Boron neutron capture therapy (BNCT) is a cancer treatment with clinically demonstrated efficacy using boronophenylalanine (BPA) and sodium mercaptododecaborate (BSH). However, tumor tissue selectivity of BSH and retention of BPA in tumor cells is a constant problem. To ensure boron accumulation and retention in tumor tissues, we designed a novel polyethylene glycol (PEG)-based boron-containing lipid (PBL) and examined the potency of delivery of boron using novel PBL-containing liposomes, facilitated by the enhanced permeability and retention (EPR) effect. PBL was synthesized by the reaction of distearoylphosphoethanolamine and BSH linked by PEG with Michael addition while liposomes modified using PBL were prepared from the mixed lipid at a constant molar ratio. In this manner, novel boron liposomes featuring BSH in the liposomal surfaces, instead of being encapsulated in the inner aqueous phase or incorporated in the lipid bilayer membrane, were prepared. These PBL liposomes also carry additional payload capacity for more boron compounds (or anticancer agents) in their inner aqueous phase. The findings demonstrated that PBL liposomes are promising candidates to effect suitable boron accumulation for BNCT.

Boron neutron capture therapy (BNCT) is expected to be a promising next-generation cancer treatment. In 2020, Japan, which has led the research on this treatment modality, was the first country in the world to approve BNCT. The boron agents that have been clinically applied in BNCT include a caged boron compound (mercaptoundecahydrododecaborate: BSH) and a boron-containing amino acid (p-boronophenylalanine: BPA). In particular, the BPA preparation Steboronine^® is the only approved drug for BNCT. However, the problem with BPA is that it is poorly retained in the tumor and has very low solubility in water. This cannot be overlooked for BNCT, which requires large amounts of boron in the tumor. The high dosage volume, together with low tumor retention, leads to reduced therapeutic efficacy and increased physical burden on the patient. In the case of BSH, its insufficient penetration into the tumor is problematic. Based on drug delivery system (DDS) technology, we have developed a next-generation boron pharmaceutical superior to Steboronine^®. Our approach involves the redevelopment of BPA using innovative ionic liquid formulation technology. Here, we describe previous boron agents and introduce our recent efforts in the development of boron compounds.

Background/Objectives: Boron neutron capture therapy requires the efficient delivery of sufficient amounts of ¹⁰B to tumor cells. In this study, we evaluated a liposomal boron-delivery system based on the B5-TAT-lipopeptide, which contains five boronophenylalanine (BPA) residues within its peptide portion and is anchored to the liposomal membrane through a hydrophobic lipid moiety. Methods: B5-TAT-lipopeptide 5% liposomes with a particle size of approximately 100 nm were prepared, and boron delivery to CT26 murine colon carcinoma cells was evaluated. Results: At an exposure concentration of 25 ppm boron, B5-TAT-lipopeptide 5% liposomes achieved a cell-associated boron level of approximately 4.5 µg B per 1 × 10⁶ cells. Separately, sodium mercaptoundecahydro-closo-dodecaborate (BSH)-encapsulated B5-TAT-lipopeptide 5% liposomes achieved approximately 11 µg B per 1 × 10⁶ cells when evaluated at an exposure concentration of 50 ppm. Following thermal neutron irradiation, B5-TAT-lipopeptide 5% liposome-treated cells showed marked loss of clonogenic survival, with surviving fractions of approximately 0.12 and 0.01 after 15 and 45 min of irradiation, respectively. In the preliminary in vivo tolerability study, rapid intravenous administration of B5-TAT-lipopeptide 5% liposomes without encapsulated BSH at 10 mg B/kg resulted in the death of all treated mice within 5–10 min, whereas no mortality occurred following the administration of phosphate-buffered saline (PBS), free BSH, or BSH-encapsulated PEGylated liposomes. Conclusions: These findings demonstrate substantial cell-associated boron delivery and neutron-induced clonogenic cell killing by B5-TAT-lipopeptide-modified liposomes while revealing a critical limitation in acute in vivo tolerability under the examined administration conditions.