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1.
J Control Release ; 371: 445-454, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38844180

RESUMO

In boron neutron capture therapy (BNCT), boron drugs should exhibit high intratumoral boron concentrations during neutron irradiation, while being cleared from the blood and normal organs. However, it is usually challenging to achieve such tumor accumulation and quick clearance simultaneously in a temporally controlled manner. Here, we developed a polymer-drug conjugate that can actively control the clearance of the drugs from the blood. This polymer-drug conjugate is based on a biocompatible polymer that passively accumulates in tumors. Its side chains were conjugated with the low-molecular-weight boron drugs, which are immediately excreted by the kidneys, via photolabile linkers. In a murine subcutaneous tumor model, the polymer-drug conjugate could accumulate in the tumor with the high boron concentration ratio of the tumor to the surrounding normal tissue (∼10) after intravenous injection while a considerable amount remained in the bloodstream as well. Photoirradiation to blood vessels through the skin surface cleaved the linker to release the boron drug in the blood, allowing for its rapid clearance from the bloodstream. Meanwhile, the boron concentration in the tumor which was not photoirradiated could be maintained high, permitting strong BNCT effects. In clinical BNCT, the dose of thermal neutrons to solid tumors is determined by the maximum radiation exposure to normal organs. Thus, our polymer-drug conjugate may enable us to increase the therapeutic radiation dose to tumors in such a practical situation.


Assuntos
Terapia por Captura de Nêutron de Boro , Polímeros , Terapia por Captura de Nêutron de Boro/métodos , Animais , Polímeros/química , Polímeros/farmacocinética , Polímeros/administração & dosagem , Linhagem Celular Tumoral , Compostos de Boro/farmacocinética , Compostos de Boro/administração & dosagem , Compostos de Boro/química , Luz , Feminino , Camundongos , Neoplasias/radioterapia , Neoplasias/tratamento farmacológico , Boro/farmacocinética , Boro/administração & dosagem , Boro/química , Camundongos Endogâmicos BALB C , Humanos
2.
Mol Nutr Food Res ; 65(15): e2100345, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34061440

RESUMO

SCOPE: Boron is a trace element that naturally occurs in soil, making mineral and medicinal water important contributors to overall intake. Thus, in a systematic screening, the mean boron concentrations of 381 German mineral and medicinal waters are determined. METHODS AND RESULTS: Boron concentrations in mineral and medicinal waters are analyzed by inductively coupled mass spectrometry (ICP-MS). Highest boron values find in waters from the southwest of Germany. The boron content of the waters is positively correlated with the concentration of most other analyzed bulk elements, including calcium, potassium, magnesium, and sodium. Mineral waters with either low (7.9 µg L-1 ), medium (113.9 µg L-1 ), or high (2193.3 µg L-1 ) boron content are chosen for boron exposure experiments in fruit flies (Drosophila melanogaster) and humans. In flies, boron-rich mineral water significantly increases boron accumulation, with the accumulation predominantly occurring in the exoskeleton. In humans, serum boron and 24-h urinary boron excretion significantly increase only in response to the intake of boron-rich mineral water. CONCLUSION: Overall, the current data demonstrate that mineral and medicinal waters vary substantially in the content of boron and that boron-rich mineral water can be used to elevate the boron status, both in flies and humans.


Assuntos
Boro/análise , Boro/farmacocinética , Drosophila melanogaster/efeitos dos fármacos , Água Doce/análise , Águas Minerais/análise , Adulto , Alumínio/análise , Animais , Disponibilidade Biológica , Boro/sangue , Boro/urina , Suplementos Nutricionais , Água Doce/química , Alemanha , Voluntários Saudáveis , Humanos , Lítio/análise , Masculino , Oligoelementos/análise
3.
Molecules ; 25(20)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066470

RESUMO

In comparison with pristine sinomenine and carborane precursors, the calculations of molecular docking with matrix metalloproteinases (MMPs) and methylcarboranyl-n-butyl sinomenine showed improved interactions. Accordingly, methylcarboranyl-n-butyl sinomenine shows a high potential in the treatment of rheumatoid arthritis (RA) in the presence of slow neutrons. The reaction of potassium salt of sinomenie, which is generated from the deprotonation of sinomenine (1) using potassium carbonate in a solvent of N,N-dimethyl formamide, with 4-methylcarboranyl-n-butyl iodide, (2) forms methylcarboranyl-n-butyl sinomenine (3) in 54.3% yield as a new product. This new compound was characterized by 1H, 13C, and 11B NMR spectroscopy, FT-IR spectroscopy, and elemental analyses to confirm its molecular composition. In addition to molecular docking interactions with MMPs, the in vitro killing effects of 3, along with its toxicity measurements, exhibited its potential to be the new drug delivery agent for boron neutron capture synovectomy (BNCS) and boron neutron capture therapy (BNCT) for the treatment of rheumatoid arthritis (RA) and cancers in the presence of slow neutrons, respectively.


