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PubMed2003

Promising survival in patients with high-grade gliomas following therapy with a novel boronated porphyrin.

Current treatment strategies for high-grade gliomas are inadequate with high rates of disease recurrence and poor overall survival. Photodynamic therapy has been extensively investigated for a variety of tumours including high-grade gliomas. We have previously described a novel boronated porphyrin (BOPP) which has highly selective uptake by tumour cells. A Phase I study documented that BOPP at a dose of 4mg/kg was well tolerated. We report here the survival data arising from this Phase I study. Overall 28 patients (pts) with high-grade gliomas were treated with BOPP photodynamic therapy with a median overall survival (OS) of 14 months (2-48+ months). Sixteen pts had glioblastoma multiforme (GBM) with a median OS of 8 months (2-38+). Of 9 pts with recurrent GBM, the median OS was 11 months (3-38+), with 56% surviving at least 12 months. In conclusion, BOPP photodynamic therapy was associated with encouraging survival particularly in the recurrent GBM setting.

Adult↗
PubMed2002

Linkage of boronated polylysine to glycoside moieties of polyclonal antibody; boronated antibodies as potential delivery agents for neutron capture therapy.

Among the ways to deliver comparatively large amounts of boron to cells in vitro for boron neutron capture studies is the linkage of a boronated macromolecule such as polylysine to an antibody. In order to reduce interference with immunoreactivity, boronated polylysine (BPL) was linked to oligosaccharide moieties on the IgG molecule distant from the antibody combining sites. The resultant bioconjugate was chromatographically separated from free BPL and unconjugated antibody using a Sephacryl S300 column. The total measured boron per BPL-IgG conjugate, determined by direct current plasma atomic emission spectroscopy, was estimated to be approximately 6 x 10(3) atoms. This, together with molecular weight estimations, indicated conjugation of about 3 polylysines to each IgG molecule. Immunoreactivity of the conjugate was found to be the same as that of the unconjugated polyclonal antibody. This was based on its concentration dependent interference with immunometric reactions for an antigen (TSH), whereas heat inactivated or non-specific antibody had no such inhibitory effects. The results support the hypothesis that the binding affinity of the conjugate for antigen was preserved after its linkage to BPL under the conditions described. The methodology described in this report may have applicability for the preparation of boronated antibodies as delivery agents for BNCT.

Antibodies↗
PubMed1998

New horizons for therapy based on the boron neutron capture reaction.

Boron neutron capture therapy (BNCT) is currently undergoing clinical trials in the USA, Japan and The Netherlands with patients afflicted with deadly brain cancer (glioblastoma multiforme) or melanoma. This therapy relies on a binary process in which the capture of a slow neutron by a 10B nucleus leads to an energetic nuclear fission reaction, with the formation of 7Li3+ and 4He2+ and accompanied by about 2.4 MeV of energy. The fleeting 7Li3+ and 4He2+ travel a distance of only about the diameter of one cell, and they are deadly to any cell in which they have been produced. Research in progress is concerned with the development of advanced boron agents and neutron sources, other than nuclear reactors, for the treatment of a variety of cancer types using novel 10B delivery methods. Non-malignant diseases such as rheumatoid arthritis offer additional opportunities for BNCT. The entire BNCT area awaits commercialization.

Animals↗
PubMedDate not supplied

Boronated starburst dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture therapy.

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy or thermal neutrons (< or = 0.025 eV) to yield high LET alpha particles and recoiling 7Li nuclei [10B + nth-->[11B]-->4He(alpha) + 7Li + 2.39 MeV]. Approximately 10(9) boron-10 atoms must be delivered to each target cell in order to sustain a lethal 10B(n,alpha)7Li reaction. If MoAbs are to be used for targeting boron-10, then it is essential that they recognize a surface membrane epitope that is highly expressed on tumor cells and that a large number of boron-10 atoms be attached to each antibody molecule. In order to heavily boronate MoAbs, we have utilized starburst dendrimers (SD), which are precise, spherical macromolecules composed of repetitive poly(amidoamino) groups. Second- and fourth-generation dendrimers, having 12 and 48 reactive terminal amino groups and molecular weights of 2414 and 10,632 Da, respectively, were boronated using an isocyanato polyhedral borane, Na(CH3)3NB10H8NCO. The boronated starburst dendrimers (BSD), in turn, were derivatized with m-maleimidobenzoyl N-hydroxysulfosuccinimide ester (sulfo-MBS). The MoAbIB16-6, which is directed against the murine B16 melanoma, was derivatized with N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP). The MBS-derivatized BSD and SPDP-derivatized MoAb were reacted to yield stable immunoconjugates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Synthesis and biological evaluation of folate receptor-targeted boronated PAMAM dendrimers as potential agents for neutron capture therapy.

