Development of High Boron Content Liposomes and Their Promising Antitumor Effect for Neutron Capture Therapy of Cancers

Abstract

Mercaptoundecahydrododecaborate (BSH)-encapsulating 10% distearoyl boron lipid (DSBL) liposomes were developed as a boron delivery vehicle for neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in addition to its encapsulated agents. BSH-encapsulating 10% DSBL liposomes have high boron content (B/P ratio: 2.6) that enables us to prepare liposome solution with 5000 ppm boron concentration. BSH-encapsulating 10% DSBL liposomes displayed excellent boron delivery efficacy to tumor: boron concentrations reached 174, 93, and 32 ppm at doses of 50, 30, and 15 mg B/kg, respectively. Magnescope was also encapsulated in the 10% DSBL liposomes and the real-time biodistribution of the Magnescope-encapsulating DSBL liposomes was measured in a living body using MRI. Significant antitumor effect was observed in mice injected with BSH-encapsulating 10% DSBL liposomes even at the dose of 15 mg B/kg; the tumor completely disappeared three weeks after thermal neutron irradiation ((1.5-1.8) × 10(12) neutrons/cm(2)). The current results enabled us to reduce the total dose of liposomes to less than one-fifth compared with that of the BSH-encapsulating liposomes without reducing the efficacy of boron neutron capture therapy (BNCT).

Hemorrhage in mouse tumors induced by dodecaborate cluster lipids intended for boron neutron capture therapy

“…Uptake in the liver and spleen was considerably higher, in agreement with the experience of others with other boron lipids. 11,21 histology Both types of tumors, injected with THF-S-12, THF-S-16, and Dioxan-S-16, were subjected to histological staining. In histology, pronounced hemorrhage was visible ( Figure 3).…”

“…Preliminary experiments have shown that liposomes containing these boron lipids are taken up by cells, and especially by human umbilical vein endothelial cells. Koganei et al 21 have used a similar boron lipid in mice. Liposomes were prepared which contained both the boron lipids and BSH as a liposome-encapsulated BNCT agent, and neutron irradiation led to considerable reduction of the growth of tumors.…”

“…14,21,28 Liver and spleen are the organs where most boron is found. For therapy, this is of no consequence if these organs are not exposed to the neutron beam.…”

Development of Albumin‐closo‐Dodecaborate Conjugates as Boron Carriers for Neutron‐Capture Therapy by Ru(bpy)3‐Photocatalyzed Modification of Tyrosine

“…In several attempts that utilized the EPR effect, not only passive targeting carriers, such as boron-encapsulating liposomes, [9][10][11][12][13][14][15][16] but also active targeting liposomes in conjunction with tumorspecific ligands, such as monoclonal antibodies, [17][18][19] folate, [20,21] epidermal growth factor, [22] and transferrin (TF), [23] were reported. We thought that serum albumin would be a suitable carrier of boron atoms.…”

Therapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch model

“…Small liposomes (<100 nm) pass through aberrant tumor vessels (17) and passively accumulate by the enhanced permeability and retention effect (18,19). Small unilamellar liposomes in particular are viewed as potentially useful boron delivery vehicles for BNCT and have been extensively studied by Hawthorne and coworkers (20)(21)(22)(23)(24)(25)(26) and other groups (27)(28)(29) (26).…”