The application of boron neutron capture therapy (BNCT) following liposomal delivery of a ¹⁰B-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 ₃1-(2′-B ₁₀H ₉)-2-NH ₃B ₁₀H ₈ in the aqueous interior and K nido -7-CH ₃(CH ₂) ₁₅-7,8-C ₂B ₉H 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.
The synthesis and hydrogen uptake properties of metal−organic framework (MOFs) materials based on carboranes have been investigated. These are the first MOFs to make use of boron-rich components as ...building blocksspecifically, the deprotonated form of 1,12-dihydroxycarbonyl-1,12-dicarba-closo-dodecaborane. In evacuated form the initially obtained compound, featuring zinc-coordinated solvent molecules, displays modest H2 uptake at 77 K and 1 atm. Upon removal of the coordinated solvent, however, the uptake triples (2.1 wt. %), the heat of adsorption substantially increases, and the structure adjusts such that the pore size decreases.
An icosahedral closo-B12 2– scaffold supports 12 copies of Gd3+-chelate held in close proximity with each other by suitable linkers which employ azide–alkyne click chemistry. This design is the first ...member of a new class of polyfunctional MRI contrast agents carrying a high payload of Gd3+-chelate in a sterically constrained configuration. The resulting contrast agent shows higher relaxivity values at high magnetic fields. MRI contrast agents currently in use are not as effective in this regard, presumably due to a lack of steric constraint of gadolinium centers and lower water exchange rates. In vivo MRI studies in mice show excellent contrast enhancement even at one-seventh of the safe clinical dose (0.04 mmol Gd/kg) for up to a 1 h exposure.
Hawthorne and Maderna survey the synthesis and use of radio-labeled boron clusters in view of their possible application both to tumor imaging for general diagnosis of cancer and to the analytical ...support of boron neutron capture therapy.
Compounds with polyhedral borane moieties have demonstrated numerous unique properties for a variety of applications, including nanoelectronics, drug delivery vehicles, and live cell imaging. ...Polyhedral boranes are good pharmacophore analogs of carbocycles because polyhedral boranes are inherently insensitive to many undesirable enzymatic metabolic transformations typical for a majority of aromatic compounds. The defined shape, low molecular volume, and high 3D symmetry of the surface are useful for the application of the polyhedral borane scaffolds as universal and convenient spacers for the modular assembly approach with a controllable predisposition of peripheral groups.
The application of boron neutron capture therapy (BNCT) mediated by liposomes containing ¹⁰B-enriched polyhedral borane and carborane derivatives for the treatment of head and neck cancer in the ...hamster cheek pouch oral cancer model is presented. These liposomes are composed of an equimolar ratio of cholesterol and 1,2-distearoyl- sn -glycero-3-phosphocholine, incorporating K nido -7-CH ₃(CH ₂) ₁₅-7,8-C ₂B ₉H ₁₁ (MAC) in the bilayer membrane while encapsulating the hydrophilic species Na ₃ ae -B ₂₀H ₁₇NH ₃ (TAC) in the aqueous core. Unilamellar liposomes with a mean diameter of 83 nm were administered i.v. in hamsters. After 48 h, the boron concentration in tumors was 67 ± 16 ppm whereas the precancerous tissue contained 11 ± 6 ppm, and the tumor/normal pouch tissue boron concentration ratio was 10:1. Neutron irradiation giving a 5-Gy dose to precancerous tissue (corresponding to 21 Gy in tumor) resulted in an overall tumor response (OR) of 70% after a 4-wk posttreatment period. In contrast, the beam-only protocol gave an OR rate of only 28%. Once-repeated BNCT treatment with readministration of liposomes at an interval of 4, 6, or 8 wk resulted in OR rates of 70–88%, of which the complete response ranged from 37% to 52%. Because of the good therapeutic outcome, it was possible to extend the follow-up of BNCT treatment groups to 16 wk after the first treatment. No radiotoxicity to normal tissue was observed. A salient advantage of these liposomes was that only mild mucositis was observed in dose-limiting precancerous tissue with a sustained tumor response of 70–88%.
Significance Boron neutron capture therapy (BNCT) for cancer is based on the selective uptake of ¹⁰B target compounds by tumor cells followed by neutron irradiation. The capture reaction between ¹⁰B 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 ₂B ₉H ₁₁ (MAC) in the bilayer membrane and encapsulating the hydrophilic species Na ₃ ae -B ₂₀H ₁₇NH 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, -NH(2), -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., PEG(16) and PEG(24)) 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(v)β(3)) 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.
A mild protocol for the palladium-catalyzed Buchwald−Hartwig amidation of icosahedral carboranes is described. Employing 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (1) as a ligand and ...K3PO4 as a base, benzamide, trifluoroacetamide, acetamide, and formamide were coupled to a series of mono- and di-iodo carboranes furnishing the respective carborane derivatives in good to excellent yields. Subsequent base-mediated saponification of the trifluoroacetamide derivatives was shown to provide the free aminocarboranes. The structures of N-(1,7-dicarba-closo-dodecaboran-9-yl)benzamide (8a), N-(1,7-dicarba-closo-dodecaboran-9-yl)trifluoroacetamide (8b), N-(1,12-dicarba-closo-dodecaboran-2-yl)benzamide (10a), N-(1,2-dicarba-closo-dodecaboran-9-yl)benzamide (12a), N-(1,2-dicarba-closo-dodecaboran-9-yl)acetamide (12c), N-(1,2-dicarba-closo-dodecaboran-9-yl)formamide (12d), N-(1,2-dicarba-closo-dodecaboran-3-yl)benzamide (13a), N,N′-(1,7-dicarba-closo-dodecaboran-9,10-diyl)dibenzamide (15a), and N,N′-(1,7-dicarba-closo-dodecaboran-9,10-diyl)bis(trifluoroacetamide) (15b) have been established through X-ray single-crystal diffraction studies.
Rotary biomolecular machines rely on highly symmetric supramolecular structures with rotating units that operate within a densely packed frame of reference, stator, embedded within relatively rigid ...membranes. The most notable examples are the enzyme FoF1 ATP synthase and the bacterial flagellum, which undergo rotation in steps determined by the symmetries of their rotators and rotating units. Speculating that a precise control of rotational dynamics in rigid environments will be essential for the development of artificial molecular machines, we analyzed the relation between rotational symmetry order and equilibrium rotational dynamics in a set of crystalline molecular gyroscopes with rotators having axial symmetry that ranges from two- to fivefold. The site exchange frequency for these molecules in their closely related crystals at ambient temperature varies by several orders of magnitude, up to ca. 4.46 × 10 8 s −1 .
Rotary motion around a molecular axis has been controlled by simple electron transfer processes and by photoexcitation. The basis of the motion is intramolecular rotation of a carborane cage ligand ...(7,8-dicarbollide) around a nickel axle. The Ni(III) metallacarborane structure is a transoid sandwich with two pairs of carbon vertices reflected through a center of symmetry, but that of the Ni(IV) species is cisoid. The interconversion of the two provides the basis for controlled, rotational, oscillatory motion. The energies of the Ni(III) and Ni(IV) species are calculated as a function of the rotation angle.
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