Boron delivery with liposomes for boron neutron capture therapy (BNCT): biodistribution studies in an experimental model of oral cancer demonstrating therapeutic potential

Abstract

Boron neutron capture therapy (BNCT) combines selective accumulation of (10)B carriers in tumor tissue with subsequent neutron irradiation. We previously demonstrated the therapeutic efficacy of BNCT in the hamster cheek pouch oral cancer model. Optimization of BNCT depends largely on improving boron targeting to tumor cells. Seeking to maximize the potential of BNCT for the treatment for head and neck cancer, the aim of the present study was to perform boron biodistribution studies in the oral cancer model employing two different liposome formulations that were previously tested for a different pathology, i.e., in experimental mammary carcinoma in BALB/c mice: (1) MAC: liposomes incorporating K[nido-7-CH(3)(CH(2))(15)-7,8-C(2)B(9)H(11)] in the bilayer membrane and encapsulating a hypertonic buffer, administered intravenously at 6 mg B per kg body weight, and (2) MAC-TAC: liposomes incorporating K[nido-7-CH(3)(CH(2))(15)-7,8-C(2)B(9)H(11)] in the bilayer membrane and encapsulating a concentrated aqueous solution of the hydrophilic species Na(3) [ae-B(20)H(17)NH(3)], administered intravenously at 18 mg B per kg body weight. Samples of tumor, precancerous and normal pouch tissue, spleen, liver, kidney, and blood were taken at different times post-administration and processed to measure boron content by inductively coupled plasma mass spectrometry. No ostensible clinical toxic effects were observed with the selected formulations. Both MAC and MAC-TAC delivered boron selectively to tumor tissue. Absolute tumor values for MAC-TAC peaked to 66.6 ± 16.1 ppm at 48 h and to 43.9 ± 17.6 ppm at 54 h with very favorable ratios of tumor boron relative to precancerous and normal tissue, making these protocols particularly worthy of radiobiological assessment. Boron concentration values obtained would result in therapeutic BNCT doses in tumor without exceeding radiotolerance in precancerous/normal tissue at the thermal neutron facility at RA-3.

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

“…No systemic toxicity or side effects have been observed in any biodistribution studies performed with the use of TAC and MAC (35). It is also noteworthy that both compounds are readily attainable by straightforward, high-yield, scalable processes, and they are stable for long periods of time before administration.…”

“…Research efforts by our group and affiliates (35) are currently directed at applying the treatment protocol reported here to other cancer types and have, in some instances, achieved complete cancer remission. Furthermore, ongoing neutron dose-escalation studies performed on the same cancer type (EMT6) by using our delivery system have demonstrated enhanced tumor control beyond the results presented in this report.…”

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

“…Our previous biodistribution studies with this model using MAC-TAC liposomes showed that tumor boron values peaked at 67 ppm after 48 h with a very favorable 10:1 tumor/ normal tissue ratio (30). Thus, this protocol was very attractive for radiobiological study.…”

“…SI Materials and Methods provides detailed experimental procedures. Also, please refer to our previously published boron biodistribution study (30) for a detailed description of MAC-TAC liposome administration protocols.…”

“…at a dose of 18 mg 10 B per kilogram bw (SI Materials and Methods, S2). The dose and postadministration times used for neutron irradiation were selected on the basis of a previous study (30). This biodistribution study involved ∼25 hamsters each with multiple tumors (total of 68 tumors of varying size).…”