Assuntos
Antineoplásicos/química , Antirreumáticos/química , Antirreumáticos/farmacologia , Terapia por Captura de Nêutron de Boro/métodos , Morfinanos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antirreumáticos/síntese química , Boro/farmacocinética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Espectroscopia de Ressonância Magnética , Metaloproteinase 1 da Matriz/química , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/química , Metaloproteinase 13 da Matriz/metabolismo , Simulação de Acoplamento Molecular , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Sinoviócitos/efeitos dos fármacos
4.
Mol Pharm ; 17(10): 3885-3899, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32787269

RESUMO

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro/administração & dosagem , Portadores de Fármacos/efeitos da radiação , Glucose/efeitos da radiação , Isótopos/administração & dosagem , Neoplasias/radioterapia , Boro/farmacocinética , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos/efeitos da radiação , Glucose/análogos & derivados , Glucose/síntese química , Glucose/farmacocinética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Isótopos/farmacocinética , Simulação de Acoplamento Molecular
5.
Appl Radiat Isot ; 166: 109308, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32823081

RESUMO

We reviewed 10B concentration kinetics in the blood and tumors in human patients administered with BPA. The 10B concentration in the blood peaked at the end of intravenous infusion of BPA, followed by a biphasic-decreasing curve with half-lives for the first and second components of the curve being 0.7-3.7 and 7.2-12.0 h, respectively. The mean tumor-to-blood (T/B) ratio obtained from resected tumor samples was 3.40 ± 0.83 for melanoma and the ratio ranged from 1.4 to 4.7 for glioblastoma.


Assuntos
Compostos de Boro/farmacocinética , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias/radioterapia , Fenilalanina/análogos & derivados , Boro/administração & dosagem , Boro/sangue , Boro/farmacocinética , Compostos de Boro/administração & dosagem , Compostos de Boro/sangue , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Glioblastoma/sangue , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Humanos , Isótopos/administração & dosagem , Isótopos/sangue , Isótopos/farmacocinética , Melanoma/sangue , Melanoma/metabolismo , Melanoma/radioterapia , Neoplasias/sangue , Neoplasias/metabolismo , Fenilalanina/administração & dosagem , Fenilalanina/sangue , Fenilalanina/farmacocinética , Tomografia por Emissão de Pósitrons
6.
Appl Radiat Isot ; 165: 109331, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32777741

RESUMO

In Argentina, a multi-institutional project has been established to assess the feasibility of applying BNCT ex-situ to the treatment of patients with multiple metastases in both lungs. Within this context, this work aims at applying the neutron autoradiography technique to study boron microdistribution in the lung. A comprehensive analysis of the different aspects for the generation of autoradiographic images of both normal and metastatic BDIX rat lungs was achieved. Histology, boron uniformity, optimal tissue thickness and water content in tissue were explored for the two types of samples. A qualitative and a quantitative analysis were performed. No heterogeneities in uptake were observed in normal lung. Conversely, samples with metastasis showed preferential boron uptake in the tumour areas with respect to surrounding tissue. Surrounding tissue would present a slightly higher uptake of boron than the normal lung. Quantitative results of boron concentration values and ratios determined by neutron autoradiography were obtained. In order to contribute to BNCT dosimetry, further analysis increasing the number of samples is warranted.


