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Polymers and Boron Neutron Capture Therapy (BNCT): a Potent Combination Cite This: Polym Polymer Chemistry View Article Online REVIEW View Journal | View Issue Polymers and boron neutron capture therapy (BNCT): a potent combination Cite this: Polym. Chem., 2021, 12, 2035 Anaïs Pitto-Barry * Boron neutron capture therapy (BNCT) has a long history of unfulfilled promises for the treatment of aggressive cancers. In the last two decades, chemists, physicists, and clinical scientists have been coordi- nating their efforts to overcome practical and scientific challenges needed to unlock its full therapeutic potential. From a chemistry point of view, the two current small-molecule drugs used in the clinic were developed in the 1950s, however, they both lack some of the essential requirements for making BNCT a successful therapeutic modality. Novel strategies are currently used to design new drugs, more selective towards cancer cells and tumours, as well as able to deliver high boron contents to the target. In this Received 30th September 2020, context, macromolecules, including polymers, are promising tools to make BNCT an effective, accepted, Accepted 8th February 2021 and front-line therapy against cancer. In this review, we will provide a brief overview of BNCT, and its Creative Commons Attribution 3.0 Unported Licence. DOI: 10.1039/d0py01392g potential and challenges, and we will discuss the most promising strategies that have been developed so rsc.li/polymers far. Introduction Locher in 1936.1 Some nuclides have a high propensity for absorbing low energy or thermal neutrons, and this is referred Boron neutron capture therapy (BNCT) is a two-component, or to as the neutron capture cross-section. 10B is one of the most binary, radiotherapeutic modality. BNCT was initially devel- attractive nuclides for neutron capture with a cross section of oped in the clinic in the 1950s by the neurosurgeon 3836 barns. It is a stable, non-radioactive isotope, with a This article is licensed under a W. H. Sweet, while its therapeutic potential was discovered by natural occurrence of 20%. The capture of thermal neutrons by 10B leads to the production of high linear energy transfer (LET) particles, alpha particles (He4) and recoiling lithium-7 2 Open Access Article. Published on 23 March 2021. Downloaded 9/24/2021 6:30:03 PM. School of Chemistry and Biosciences, University of Bradford, Richmond Road, nuclei (Fig. 1). The path lengths of these particles are limited Bradford BD7 1DP, UK. E-mail: [email protected] and approximately one cell in diameter (10–14 μm), and there- Anaïs became a Lecturer in Inorganic Chemistry at the University of Bradford in 2019. Her research interests include using polymers for the transport of inorganic compounds for bio- medical applications. Previously, she obtained an MSc degree from ENSCR (France) and a PhD degree from the University of Neuchâtel (Switzerland) with Prof. Robert Deschenaux. In Anaïs Pitto-Barry 2012, she initially joined the University of Warwick as a Swiss National Science Foundation Fellow to work with Profs Rachel ’ O Reilly and Andrew Dove. She also worked with Prof. Nicolas Fig. 1 Schematic representation of the nuclear reaction that happens Barry on the applications of metallated compounds at the during the BNCT process. Reproduced from ref. 2 with permission from University of Warwick and the University of Bradford. Elsevier, copyright 2020. This journal is © The Royal Society of Chemistry 2021 Polym. Chem.,2021,12,2035–2044 | 2035 View Article Online Review Polymer Chemistry fore only cells that have internalised 10B are impacted by irradiation. Indeed, the neutron capture cross section of hydro- gen and nitrogen is weak enough to prevent any damage to biological tissues from their reaction with thermal neutrons (0.3326 and 1.91 barns, respectively). This nuclear reaction leads to the destruction of a wide variety of biologically active molecules (e.g., DNA, RNA, and proteins) whilst the surround- Fig. 2 Chemical structures of BSH, a boron cluster (left), and BPA ing tissues remain unaffected. (right). For successful BNCT treatment, a critical amount of 10B and a sufficient number of thermal neutrons are therefore needed to be delivered to individual tumour cells. initially in Japan for brain tumours from the late 1960s.7 Ideal boron compounds should exhibit the following Boron clusters with one or two sulfur atoms showed some characteristics: success, with the presence of the mercapto moieties being - low systemic toxicity; hypothesised to allow binding to antibodies via a thiol–di- - low healthy tissue uptake and high tumour uptake; sulfide exchange.8 Of these boron clusters, sodium borocap- - high tumour/blood and tumour/surrounding normal tate (BSH, Na2B12H11SH, Fig. 2) is the most promising owing tissue concentration ratios (greater than 3–4 : 1). This mini- to its high and persistent boron concentrations in tumour and mises the impact that the capture of neutrons by hydrogen low systemic toxicity even if it exhibits a low mean tumour/ and nitrogen, the two elements present in high concentrations blood ratio. p-Boronophenylalanine (BPA, Fig. 