Successful treatment of cancer by boron neutron capture therapy (BNCT) requires the selective delivery of (10)B to constituent cells within a tumor. The expression of the folate receptor is amplified in a variety of human tumors and potentially might serve as a molecular target for BNCT. In the present study we have investigated the possibility of targeting the folate receptor on cancer cells using folic acid conjugates of boronated poly(ethylene glycol) (PEG) containing 3rd generation polyamidoamine dendrimers to obtain (10)B concentrations necessary for BNCT by reducing the uptake of these conjugates by the reticuloendothelial system. First we covalently attached 12-15 decaborate clusters to 3rd generation polyamidoamine dendrimers. Varying quantities of PEG units with varying chain lengths were then linked to these boronated dendrimers to reduce hepatic uptake. Among all prepared combinations, boronated dendrimers with 1-1.5 PEG(2000) units exhibited the lowest hepatic uptake in C57BL/6 mice (7.2-7.7% injected dose (ID)/g liver). Thus, two folate receptor-targeted boronated 3rd generation polyamidoamine dendrimers were prepared, one containing approximately 15 decaborate clusters and approximately 1 PEG(2000) unit with folic acid attached to the distal end, the other containing approximately 13 decaborate clusters, approximately 1 PEG(2000) unit, and approximately 1 PEG(800) unit with folic acid attached to the distal end. In vitro studies using folate receptor (+) KB cells demonstrated receptor-dependent uptake of the latter conjugate. Biodistribution studies with this conjugate in C57BL/6 mice bearing folate receptor (+) murine 24JK-FBP sarcomas resulted in selective tumor uptake (6.0% ID/g tumor), but also high hepatic (38.8% ID/g) and renal (62.8% ID/g) uptake, indicating that attachment of a second PEG unit and/or folic acid may adversely affect the pharmacodynamics of this conjugate.

Animals↗
PubMedDate not supplied

Functionalization and cellular uptake of boron carbide nanoparticles. The first step toward T cell-guided boron neutron capture therapy.

In this paper we present surface modification strategies of boron carbide nanoparticles, which allow for bioconjugation of the transacting transcriptional activator (TAT) peptide and fluorescent dyes. Coated nanoparticles can be translocated into murine EL4 thymoma cells and B16 F10 malignant melanoma cells in amounts as high as 0.3 wt. % and 1 wt. %, respectively. Neutron irradiation of a test system consisting of untreated B16 cells mixed with B16 cells loaded with boron carbide nanoparticles were found to inhibit the proliferative capacity of untreated cells, showing that cells loaded with boron-containing nanoparticles can hinder the growth of neighboring cells upon neutron irradiation. This could provide the first step toward a T cell-guided boron neutron capture therapy.

Animals↗
PubMedDate not supplied

Transferrin-loaded nido-carborane liposomes: tumor-targeting boron delivery system for neutron capture therapy.

The nido-carborane lipid 2 as a double-tailed boron lipid was synthesized from heptadecanol in five steps. The lipid 2 formed stable liposomes at 25% molar ratio toward DSPC with cholesterol. Transferrin was able to be introduced on the surface of boron liposomes (Tf(+)-PEG-CL liposomes) by the coupling of transferrin to the PEG-CO(2)H moieties of Tf(-)-PEG-CL liposomes. The biodistribution of Tf(+)-PEG-CL liposomes, in which (125)I-tyraminyl inulins were encapsulated, showed that Tf(+)-PEG-CL liposomes accumulated in tumor tissues and stayed there for a sufficiently long time to increase tumor/blood concentration ratio, although Tf(-)-PEG-CL liposomes were gradually released from tumor tissues with time. A boron concentration of 22 ppm in tumor tissues was achieved by the injection of Tf(+)-PEG-CL liposomes at 7.2 mg/kg body weight boron in tumor-bearing mice. After neutron irradiation, the average survival rate of mice not treated with Tf(+)-PEG-CL liposomes was 21 days, whereas that of the treated mice was 31 days. Longer survival rates were observed in the mice treated with Tf(+)-PEG-CL liposomes; one of them even survived for 52 days after BNCT.