Assuntos
Autorradiografia/métodos , Boro/farmacocinética , Pulmão/metabolismo , Nêutrons , Animais , Terapia por Captura de Nêutron de Boro/métodos , Ratos
7.
Biol Trace Elem Res ; 193(2): 364-376, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31069715

RESUMO

Metabolic diseases or injuries damage bone structure and self-renewal capacity. Trace elements and hydroxyapatite crystals are important in the development of biomaterials to support the renewal of bone extracellular matrix. In this study, it was assumed that the boron-loaded nanometer-sized hydroxyapatite composite supports the construction of extracellular matrix by controlled boron release in order to prevent its toxic effect. In this context, boron release from nanometer-sized hydroxyapatite was calculated by ICP-MS as in large proportion within 1 h and continuing release was provided at a constant low dose. The effect of the boron-containing nanometer-sized hydroxyapatite composite on the proliferation of SaOS-2 osteoblasts and human bone marrow-derived mesenchymal stem cells was evaluated by WST-1 and compared with the effects of nano-hydroxyapatite and boric acid. Boron increased proliferation of mesenchymal stem cells at high doses and exhibited different effects on osteoblastic cell proliferation. Boron-containing nano-hydroxyapatite composites increased osteogenic differentiation of mesenchymal stem cells by increasing alkaline phosphatase activity, when compared to nano-hydroxyapatite composite and boric acid. The molecular mechanism of effective dose of boron-containing hydroxyapatite has been assessed by transcriptomic analysis and shown to affect genes involved in Wnt, TGF-ß, and response to stress signaling pathways when compared to nano-hydroxyapatite composite and boric acid. Finally, a safe osteoconductive dose range of boron-containing nano-hydroxyapatite composites for local repair of bone injuries and the molecular effect profile in the effective dose should be determined by further studies to validation of the regenerative therapeutic effect window.


Assuntos
Boro/farmacologia , Durapatita/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/farmacologia , Regeneração Óssea/efeitos dos fármacos , Boro/química , Boro/farmacocinética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Liberação Controlada de Fármacos , Durapatita/química , Durapatita/farmacocinética , Humanos , Células-Tronco Mesenquimais/metabolismo , Nanocompostos/química , Osteoblastos/metabolismo
8.
J Med Chem ; 63(5): 2358-2371, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31589041

RESUMO

G-protein-coupled receptors like the human Y1 receptor (hY1R) are promising targets in cancer therapy due to their high overexpression on cancer cells and their ability to internalize together with the bound ligand. This mechanism was exploited to shuttle boron atoms into cancer cells for the application of boron neutron capture therapy (BNCT), a noninvasive approach to eliminate cancer cells. A maximized number of carboranes was introduced to the hY1R-preferring ligand [F7,P34]-NPY by solid phase peptide synthesis. Branched conjugates loaded with up to 80 boron atoms per peptide molecule exhibited a maintained receptor activation profile, and the selective uptake into hY1R-expressing cells was demonstrated by internalization studies. In order to ensure appropriate solubility in aqueous solution, we proved the need for eight hydroxyl groups per carborane. Thus, we suggest the utilization of bis-deoxygalactosyl-carborane building blocks in solid phase peptide synthesis to produce selective boron delivery agents for BNCT.


Assuntos
Boranos/administração & dosagem , Boro/administração & dosagem , Portadores de Fármacos/metabolismo , Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Boranos/química , Boranos/farmacocinética , Boro/química , Boro/farmacocinética , Terapia por Captura de Nêutron de Boro , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Células HEK293 , Humanos , Células MCF-7 , Neoplasias/metabolismo , Neoplasias/radioterapia , Neuropeptídeo Y/química
9.
Mater Sci Eng C Mater Biol Appl ; 107: 110340, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761244

RESUMO

Bioactive glass (BAG)/Poly (Lactic Acid) (PLA) composites have great potential for bone tissue engineering. The interest in these materials is to obtain a scaffold with tailorable properties bringing together the advantages of the composites' constituents such as the biodegradability, bioactivity and osteoinduction. The materials studied are PLA/13-93 and PLA/13-93B20 (20% of SiO2 is replaced with B2O3 in the 13-93 composition). To characterize them, they were dissolved in TRIS buffer and Simulated Body Fluid (SBF) in vitro. Over the 10 weeks of immersion in TRIS, the ion release from the composites was constant. Following immersion in SBF for 2 weeks, the hydroxyapatite (HA) layer was found to precipitate at the composites surface. By adding Boron, both these reactions were accelerated, as the borosilicate glass dissolves faster than pure silicate glass alone. Polymer degradation was studied and showed that during immersion, the pure PLA rods maintained their molecular weight whereby the composites decreased with time, but despite this the mechanical properties remained stable for at least 10 weeks. Their ability to induce osteogenic differentiation of myoblastic cells was also demonstrated with cell experiments showing that C2C12 cells were able to proliferate and spread on the composites. The Myosin Heavy Chain and Osteopontin were tracked by immunostaining the cells and showed a suppression of the myosin signal and the presence of osteopontin, when seeded onto the composites. This proves osteoinduction occurred. In studying the mineralization of the cells, it was found that BAG presence conditions the synthesizing of mineral matter in the cells. The results show that these composites have a potential for bone tissue engineering.


