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

Abstract

The application of boron neutron capture therapy (BNCT) following liposomal delivery of a 10 B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl- sn -glycero-3-phosphocholine and incorporating Na 3 [1-(2′-B 10 H 9 )-2-NH 3 B 10 H 8 ] in the aqueous interior and K[ nido -7-CH 3 (CH 2 ) 15 -7,8-C 2 B 9 H 11 ] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h—with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)—following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 10 12 neutrons per cm 2 (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study.

Synthesis of a carborane-containing cholesterol derivative and evaluation as a potential dual agent for MRI/BNCT applications

“…Alcohol 2 was then oxidized to the corresponding carboxylic acid, following the classical Jones reaction conditions with an overall yield of 78%. The formation of 3-(Cholesten-5-en-3-yloxy)-propionic acid (3,Scheme 1) was confirmed by the detection of a resonance at 170 ppm in the 13 C spectrum pertinent to the carbonyl group. The COOH moiety was then coupled to C-(2-benzyloxy)-ethyl-C'-aminomethyl-o-carborane 7 (prepared as previously reported).…”

“…The 1 H NMR spectrum showed the disappearance of the signal at 3.75 ppm assigned to the HOCH 2 -group, with the concomitant growth in the 13 C NMR spectrum, of the signal at 172 ppm corresponding to the carbonyl group.…”

“…In fact, there are many examples in the literature of formulations containing boron compounds encapsulated into the aqueous cavity or, after conjugation with lipids, incorporated into the liposomal bilayer. [13][14][15] A specific class of liposomes, named "long time circulating" polyethylene glycol (PEG)-coated liposomes, is able to accumulate in solid tumors as a consequence of microvascular permeability and defective lymphatic drainage. [16][17][18] The extent of passive extravasation is directly dependent on the prolonged residence time of liposomes in the blood stream.…”

Multiplexed imaging for diagnosis and therapy

“…In essence, this constitutes a way of achieving 'activatable' high LET radiotherapy. In a landmark study, BNCT using liposomal delivery of 10 B significantly reduced tumour growth in a preclinical EMT6 model of mammary adenocarcinoma 242 . As in EBT, beam positioning is a critical element in BNCT.…”

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).…”