Synthesis of oligo-closo-dodecaborates by Hüisgen click reaction as encapsulated agents for the preparation of high-boron-content liposomes for neutron capture therapy

Abstract

High-boron-content compounds, 8, 10, and 13, were designed and synthesized as boron agents encapsulated in liposomes by the Hüisgen click cycloaddition of closo-dodecaborate-containing azides and alkynes. These compounds have relatively low cytotoxicities and their GI 50 values for B16, CT26, and HeLa cells are higher than 0.14 mM, indicating toxicities similar to that of BSH. High-boron-content liposomes were prepared using 13, which has the largest number of boron atoms in a molecule among the synthesized compounds. The final boron concentration in 13-encapsulating liposomes reached 11.0 Â 10 3 ppm with a B/P ratio of 5.1. A significantly high tumor boron accumulation (72.2 ppm) was observed in tumor-bearing mice 36 h after the injection of 13-encapsulating liposomes at a dose of 15 mgB kg À1 body weight with the tumor/blood (T/B) ratio of approximately 14.

Design, Synthesis, and Biological Evaluation of Boron-Containing Macrocyclic Polyamines and Their Zinc(II) Complexes for Boron Neutron Capture Therapy

“…To date, numerous boron-containing analogues including amino acids, 6 biochemical precursors of nucleic acids, 7 carbohydrates, 8 amines, 9 porphyrins, 10 peptides, 11 liposomes, 12 and monoclonal antibodies have been developed. 13 However, most of them do not satisfy the above criteria for clinical applications.…”

Lipid-membrane-incorporated arylboronate esters as agents for boron neutron capture therapy

“…Fig. 3C shows that the molecules of 3 in the liposomes were stable for one week at ambient temperature, as evidenced by the lack of any peaks corresponding to 2,6-dimethylphenylboronic acid (5) or pinacol. It is suggested that the reason for the stability of 3 is that the methyl groups in both of the ortho positions of the phenyl ring and in pinacol protect the boronate ester against attack by water (Fig.…”

“…3B). The 1 H NMR spectrum of LMI3 did not contain any peaks belonging to 2,6-dimethylphenylboronic acid (5) or the pinacol formed by the hydrolysis of 3 (Fig. 3A and 3B, blue circles).…”

“…Liposomal boron carriers have been studied extensively as efficient boron delivery systems in BNCT. [3][4][5][6][7][8][9][10][11][12] Although lipids generally exhibit low toxicity, high lipid doses can lead to liver toxicity as a result of saturating the lipid uptake mechanisms. To reduce the total lipid dose associated with the liposomal delivery systems used in BNCT, there is an urgent need for the development of liposomes with higher boron contents [i.e., a higher boron/phosphorous concentration (B/P) ratio].…”

“…To reduce the total lipid dose associated with the liposomal delivery systems used in BNCT, there is an urgent need for the development of liposomes with higher boron contents [i.e., a higher boron/phosphorous concentration (B/P) ratio]. Two strategies have been investigated to date for the preparation of liposomal boron systems, including (i) the introduction of water-soluble boron compounds to liposomes via an internal water phase (Scheme 1A); [3][4][5] and (ii) the use of amphiphilic boron compounds embedded in a liposomal bilayer (Scheme 1B). [6][7][8] Recent developments in this area have made it possible to reduce the total lipid dose used in liposomal delivery systems based on a combination of these two methods; however, these systems are only capable of a B/P value of 3.6, which is unsatisfactory for BNCT.…”