A critical assessment of boron target compounds for boron neutron capture therapy

Abstract

Boron neutron capture therapy (BNCT) has undergone dramatic developments since its inception by Locher in 1936 and the development of nuclear energy during World War II. The ensuing Cold War spawned the entirely new field of polyhedral borane chemistry, rapid advances in nuclear reactor technology and a corresponding increase in the number to reactors potentially available for BNCT. This effort has been largely oriented toward the eradication of glioblastoma multiforme (GBM) and melanoma with reduced interest in other types of malignancies. The design and synthesis of boron-10 target compounds needed for BNCT was not channeled to those types of compounds specifically required for GBM or melanoma. Consequently, a number of potentially useful boron agents are known which have not been biologically evaluated beyond a cursory examination and only three boron-10 enriched target species are approved for human use following their Investigational New Drug classification by the US Food and Drug Administration; BSH, BPA and GB-10. All ongoing clinical trials with GBM and melanoma are necessarily conducted with one of these three species and most often with BPA. The further development of BNCT is presently stalled by the absence of strong support for advanced compound evaluation and compound discovery driven by recent advances in biology and chemistry. A rigorous demonstration of BNCT efficacy surpassing that of currently available protocols has yet to be achieved. This article discusses the past history of compound development, contemporary problems such as compound classification and those problems which impede future advances. The latter include means for biological evaluation of new (and existing) boron target candidates at all stages of their development and the large-scale synthesis of boron target species for clinical trials and beyond. The future of BNCT is bright if latitude is given to the choice of clinical disease to be treated and if a recognized study demonstrating improved efficacy is completed. Eventually, BNCT in some form will be commercialized.

Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

“…Use of these agents for BNCT of GBM, melanoma, and head and neck cancers has met with limited success; treatments are largely palliative or last-line and are therefore only marginally more effective than conventional external-beam radiation therapy in increasing survival times (10)(11)(12)(13)(14)(15). With BNCT research having been so limited in scope, many agents that might have been highly effective against other more treatable types of cancer were never evaluated beyond preliminary studies.…”

Polyester Dendrimers: Smart Carriers for Drug Delivery

“…Consequently, efficient methods for the delivery of boron-10 to biological tissues have been the subject of longstanding research. However, an obstacle to mainstream application of BNCT for cancer treatment has been the selective delivery of adequate boron concentrations to target tissues [162]. To address this problem, high boron content species such as polyhedral borane clusters, closo-[B 10 [158].…”

A theranostic approach based on the use of a dual boron/Gd agent to improve the efficacy of Boron Neutron Capture Therapy in the lung cancer treatment

“…The selective delivery to tumour cells is crucial to increase the amount of internalized boron maintaining, at the same time, a low concentration in surrounding healthy tissues and in blood to minimize damage. Currently, two BNCT drugs are available for clinical investigation namely: i)Lpara-boronophenylalanine (BPA), structurally related to the amino acid phenylalanine, that has been used in clinical trials to treat glioblastoma, head and neck recurrent cancer and melanoma 7 and ii) sodium mercaptoundecahydro-closo-dodecaborate (BSH) that has been investigated for the . Carboranes are icosahedral cages containing 10 boron atoms and they have been used to design boron delivery vehicles due to their high boron content, chemical versatility and in vivo stability [10][11] .…”