2) is another in the body, can have on the absorbed radiation dose; compound which received a lot of interest, especially in the 10 - tumour concentrations of 20–35 μgof B per gram of treatment of malignant melanoma. Malignant melanoma cells 9 10 tumour, which accounts for 10 atoms of B per cell; preferentially take up BPA because its chemical structure is Creative Commons Attribution 3.0 Unported Licence. - rapid clearance from blood and normal tissues; similar to that of tyrosine, which is required for melanogen- 3 - persistence in the tumour for the duration of the treatment. esis. Other boron-containing amino acids were synthesised fol- This review will first introduce the early stages of BNCT in lowing the promising clinical trial results obtained for BPA. terms of the compounds used, before focusing on high-mole- Clinical trials have been carried out since the 1960s with cular weight polymeric systems that have been used for in vitro these second-generation compounds, either alone or in combi- and in vivo studies for potential BNCT applications. nation with another treatment regimen (surgery or radiother- apy).9 Completed phase I/II studies have shown encouraging results for difficult-to-treat and recurrent head and neck cancers, melanoma, and gliomas (by intratumoural exposure) This article is licensed under a First generation of compounds in Japan, Taiwan, USA, and in several European countries The first boron-containing molecules used for BNCT were not (Finland, Germany, Austria, France, and UK).10,11 Owing to the designed for such an application, but were selected because of progress of nuclear physics, it is now possible to produce low- Open Access Article. Published on 23 March 2021. Downloaded 9/24/2021 6:30:03 PM. their availability, known pharmacology, and lack of toxicity. energy thermal neutrons using accelerators rather than 12 Boric acid (H3BO3), sodium tetraborate (borax) and their nuclear reactors. This has allowed for easier access to such derivatives were initially used. The first experiments of neutrons. For example, one recently reported phase II study neutron irradiation were conducted on samples of mammary using BPA–10B has used BNCT in a Japanese urban hospital carcinoma, lymphoma and undifferentiated sarcoma grown on setting on patients with unresectable carcinoma of the head mice and infused with boronic acid. The tissues were shown and neck, with very promising results.13 not to regenerate in vivo. These experiments carried out in the Despite this encouraging progress made by physicists and 1930–40s were the first demonstration that neoplastic cells clinicians, both BSH and BPA do not fulfil the criteria needed 4 could be destroyed in vivo with BNCT treatment. for efficient boron delivery agents (e.g., poor uptake, low Early clinical trials of BNCT were conducted in the US at selectivity between healthy and cancer cells). These com- the Brookhaven National Laboratory Reactor using thermal pounds were selected because they were the best benchmark neutrons and sodium tetraborate during the 1950s on malig- molecules available to gauge the progress made with the 5 nant gliomas that were resisting all forms of treatment. technology. With better facilities and technical understanding Between severe damage of the scalp and no significant pro- of the methodology, a third generation of compounds for longation of survival nor evidence of therapeutic efficacy, clini- making BNCT a viable therapeutic modality was therefore 6 cal trials in the US were stopped in 1961. needed. Second generation of compounds Third generation of compounds Following the poor clinical outcomes of the derivatives of boric Many boron delivery agents have been designed in the last few acid, a second generation of compounds was investigated, decades, ranging from low- to high-molecular weight com- 2036 | Polym. Chem.,2021,12,2035–2044 This journal is © The Royal Society of Chemistry 2021 View Article Online Polymer Chemistry Review Fig. 3 Overview of the various polymeric systems containing boron, either conjugated or encapsulated, and the possible conjugation to tar- Scheme 1 Structure of the amphiphilic carborane-conjugated polycar- geting or labelling moieties: (A) micelles made from polymers or den- bonate and self-assembly in water, adapted from ref. 20 with permission dronised polymers; (B) dendrimers; and (C) liposomes. from the American Chemical Society, copyright 2016. pounds to overcome the limitations of BPA and BSH, with a 50 nm, with shorter PEG chains) were more likely to be inter- focus on selective tumour cell targeting and the delivery of nalised into cancer cells. No toxicity was observed for the therapeutic concentrations of boron. They can be classified range of nanoparticles on normal mouse fibroblast L929 cells into three different types of boron-carriers: boron-containing and human cervical cancer HeLa cells, while the carborane- small molecules (which will not be discussed here), boron containing monomer exhibited a 50% inhibitory concentration compound conjugates and boron delivery nanoparticles of 1.8 mM on L929 cells which is higher than other small (Fig.
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