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A H Soloway

Publications and source records attributed to A H Soloway.

83 records · Page 5Linked to original sources
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)

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PubMedDate not supplied

Boronated epidermal growth factor as a potential targeting agent for boron neutron capture therapy of brain tumors.

In order for boron neutron capture therapy (BNCT) to be successful, a large number (approximately 10(9)) of 10B atoms must be delivered to each cancer cell in order to sustain a lethal 10B(n, alpha)7Li reaction. The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and increased numbers of EGFR are found on the cell surface. If a sufficiently large number of 10B atoms could be attached to EGF, the resulting bioconjugates might be useful for targeting brain tumors. In order to accomplish this, we have boronated a fourth-generation starburst dendrimer (SD) using an isocyanato polyhedral borane, Na(CH3)3NB10H8NCO. For conjugation, reactive thiol groups were introduced into the boronated SD using N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), and EGF was derivatized with m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (sMBS). Subsequent reaction of thiol groups of derivatized BSD with maleimide groups of derivatized EGF produced stable BSD-EGF bioconjugates containing approximately 960 atoms of boron per molecule of EGF. As determined by electron spectroscopic imaging, the BSD-EGF initially was bound to the cell surface membrane and then was endocytosed, which resulted in accumulation of boron in lysosomes. The favorable in vitro properties of these bioconjugates suggest that they may be useful for the in vivo targeting of EGFR positive brain tumors.

Amino Acid Sequence↗
PubMedDate not supplied

In vivo evaluation of phosphorous-containing derivatives of dodecahydro-closo-dodecaborate for boron neutron capture therapy of gliomas and sarcomas.

The in vivo uptake of dodecahydro-closo-dodecaborate derivatives substituted with phosphate- and bisphosphonate groups was evaluated in two different experimental tumor model systems and compared to other boronated and non-boronated compounds. These phosphorous-containing boron clusters may have potential for use in boron neutron capture therapy, a chemoradiotherapeutic form of cancer treatment. Using the F98 rat glioma as a brain tumor model in syngeneic Fischer rats, there was selective tumor uptake of the phosphate derivative with 21.5 micrograms boron/g tumor versus 5.2 micrograms/g normal brain and a tumor:blood ratio of 2.7. However, this compound was toxic to test animals and lethal at relatively low doses. The uptake of the bisphosphonate by the murine K8 osteosarcoma was approximately 18 micrograms boron/g tumor with a T:Bl ratio of 7.6 and a tumor:bone ratio of 1.5. This compound was non toxic to the test animals. The results indicate that phosphate- and bisphosphonate derivatives of dodecahydro-closo-dodecaborate may have potential for BNCT of gliomas and osteosarcomas, respectively.

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PubMedDate not supplied

In vitro and in vivo evaluation of o-carboranylalanine as a potential boron delivery agent for neutron capture therapy.

o-Carboranylalanine (B10H10C2CH2CHNH2COOH) is a carborane-containing amino acid, which has been synthesized as a potential capture agent for boron neutron capture therapy (BNCT) of cancer. The purpose of the present study was to develop a rational approach for the in vitro and in vivo evaluation of boron containing compounds that possibly might be used for BNCT. The in vitro uptake of carboranylalanine (CBA) was evaluated using two cell lines, the human melanoma MRA 27, and the murine Harding-Passey melanoma. Uptake of CBA by MRA 27 cells ranged from 135-551 micrograms B/10(9) cells following 3 hrs incubation with medium containing 100-113 micrograms B/ml and was not reduced by exposing the tumor cells to either rotenone, an inhibitor of electron transport, or by culturing them at ambient temperature (approximately 22 degrees C). Cellular uptake and elution of CBA occurred rapidly under in vitro conditions. Uptake of CBA was slightly greater than that of boronophenylalanine (BPA). Following a 3 hr incubation with CBA at a concentration of 106 micrograms B/ml, cell boron content was 255 micrograms B/10(9) MRA 27 cells, compared to 192 micrograms B/10(9) cells when cells were incubated with BPA at a concentration of 95 micrograms B/ml. In vivo studies initially were carried out using the Harding-Passey melanoma, which had been implanted intramuscularly (i.m.) into the right flank of BALB/c mice. Tumors were allowed to grow for 14 days at which time mice were injected intraperitoneally (i.p.) with either CBA or BPA (1.25 mgB/mouse), and were killed 3, 6 and 8 hrs later. CBA attained a low tumor to blood ratio(1.0-1.4), and the tumor boron levels ranged from 15.7-26.2 micrograms B/g at 3 hrs and 3.3-19.9 micrograms B/g at 6 hrs. Higher blood and lower tumor boron levels were observed at all time points with CBA compared to BPA, suggesting that CBA was not taken up selectively by the melanoma. Similar studies, carried out in rats bearing intra-cerebral gliomas, failed to reveal detectable amounts of boron in the tumor. From the present study, it can be concluded that CBA does not appear to possess the requisite properties to be useful as a boron delivery agent for BNCT.

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PubMedDate not supplied

Evaluation of in vitro cytotoxicity of carboranyl amino acids, their chemical precursors and nido carboranyl amino acids for boron neutron capture therapy.