Assuntos
Materiais Biocompatíveis/química , Compostos de Boro/química , Osteogênese/efeitos dos fármacos , Poliésteres/química , Silicatos/química , Animais , Líquidos Corporais , Boro/farmacocinética , Fosfatos de Cálcio/química , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Durapatita/química , Vidro/química , Teste de Materiais , Camundongos , Mioblastos/citologia , Dióxido de Silício/química , Engenharia Tecidual/métodos
10.
Chemosphere ; 245: 125665, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31877459

RESUMO

Selenium (Se) is present in a wide variety of natural and man-made materials on Earth. Plants are able to tolerate and (hyper)accumulate Se to different extents. In fact, some species can tolerate and accumulate multiple elements. Puccinellia distans (P. distans), weeping alkali grass, is known to hyperaccumulate extreme concentrations of boron and tolerate high levels of salinity, therefore, we investigated the Se accumulation and tolerance capacities of this species. In addition, P. distans' Se tolerance mechanism was studied using a transcriptomic approach. The results of this study indicated that, when grown in a hydroponic system containing 80 or 120 µM Se, P. distans shoots accumulated from 1500 to 2500-fold more Se than plants grown without the element. Thus, P. distans was discovered to be a novel Se accumulator plant. RNA sequencing results and biochemical analyses helped to shed light on the Se tolerance and accumulation mechanism of P. distans. Here, we suggest that upregulation of Se assimilation and stress response genes may be due to induction of jasmonic acid signaling. In addition, we propose that the cell wall may play an important role in restriction of Se movement to the cytoplasm. Also, we hypothesize that Se accumulates in cells by sequestration of selenate in the vacuole.


Assuntos
Perfilação da Expressão Gênica , Poaceae/metabolismo , Selênio/farmacocinética , Boro/farmacocinética , Ciclopentanos , Tolerância a Medicamentos , Hidroponia , Oxilipinas , Poaceae/fisiologia , Ácido Selênico , Selênio/farmacologia , Análise de Sequência de RNA
11.
PLoS One ; 14(9): e0222022, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31479484

RESUMO

In the United States, breast cancer is one of the most common and the second leading cause of cancer-related death in women. Treatment modalities for mammary tumor are surgical removal of the tumor tissue followed by either chemotherapy or radiotherapy or both. Radiation therapy is a whole body irradiation regimen that suppresses the immune system leaving hosts susceptible to infection or secondary tumors. Boron neutron capture therapy (BNCT) in that regard is more selective, the cells that are mostly affected are those that are loaded with 109 or more 10B atoms. Previously, we have described that liposomal encapsulation of boron-rich compounds such as TAC and MAC deliver a high payload to the tumor tissue when injected intravenously. Here we report that liposome-mediated boron delivery to the tumor is inversely proportional to the size of the murine mammary (EMT-6) tumors. The plausible reason for the inverse ratio of boron and EMT-6 tumor size is the necrosis in these tumors, which is more prominent in the large tumors. The large tumors also have receding blood vessels contributing further to poor boron delivery to these tumors. We next report that the presence of boron in blood is essential for the effects of BNCT on EMT-6 tumor inhibition as direct injection of boron-rich liposomes did not provide any added advantage in inhibition of EMT-6 tumor in BALB/c mice following irradiation despite having a significantly higher amount of boron in the tumor tissue. BNCT reaction in PBMCs resulted in the modification of these cells to anti-tumor phenotype. In this study, we report the immunomodulatory effects of BNCT when boron-rich compounds are delivered systemically.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Imunomodulação/efeitos da radiação , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/radioterapia , Animais , Boro/administração & dosagem , Boro/sangue , Boro/farmacocinética , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Humanos , Isótopos/administração & dosagem , Isótopos/sangue , Isótopos/farmacocinética , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/efeitos da radiação , Lipossomos , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Necrose , Distribuição Tecidual
12.
Mater Sci Eng C Mater Biol Appl ; 105: 110099, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546395

