Boron Neutron Capture Therapy (BNCT) Mediated by Maleimide-Functionalized Closo-Dodecaborate Albumin Conjugates (MID:BSA) for Oral Cancer: Biodistribution Studies and In Vivo BNCT in the Hamster Cheek Pouch Oral Cancer Model

Abstract

Background: BNCT (Boron Neutron Capture Therapy) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Although p-boronophenylalanine (BPA) has been clinically used, new boron compounds are needed for the advancement of BNCT. Based on previous studies in colon tumor-bearing mice, in this study, we evaluated MID:BSA (maleimide-functionalized closo-dodecaborate conjugated to bovine serum albumin) biodistribution and MID:BSA/BNCT therapeutic effect on tumors and associated radiotoxicity in the hamster cheek pouch oral cancer model. Methods: Biodistribution studies were performed at 30 mg B/kg and 15 mg B/kg (12 h and 19 h post-administration). MID:BSA/BNCT (15 mg B/kg, 19 h) was performed at three different absorbed doses to precancerous tissue. Results: MID:BSA 30 mg B/kg protocol induced high BSA toxicity. MID:BSA 15 mg B/kg injected at a slow rate was well-tolerated and reached therapeutically useful boron concentration values in the tumor and tumor/normal tissue ratios. The 19 h protocol exhibited significantly lower boron concentration values in blood. MID:BSA/BNCT exhibited a significant tumor response vs. the control group with no significant radiotoxicity. Conclusions: MID:BSA/BNCT would be therapeutically useful to treat oral cancer. BSA toxicity is a consideration when injecting a compound conjugated to BSA and depends on the animal model studied.

The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology

“…Also, some pharmacokinetic profiles have been reported for maleimide-carboranes. In this sense, some data for maleimide-functionalized closo-dodecaborate albumin conjugates indicate their biased distribution after intravenous administration to some cells as those neoplastic cells in oral cancer in hamster and glioma in rats, a maximal accumulation between 8 and 12 h after injection. − Also, a low biodistribution is shared, but a sustained detection in some body samples (12–48 h) suggest slow metabolism compared to other known BNCT-agents as BPA; , similarly, longer effects and sustained detection were observed compared with BSH against murine colon cancer cells …”

Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment

“…It offers advantages as low toxicity, amount of functional groups that are available for conjugation, biocompatibility. Some authors reported recently maleimide‐functionalized closo‐dodecaborate derivatives conjugated to HSA reached therapeutically useful boron concentration values in the malignant cells and T/N tissue ratios with no significant toxicity 93,94 . Interesting works of Popova et al where authors prepared fluorophore‐labeled homocystamide conjugates of HAS with multimodal functions (Figure 6).…”

Enhancement in the Therapeutic Efficacy of In Vivo BNCT Mediated by GB-10 with Electroporation in a Model of Oral Cancer

“…Control group: cancerized, not treated (data extracted from previous studies performed by our group [45] (n = 6 hamsters, 34 tumors).…”

“…The absolute boron concentration values in tumor and precancerous tissues (the dose-limiting tissue) for the early EP + GB-10 group were 20.2 ± 9.6 ppm and 8.9 ± 1.1 ppm, respectively (tumor/precancerous tissue ratio = 2.3 ± 1.2). For the GB-10 group, the tumor and precancerous tissue absolute boron concentration values were 9.5 ± 2.4 ppm and 12.4 ± 1.4 Control group: cancerized, not treated (data extracted from previous studies performed by our group [45] (n = 6 hamsters, 34 tumors).…”

“…We considered (1) complete response (CR) as when tumors disappear on visual inspection; (2) partial response (PR) as when they undergo a reduction in their pre-treatment volume; (3) no response (NR) as when tumors grow or remain the same as at T0; and (4) overall response (OR) as partial response (PR) + complete response (CR). Mucositis in precancerous tissue was evaluated semi-quantitatively employing an oral mucositis scale adapted from studies in hamsters and humans [45][46][47]: Grade 0: healthy appearance, no erosion or vasodilation; Grade 1 (slight): erythema and/or edema and/or vasodilation, no evidence of mucosal erosion; Grade 2 (slight): severe erythema and/or edema, vasodilation and/or superficial erosion; Grade 3 (moderate): severe erythema and/or edema, vasodilation, and the formation of ulcers <2 mm in diameter; Grade 4 (severe): severe erythema and/or edema, vasodilation, and the formation of ulcers ≥2 mm and <4 mm in diameter, and/or necrosis areas <4 mm in diameter; Grade 5 (severe): the formation of ulcers ≥4 mm in diameter or multiple ulcers ≥2 mm in diameter, and/or necrosis areas ≥4 mm in diameter. Grading was based on the most severe macroscopic feature.…”