Animals↗
PubMed1995

Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine, and ornithine analogs.

The X-ray crystallographic structure of Ac-(D)Phe-Pro-boroArg-OH [DuP714, Ki = 0.04 nM; Kettner, C., Mersinger, L., & Knabb, R. (1990) J. Biol. Chem. 265, 18289] complexed with human alpha-thrombin shows the boron atom covalently bonded to the side-chain oxygen of the active site serine, Ser195. The boron adopts a nearly tetrahedral geometry, and the boronic acid forms a set of interactions with the protein that mimic the tetrahedral transition state of serine proteases. Contributions of the arginine side chain to inhibitor affinity were examined by synthesis of the ornithine, lysine, homolysine, and amidine analogs of DuP714. The basic groups interact with backbone carbonyl groups, water molecules, and an aspartic acid side chain (Asp189) located in the thrombin S1 specificity pocket. The variation in inhibition constant by 3 orders of magnitude appears to reflect differences in the energetics of interactions made with thrombin and differences in ligand flexibility in solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Amidines↗
PubMed2001

Slow-binding inhibition of gamma-glutamyl transpeptidase by gamma-boroGlu.

gamma-Glutamyl transpeptidase (gammaGTase) catalyzes the transfer of the gamma-glutamyl moiety of gamma-glutamyl-derived peptides, such as glutathione (gammaGlu-Cys-Gly), and anilides, such as gamma-glutamyl-7-amido-4-methylcoumarin (gammaGlu-AMC), to acceptor molecules, including water and various dipeptides. These acyl-transfer reactions all occur through a common acyl-enzyme intermediate formed from attack of an active site hydroxyl on the gamma-carbonyl carbon of gammaGlu-X with displacement of X. In this paper, we report that gammaGTase is potently inhibited by the gamma-boronic acid analogue of L-glutamic acid, 3-amino-3-carboxypropaneboronic acid (gamma-boroGlu). We propose that gamma-boroGlu adds to the active site hydroxyl of gammaGTase to form a covalent, tetrahedral adduct that resembles tetrahedral transition states and intermediates that occur along the reaction pathway for gammaGTase-catalyzed reactions. Our studies demonstrate that gamma-boroGlu is a competitive inhibitor of the gammaGTase-catalyzed hydrolysis of gammaGlu-AMC with a K(i) value of 35 nM. Kinetics of inhibition studies allow us to estimate the following values: k(on) = 400 mM(-1) s(-1) and k(off) = 0.02 s(-1). We also found that gamma-boroGlu is an uncompetitive inhibitor of Gly-Gly-promoted transamidation of gammaGlu-AMC. This observation is consistent with the kinetic mechanism we determined for gammaGTase-catalyzed transamidation of gammaGlu-AMC by Gly-Gly to form gammaGlu-Gly-Gly. To probe rate-limiting transition states for gammaGTase catalysis and inhibition, we determined solvent deuterium isotope effects. Solvent isotope effects on k(c)/K(m) for hydrolysis of gammaGlu-AMC and k(on) for inhibition by gamma-boroGlu are identical and equal unity, suggesting that the processes governed by these rate constants are both rate-limited by a step that is insensitive to solvent deuterium such as a conformational fluctuation of the initially formed E-S or E-I complex. In contrast, the solvent isotope effect on k(c) is 2.4. k(c) is rate-limited by hydrolysis of the acyl-enzyme intermediate that is formed during reaction of gammaGTase with gammaGlu-AMC. Thus, the magnitude of this isotope effect suggests the formation of a catalytically important protonic bridge in the rate-limiting transition state for deacylation.

Acylation↗
PubMed2001

Classical and slow-binding inhibitors of human type II arginase.