RESUMO

Multi-modality strategies of albumin-mediated drug accumulation in tumor, boronate-based active tumor targeting and synergistic cancer therapy were combined together for effective treatment of breast cancer. Herein we report the development of albumin-shell oily-core nanocapsules (NCs), loaded with novel combination of hydrophobic drugs, exemestane (EXE) and hesperetin (HES), for targeted breast cancer therapy. This protein-lipid nanohybrid carrier was successfully fabricated using a simple protein-coating method based on the electrostatic adsorption of negatively charged albumin shell onto the oily core containing cationic surfactant. While EXE was directly encapsulated into the oily core, HES was pre-formulated in the form of phospholipid complex before solubilization in oily phase. In addition to albumin-mediated binding to albondin and SPARC, phenylboronic acid was chemically coupled to the albumin shell to confer additional tumor targeting. The targeted nanocarrier (TNC) demonstrated enhanced internalization into MCF-7 breast cancer cells resulting in synergistic cytotoxic activity with a combination index (CI) of 0.662 and dose reduction index (DRI) of 8.22 and 1.84 for EXE and HES, respectively. In vivo, TNC displayed superior anti-cancer activity in tumor-bearing mice compared to their non-targeted counterparts and the free drug combination. A significant reduction of both tumor volume (7-folds) and Ki67 expression (3-folds) was obtained by the targeted nanocarriers compared to positive control. Overall, the boronic-targeted albumin NCs offer a promising platform for hydrophobic drug combination against cancer therapy.


Assuntos
Androstadienos , Antineoplásicos Fitogênicos , Inibidores da Aromatase , Neoplasias da Mama , Hesperidina , Nanocápsulas , Albuminas/química , Albuminas/farmacocinética , Albuminas/farmacologia , Androstadienos/química , Androstadienos/farmacocinética , Androstadienos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Boro/química , Boro/farmacocinética , Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Hesperidina/química , Hesperidina/farmacocinética , Hesperidina/farmacologia , Humanos , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Fosfolipídeos/farmacologia
13.
Sci Rep ; 9(1): 6260, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000729

RESUMO

Boron (B) is an essential element for plants, but excess B is phytotoxic. Since excess B often occurs along with high salinity in the environment, the purposes of the experiments are to screen plants that tolerate both excess B and high salinity for the remediation of B-contaminated saline water or soils. Here we tested the capacities of B tolerance and accumulation of four salt-tolerant plant species, Tripolium pannonicum, Suaeda glauca, Iris wilsonii, and Puccinellia tenuiflora using hydroponic culture systems, and compared their potential for application in phytoremediation. The maximum B supply concentrations for the survival of T. pannonicum, S. glauca, I. wilsonii, and P. tenuiflora are 40, 250, 700, and 300 mg/L, respectively. The maximum B concentrations in the shoot tissue of these plants are 0.45, 2.48, 15.21, and 8.03 mg/g DW, and in the root are 0.23, 0.70, 6.69, and 2.63 mg/g DW, respectively. Our results suggest that S. glauca, I. wilsonii, and P. tenuiflora are capable of tolerating and accumulating high levels of B, and I. wilsonii is a most promising candidate for the remediation of B-contaminated sites. This study will provide evidence in support of our future pilot studies (e.g., constructed wetlands) on the phytoremediation of B-contaminated water and soil.


Assuntos
Boro/farmacocinética , Boro/toxicidade , Plantas Tolerantes a Sal/efeitos dos fármacos , Biodegradação Ambiental , Biomassa , Chenopodiaceae/efeitos dos fármacos , Chenopodiaceae/metabolismo , Hidroponia , Gênero Iris/efeitos dos fármacos , Gênero Iris/metabolismo , Poaceae/efeitos dos fármacos , Poaceae/metabolismo , Plantas Tolerantes a Sal/crescimento & desenvolvimento , Plantas Tolerantes a Sal/metabolismo , Poluentes do Solo/farmacocinética , Poluentes do Solo/toxicidade , Distribuição Tecidual
14.
Plant Physiol Biochem ; 137: 93-101, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30771565

RESUMO

Aluminum (Al) toxicity in the acid soils (pH ≤ 5) is the major limiting abiotic factor affecting the productivity of crops. Boron (B) has been reported to alleviate Al toxicity. In spite of recent advances, it is not clear how B relieves Al toxicity. Results demonstrated that Al toxicity hampered the root elongation. Moreover, lumogallion fluorescent molecular probe unequivocally localized mostly bound Al to the periphery of the cell wall (CW) and to the nuclei. Additionally, Al toxicity induced variations in the CW components through the accumulation of pectin and hemicellulose. Nevertheless, B supply reduced callose deposition, increased root growth and reduced changes in the CW components under Al toxicity. Moreover, B supply reduced the un-methylated pectin while increased the degree of methyl esterification of pectin. These results imply that B due to its role in the CW formation could reduce aluminum-induced negative effects on plant growth by attenuating apoplastic Al3+ and changes in the CW components which ultimately results in the improved root growth.