The purpose of the present study was to define the in vitro cellular toxicity of three carborane-containing amino acids: p-(o-carboran-yl)-phenylalanine (CBPA), O-(o-carboran-1-ylmethyl)-tyrosine (CBT), and o-carboranylalanine (CBA), which are analogues of phenylalanine, tyrosine, and alanine respectively. In addition, two of their chemical precursors: CBACN (B10H11C2-CH2CHNH2CN) and CBTCN (B10H11C2-CH2OC6H4CH2CHNH2CN) and nido CBA were evaluated for their toxicity on human MRA 27 melanoma cells. Hydroxypropyl-beta-cyclodextrin (beta-CD) initially was used to solubilize all the compounds except nido CBA in the toxicity assays Cells were incubated with the test compounds at varying concentrations for 24 hrs, following which the proliferative activity of surviving cells was determined by pulsing with tritiated thymidine ([3H]-TdR) for an additional 18 hrs. CBT at a concentration of 280 micrograms/ml was non-toxic when solubilized with beta-CD. CBA at a concentration of 350 micrograms/ml was non-toxic when solubilized with beta-CD, but when solubilized with DMSO produced a 50% reduction in uptake of [3H]-TdR at a concentration of 75 micrograms/ml. CBPA, solubilized with beta-CD, was nontoxic at a concentration of 400 micrograms/ml, while CBTCN and CBACN at concentrations of 50 micrograms/ml and 40 micrograms/ml, respectively, were both toxic, even when solubilized with beta-CD. Nido CBA at a concentration of 400 micrograms/ml in medium was non-toxic. Although the toxicity of these boron compounds precludes their use as capture agents for Neutron Capture Therapy, they may have some potential for cytoreductive chemotherapy of cancer, and further evaluation may be warranted.

Amino Acids↗
PubMedDate not supplied

In vitro and in vivo evaluation of carboranyl uridines as boron delivery agents for neutron capture therapy.

The purpose of the present study was to evaluate 2' and 5'-O-(o-carboran-1-ylmethyl)uridine (CBU-2' and CBU-5') as delivery agents for Boron Neutron Capture Therapy (BNCT) of brain tumors. The in vitro cellular uptake, persistence, subcellular distribution and cytotoxicity, and in vivo biodistribution of CBU-2' have been studied as follows. Cellular uptake studies were carried out with the F98 rat glioma, U-87 MG human glioma, B16 melanoma, SP2/0 myeloma and MDCK fibroblasts. All tumor and non-tumor cell lines had high uptake of CBU-2' (46-75 ppm), indicating that uptake was not selective for neoplastic cells and was independent of cell proliferation. In vitro persistence studies showed high cellular retention of CBU-2' compared to sodium borocaptate (BSH), when cells were transferred from boron-containing to boron-free medium and cultured for an additional 24-48 hours. Subcellular fractionation revealed 75.6% of the recoverable boron was cell membrane associated, 15.6% was in the cytosol, and 8.8% was in the nuclear fraction, but no boron was detectable in the RNA and DNA fractions. F98 glioma cells were cultured in the presence of 3 metabolic inhibitors (rotenone, dipyridamole and NBMPR ¿6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine¿) and none of these blocked the cellular uptake of CBU-2' suggesting that uptake was neither energy nor nucleoside transport dependent. In vivo studies in F98 glioma bearing rats showed that CBU-2' in tumor attained concentrations of 8.0 +/- 2.1 micrograms B/g tissue, which was 13 x greater than that in normal brain of the ipsilateral and contralateral cerebral hemispheres (0.6 +/- 0.2 microgram B/g). The B levels, however, were still lower than the minimum 20-35 microgram B/g, which are required for in vivo BNCT. In summary, our in vitro and in vivo data indicate that CBU-2' was not sufficiently selective for in vivo targeting of brain tumors. However, CBU-2' and CBU-5' were highly toxic for F98 glioma cells in vitro (IC50 = 3 - 13 x 10(-5) M), as determined by measuring the uptake of 3H-thymidine, and the survival of F98 glioma cells using a clonogenic assay, which suggests that these compounds should be further evaluated as potential cytoreductive chemotherapeutic agents.

Animals↗
PubMedDate not supplied

Critical evaluation of bispecific antibodies as targeting agents for boron neutron capture therapy of brain tumors.

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when 10B, a stable isotope, is irradiated with low energy neutrons to produce high linear energy transfer (LET) alpha particles and recoiling 7Li nuclei. In order for BNCT to be successful in treating cancer, approximately 10(9) boron atoms must be delivered per tumor cell to sustain a lethal 10B, (n,a) 7Li capture reaction. In the present study, we have produced and characterized a bispecific antibody (BsAbB8), which was reactive with both human glioma and melanoma cell lines, as well as with a variety of polyhedral borane anions (PBA). The affinity constants (KA) of BsAb-B8 with D-54 MG and M21 cells were 3.49 and 2.57 x 10(8) M-1, respectively, which were almost identical to those of the parental mAb 9.2.27 with these cell lines. In vivo tumor localizing properties were studied in nude mice bearing subcutaneous xenografts of the D-54 MG glioma. Following intravenous injection of 131I-labeled BsAb-B8, 3.4 +/- 0.2% of the injected dose/g was detected in the tumor at 24 hours, and then slowly declined to 2.0 +/- 0.4% at 96 hours compared to 1.34 +/- 0.07% and 0.03 +/- 0.01%, respectively, for normal mouse IgG. Based on the assumption that all the tumor cell antigenic receptor sites could be saturated, the following calculations have been carried out. The maximum concentration of BsAb-B8 that could be delivered to 1 g of D-54 MG glioma cells would be 99.6 micrograms, which could bind 71.7 ng of a PBA. However, since at least 500 x more boron would be required per gram of tumor to sustain a lethal 10B (n,a) 7Li capture reaction, a macromolecule containing -10(3)-10(4) boron atoms rather than a low molecular weight PBA would be required to deliver this amount. Such boron containing macromolecules have been synthesized by us, and future studies should provide information on the feasibility of using them in combination with BsAb-B8 to deliver the requisite amount of 10B.

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