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.

Significance: Boron neutron capture therapy (BNCT) for cancer is based on the selective uptake of ¹⁰ B target compounds by tumor cells followed by neutron irradiation. The capture reaction between ¹⁰ B atoms and neutrons gives rise to short-range particles, which are highly effective in producing cell damage. Thus, BNCT is designed to damage tumor cells and preserve healthy cells. The boron carrier used is pivotal to the success of BNCT. The present study describes the therapeutic success of BNCT mediated by MAC-TAC liposomes, K[ nido -7-CH ₃ (CH ₂ ) ₁₅ -7,8-C ₂ B ₉ H ₁₁ ] (MAC) in the bilayer membrane and encapsulating the hydrophilic species Na ₃ [ ae -B ₂₀ H ₁₇ NH ₃ ] (TAC) in the aqueous core, using the hamster cheek pouch oral cancer model. A sustained tumor response of 70–88% was associated with only mild mucositis in dose-limiting precancerous tissue.

Herein we describe the sequential synthesis of a variety of azide-alkyne click chemistry-compatible heterobifunctional oligo(ethylene glycol) (OEG) linkers for bioconjugation chemistry applications. Synthesis of these bioorthogonal linkers was accomplished through desymmetrization of OEGs by conversion of one of the hydroxyl groups to either an alkyne or azido functionality. The remaining distal hydroxyl group on the OEGs was activated by either a 4-nitrophenyl carbonate or a mesylate (–OMs) group. The –OMs functional group served as a useful precursor to form a variety of heterobifunctionalized OEG linkers containing different highly reactive end groups, e.g., iodo, –NH₂, –SH and maleimido, that were orthogonal to the alkyne or azido functional group. Also, the alkyne- and azide-terminated OEGs are useful for generating larger discrete poly(ethylene glycol) (PEG) linkers (e.g., PEG₁₆ and PEG₂₄) by employing a Cu(I)-catalyzed 1,3-dipolar cycloaddition click reaction. The utility of these clickable heterobifunctional OEGs in bioconjugation chemistry was demonstrated by attachment of the integrin (α_vβ₃) receptor targeting peptide, cyclo-(Arg-Gly-Asp-D-Phe-Lys) (cRGfKD) and to the fluorescent probe sulfo-rhodamine B. The synthetic methodology presented herein is suitable for the large scale production of several novel heterobifunctionalized OEGs from readily available and inexpensive starting materials.