Assuntos
Alumínio/toxicidade , Antioxidantes/metabolismo , Boro/farmacologia , Parede Celular/efeitos dos fármacos , Citrus/efeitos dos fármacos , Alumínio/análise , Alumínio/farmacocinética , Ácido Ascórbico/metabolismo , Boro/farmacocinética , Parede Celular/química , Citrus/citologia , Citrus/metabolismo , Glucanos/metabolismo , Microscopia Confocal , Monoaminoxidase/metabolismo , Células Vegetais/efeitos dos fármacos , Células Vegetais/metabolismo , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Análise de Componente Principal , Xantina Oxidase/metabolismo
15.
Radiat Environ Biophys ; 58(1): 59-67, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30474719

RESUMO

Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl-closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)-a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21-24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26-36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25-37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28-40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro/química , Boro/uso terapêutico , Receptores de Folato com Âncoras de GPI/metabolismo , Glioma/patologia , Terapia de Alvo Molecular , Animais , Boro/farmacocinética , Compostos de Boro/química , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Glioma/metabolismo , Glioma/radioterapia , Humanos , Masculino , Ratos , Distribuição Tecidual
16.
ACS Appl Mater Interfaces ; 10(50): 43387-43395, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30451482

RESUMO

Boron neutron capture therapy (BNCT) induces high-energy radiation within cancer cells while avoiding damage to normal cells without uptake of BNCT drugs, which is holding great promise to provide excellent control over locally invasive malignant tumors. However, lack of quantitative imaging technique to determine local boron concentration has been a great challenge for nuclear physicians to apply accurate neutron irradiation during the treatment, which is a key factor that has limited BNCT's application in clinics. To meet this challenge, this study describes coating boronated porphyrins with a biocompatible poly(lactide- co-glycolide)-monomethoxy-poly(polyethylene-glycol) (PLGA-mPEG) micelle for selective tumor accumulation and reduced toxicity comparing with the previously reported boronated porphyrin drugs. Fluorescence imaging and positron emission tomography (PET) imaging were performed, unveiling the potential imaging properties of this boronated porphyrin nanocomplex (BPN) to locate tumor region and to determine tissue-localized boron concentration which facilitates treatment planning. By studying the pharmacokinetics of BPN with Cu-64 PET imaging, the treatment plan was adjusted from single bolus injection to multiple times of injections of smaller doses. As expected, high tumor uptake of boron (125.17 ± 13.54 ppm) was achieved with an extraordinarily high tumor to normal tissue ratio: tumors to liver, muscle, fat, and blood were 3.24 ± 0.22, 61.46 ± 20.26, 31.55 ± 10.30, and 33.85 ± 5.73, respectively. At last, neutron irradiation with BPN showed almost complete tumor suppression, demonstrating that BPN holds a great potential for being an efficient boron delivery agent for imaging-guided BNCT.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro , Neoplasias Experimentais , Imagem Óptica , Porfirinas , Tomografia por Emissão de Pósitrons , Animais , Boro/química , Boro/farmacocinética , Boro/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/radioterapia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia
17.
Curr Opin Plant Biol ; 46: 68-76, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30138844

RESUMO

Membrane-embedded transport proteins are fundamental to life; their co-ordinated action controls the movement and distribution of solutes into, around and out of cells for signalling, metabolism, nutrition, stress tolerance and development. Here we outline two case studies of transport systems that plants use to tolerate soil elemental toxicity, demonstrating how iterative studies of protein structure and function result in unparalleled insights into transport mechanics. Further, we propose that integrative platforms of biological, biochemical and biophysical tools can provide quantitative data on substrate specificity and transport rates, which are important in understanding transporter evolution and their roles in cell biology and whole plant physiology. Such knowledge equips biotechnologists and breeders with the power to deliver improvements in crop yields in sub-optimal soils.