Arginases catalyze the hydrolysis of L-arginine to yield L-ornithine and urea. Recent studies indicate that arginases, both the type I and type II isozymes, participate in the regulation of nitric oxide production by modulating the availability of arginine for nitric oxide synthase. Due to the reciprocal regulation between arginase and nitric oxide synthase, arginase inhibitors have therapeutic potential in treating nitric oxide-dependent smooth muscle disorders, such as erectile dysfunction. We demonstrate the competitive inhibition of the mitochondrial human type II arginase by N(omega)-hydroxy-L-arginine, the intermediate in the reaction catalyzed by nitric oxide synthase, and its analogue N(omega)-hydroxy-nor-L-arginine, with K(i) values of 1.6 microM and 51 nM at pH 7.5, respectively. We also demonstrate the inhibition of human type II arginase by the boronic acid-based transition-state analogues 2(S)-amino-6-boronohexanoic acid (ABH) and S-(2-boronoethyl)-L-cysteine (BEC), which are known inhibitors of type I arginase. At pH 7.5, both ABH and BEC are classical, competitive inhibitors of human type II arginase with K(i) values of 0.25 and 0.31 microM, respectively. However, at pH 9.5, ABH and BEC are slow-binding inhibitors of the enzyme with K(i) values of 8.5 and 30 nM, respectively. The findings presented here indicate that the design of arginine analogues with uncharged, tetrahedral functional groups will lead to the development of more potent inhibitors of arginases at physiological pH.

Aminocaproates↗
PubMed2004

The 1,4-diphosphabuta-1,3-diene ligand for coordination of divalent group 13 and 14 elements: a density functional study.

The 1,4-diphosphabuta-1,3-diene (DPB) ligand as a tool for stabilizing anionic group 13 (B, Al, Ga) and neutral group 14 (C, Si, Ge) cyclic Arduengo-type carbenes is studied by quantum chemical calculations at density functional level. Accordingly, for the former group this ligand is better suited than the corresponding 1,4-diazabuta-1,3-diene (DAB) ligand. It results in larger electron affinities for the corresponding doublet states. For the latter group the DPB ligand yields essentially smaller singlet-triplet separations than the DAB ligand. An exception is the anionic boron compound with relative low singlet stability for both the DAB and DPB ligands.

Journal Article↗
PubMed2005

Hydride affinities of borane derivatives: novel approach in determining the origin of lewis acidity based on triadic formula.

The problem of intrinsic Lewis acidities of simple boron compounds (BH3-mXm, m = 0-3, X = F, Cl, Br, CH3, and OH) is assessed by their gas-phase hydride affinities (HAs). A simple and intuitively appealing picture of the interaction process including detachment of an electron from the hydride ion H-, capture of the pruned electron to the investigated Lewis acid (LA), and subsequent formation of the homolytic chemical bond between two newly created radicals is proposed. It enables transparent and straightforward dissection of the initial and final state effects, which taken together with the intermediate relaxation stabilization determine the trend of changes in the hydride affinities. The former effect is reflected in the electron affinities of the neutral Lewis acids given within Koopmans' approximation, while the final state effect involves properties of the formed Lewis acid-base adducts mirrored in the bond dissociation energy of the formed [LA-H]- chemical bond. It is demonstrated that unexpectedly low Lewis acidity of fluoroboranes relative to the corresponding chlorine and bromine derivatives can be traced down to the unfavorable Koopmans' electron affinities. Hence, it is a consequence of the initial state effect. In contrast, chloroboranes are more potent Lewis acids than fluoroboranes, because the relaxation and final state effects decisively influence their Lewis acidity. Finally, bromine-substituted borane compounds provide the most powerful studied Lewis acids. Their hydride affinities are result of a synergic interplay of the initial state, intermediate stabilization via relaxation, and final state effects. It is shown that Pearson's global hardness indices defined within his hard and soft acid-base (HSAB) principle fail to adequately predict and interpret the calculated hydride affinities.

Journal Article↗
PubMed2006

Closomers of high boron content: synthesis, characterization, and potential application as unimolecular nanoparticle delivery vehicles for boron neutron capture therapy.

