PEG@BCNO showed higher B10 accumulation in the tumor tissues (6 μg ¹⁰B/g tissue compared to 3 μg ¹⁰B/g tissue in mice administered B10-enriched ¹⁰BPA drug) despite using the naturally occurring ¹¹B/¹⁰B boron precursor in the preparation of the BCNO nanoparticles. The in vivo biodistribution of PEG@BCNO in mice bearing MDA-MB-231 showed a tumor/blood ratio of ~3.5, which is comparable to that of the state-of-the-art ¹⁰BPA-fructose drug. We further demonstrated that upon neutron irradiation, the mice bearing MDA-MB-231 tumor cells treated with PEG@BCNO and ¹⁰BPA showed tumor growth delay times of 9 days and 1 day, respectively, compared to mice in the control group after BNCT. The doubling times (DTs) for mice treated with PEG@BCNO and ¹⁰BPA as well as mice in the control group were calculated to be 31.5, 19.8, and 17.7 days, respectively. Immunohistochemical staining for the p53 and caspase-3 antibodies revealed that mice treated with PEG@BCNO showed lower probability of cancer recurrence and greater level of cellular apoptosis than mice treated with ¹⁰BPA and mice in the control group. Our study thus demonstrates the potential of pegylated BCNO nanoparticles in effectively inhibiting the growth of TNBC tumors compared to the state-of-the-art boron drug ¹⁰BPA.

Boron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1α, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc., have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies.

This study reports the first-in-human use of a linear accelerator-based boron neutron capture therapy (BNCT) system and the first treatment of patients with scalp-angiosarcoma with accelerator-based BNCT.

A single-center open-label phase I clinical trial has been conducted using the system since November 2019. Patients with a localized node-negative scalp-angiosarcoma along with the largest diameter of the tumor ≤ 15 cm who refused primary surgery and chemotherapy were enrolled. After administration of boronophenylalanine (BPA), a single treatment of BNCT with the maximum dose delivered to the skin being 12 Gy-Eq was performed. The safety and effectiveness of accelerator-based BNCT therapy for localized scalp angiosarcoma were evaluated.

Scalp-angiosarcoma of the two patients did not develop the dose-limiting toxicity in the clinical trial. They reached CR within half a year and did not exhibit in-field failure 20 months after BNCT without any severe treatment-related adverse events. Although a grade 3 adverse event of an asymptomatic but increased serum amylase level was noted in both patients, it relieved without any treatment. Additionally, no severe acute dermatitis was observed for both patients, which is typically seen with conventional primary radiotherapy.

It was suggested that BNCT would be a promising treatment modality for scalp-angiosarcoma, which is difficult to treat.