Assuntos
Transporte Biológico , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas/metabolismo , Aquaporinas/química , Aquaporinas/metabolismo , Boro/farmacocinética , Boro/toxicidade , Proteínas de Membrana Transportadoras/química , Plantas/efeitos dos fármacos , Conformação Proteica , Salinidade , Homologia Estrutural de Proteína
18.
Environ Sci Pollut Res Int ; 25(29): 29129-29143, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30112644

RESUMO

A multielemental determination methodology in conjunction with an organic acid analysis that were supplemented with other stress parameters and an ultrastructural analysis used herein to study Verbascum olympicum Boiss. (Scrophulariaceae) under Mn stress. Uptake and accumulation characteristics of B, Cu, Fe, Mn, Mo, and Zn were evaluated in 8-week-old seedlings grown in Hoagland's nutrient solution and exposed to 5 (CK), 50, and 200 µM MnSO4 for 7 days. Hydrogen peroxide levels were determined to evaluate oxidative stress, and changes in compatible substance levels (total phenolic contents, glutathione and glutathione disulfide levels) were determined to assess antioxidant defense mechanisms. The distribution of manganese on the root surface was characterized by scanning electron microscopy images and energy-dispersive X-ray spectroscopy analysis. The levels of nicotinic acid, which is involved in nicotinamide adenine dinucleotide biosynthesis, were determined in roots and leaves to assess tolerance mechanisms. V. olympicum exhibited the ability to cope with oxidative stress originating from excessive Mn, while increased Mn concentrations were observed in both roots and leaves. The translocation factor of B was the most affected among other studied elements under the experimental conditions. Total nicotinic acid levels exhibited a trend of reduction in the roots and leaves, which could be attributed to the appropriate metabolic progress associated with oxidative stress based on the nicotinamide adenine dinucleotide cycle that may reach glutathione in response to manganese stress during plant growth.


Assuntos
Manganês/toxicidade , Verbascum/efeitos dos fármacos , Verbascum/metabolismo , Antioxidantes/metabolismo , Boro/farmacocinética , Ecotoxicologia/métodos , Peróxido de Hidrogênio/metabolismo , Manganês/farmacocinética , Metais/farmacocinética , Microscopia Eletrônica de Varredura , Ácidos Nicotínicos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Raízes de Plantas/ultraestrutura , Plântula/efeitos dos fármacos , Plântula/metabolismo , Espectrometria por Raios X , Distribuição Tecidual , Verbascum/crescimento & desenvolvimento
19.
Cancer Commun (Lond) ; 38(1): 35, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29914561

RESUMO

Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro/uso terapêutico , Neoplasias/radioterapia , Nêutrons/uso terapêutico , Boro/química , Boro/farmacocinética , Compostos de Boro/química , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Humanos , Isótopos/química , Isótopos/farmacocinética , Isótopos/uso terapêutico , Lipossomos/química , Lipossomos/farmacocinética , Neoplasias/metabolismo , Distribuição Tecidual
20.
Chemosphere ; 199: 390-401, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29453065

RESUMO

Puccinellia distans, common alkali grass, is found throughout the world and can survive in soils with boron concentrations that are lethal for other plant species. Indeed, P. distans accumulates very high levels of this element. Despite these interesting features, very little research has been performed to elucidate the boron tolerance mechanism in this species. In this study, P. distans samples were treated for three weeks with normal (0.5 mg L-1) and elevated (500 mg L-1) boron levels in hydroponic solution. Expressed sequence tags (ESTs) derived from shoot tissue were analyzed by RNA sequencing to identify genes up and down-regulated under boron stress. In this way, 3312 differentially expressed transcripts were detected, 67.7% of which were up-regulated and 32.3% of which were down-regulated in boron-treated plants. To partially confirm the RNA sequencing results, 32 randomly selected transcripts were analyzed for their expression levels in boron-treated plants. The results agreed with the expected direction of change (up or down-regulation). A total of 1652 transcripts had homologs in A. thaliana and/or O. sativa and mapped to 1107 different proteins. Functional annotation of these proteins indicated that the boron tolerance and hyperaccumulation mechanisms of P. distans involve many transcriptomic changes including: alterations in the malate pathway, changes in cell wall components that may allow sequestration of excess boron without toxic effects, and increased expression of at least one putative boron transporter and two putative aquaporins. Elucidation of the boron accumulation mechanism is important in developing approaches for bioremediation of boron contaminated soils.


Assuntos
Biodegradação Ambiental , Boro/farmacocinética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Poaceae/metabolismo , Poluição Ambiental/análise , Etiquetas de Sequências Expressas , Hidroponia
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