Unique nanosized closomers of high boron content that may exhibit potential as boron neutron capture therapy target species have been synthesized. The design of these boron-rich nanospheres is based in part on previous work involving dodeca(carboranyl)-substituted closomers [Thomas, J.; Hawthorne, M. F. Chem. Commun. 2001, 1884-1885]. Coupling of ortho-carborane moieties through ester and ether linkages to the rigid [closo-B(12)(OH)(12)](2-) scaffold resulted in the development of a 12(12)-closomer-ester derivative, dodeca[6-(1,2-dicarba-closo-dodecaboran-1-yl)hexanoate]-closo-dodecaborate (2-), 6, and 12(12)-closomer-ether derivatives, dodeca[6-(2-methy1-1,2-dicarba-nido-dodecaboran-1-yl)hexyl]-closo-dodecaborane (14-), 14, and dodeca[6-(7,8-dicarba-nido-dodecaboran-7-yl)hexyl]-closo-dodecaborane (14-), 15. These closomers were investigated by UV-visible spectroscopy and cyclic voltammetry. Additionally, a deboronation method employing NaCN as the nucleophilic reagent was utilized to obtain sodium salts of the ether-linked nido-closomer polyanions, which were purified using a newly developed size-exclusion high pressure liquid chromatography method.

Animals↗
PubMed2006

Boron macrocycles having a calix-like shape. Synthesis, characterization, X-ray analysis, and inclusion properties.

The syntheses, structure, and inclusion properties of trinuclear boron compounds having a calix-like shape are described. The compounds have been obtained via self-assembly reactions between salicylaldehyde derivatives and 3-aminophenylboronic acid, whereby the formation of three N --> B coordination bonds favored the oligomerization. The products have high melting points (>370 degrees C), are stable to moisture, and have good solubility in organic solvents; the latter property is useful for host-guest recognition experiments. The structural analysis by X-ray diffraction revealed that diverse conformations are possible because of the presence of two different units of aromatic rims. A cone-cone (double-cone) conformation is observed for three of these compounds, while the remaining one has a cone-partial cone conformation. An analysis of the molecular packing showed that the molecules are stacked in columns in two different orientations in relation to the organization of the macrocycles when referred to the N-B bonds. The inclusion properties toward primary amines and ammonium chlorides were analyzed by titration experiments and monitored by UV spectroscopy, whereby association constants on the order of 10(2)-10(3) M(-1) were determined.

Journal Article↗
PubMed2006

Tricarboranyl pentaerythritol-based building block.

A new tricarborane building block based on pentaerythritol was prepared for applications in boron neutron capture therapy (BNCT). Its X-ray single-crystal structure revealed a high degree of steric congestion. To enable the attachment of the building block to other moieties, a succinimidyl linker has been introduced at the focal point, and a generation-2 hexacarborane-containing dendron carrying 60 boron atoms has been prepared using a 2,2-bis(hydroxymethyl)propionic acid core.

Boron Compounds↗
PubMed2000

The synthesis and characterization of bis-substituted derivatives of the [a2-B20H18]4- anion and the interconversion of isomers.

The apical-apical (a2) isomer of [Et4N]4[B20H18] reacts with oxalyl chloride in dichloromethane to produce a protonated bis-substituted carbonyl species, [Et4N][a2-B20H17(CO)2] ([Et4N][H1]), in 60% yield. Removal of the bridging hydrogen of the [H1]- anion in aprotic media results in rearrangement to form the equatorial-equatorial [e2-B20H16(CO)2]2- anion ([e2-1]2-). The reaction of [Et4N][H1] with sodium azide in acetonitrile produces [Et4N]3- [a2-B20H17(NCO)2] ([Et4N]3[H2]) in 53% yield, which subsequently reacts with isopropylamine in acetonitrile to provide the urea derivative [a2-B20H16(NH2C(O)NH(i-Pr))2]2- ([Et4N]2[4]) in 89% yield. The [H1]- ion is hydrolyzed in aqueous acetonitrile to give a protonated [a2-B20H17(CO2H)2]3- ion ([H3]3-) in 61% yield. The a2 isomers of the bis-substituted species [B20H16(CO2H)2]4- ([3]4-), [B20H16(NCO)2]4- ([2]4-), and [B20H16(NH2C(O)NH(i-Pr))2]2- ([4]2-), formed by the removal of the bridging proton from their protonated precursors, rearrange to form a mixture of ae isomers in solution.

Anions↗