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1.
Int J Pharm ; 587: 119640, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32673770

RESUMO

Hydroxyethyl bearing gemini surfactants, alkanediyl-α,ω-bis(N-hexadecyl-N-2-hydroxyethyl-N-methylammonium bromide), 16-s-16(OH), were used to augment phosphatidylcholine based liposomes to achieve higher stability and enhanced cellular uptake and penetration. The developed liposomes were loaded with rhodamine B, doxorubicin hydrochloride, pralidoxime chloride to investigate release properties, cytotoxicity in vitro, as well as ability to cross the blood-brain barrier. At molar ratio of 35:1 (lipid:surfactant) the formulation was found to be of low toxicity, stable for two months, and able to deliver rhodamine B beyond the blood-brain barrier in rats. In vivo, pharmacokinetics of free and formulated 2-PAM in plasma and brain were evaluated, liposomal 2-PAM was found to reactivate 27% of brain acetylcholinesterase, which is, to our knowledge, the first example of such high degree of reactivation after intravenous administration of liposomal drug.

2.
Nanoscale ; 12(25): 13757-13770, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32573587

RESUMO

New lipid-based nanomaterials and multi-target directed ligands (MTDLs) based on sterically hindered phenol, containing a quaternary ammonium moiety (SHP-s-R, with s = 2,3) of varying hydrophobicity (R = CH2Ph and CnH2n+1, with n = 8, 10, 12, 16), have been prepared as potential drugs against Alzheimer's disease (AD). SHP-s-R are inhibitors of human cholinesterases with antioxidant properties. The inhibitory potency of SHP-s-R and selectivity ratio of cholinesterase inhibition were found to significantly depend on the length of the methylene spacer (s) and alkyl chain length. The compound SHP-2-16 showed the best IC50 for human AChE and the highest selectivity, being 30-fold more potent than for human BChE. Molecular modeling of SHP-2-16 binding to human AChE suggests that this compound is a dual binding site inhibitor that interacts with both the peripheral anionic site and catalytic active site. The relationship between self-assembly parameters (CMC, solubilization capacity, aggregation number), antioxidant activity and a toxicological parameter (hemolytic action on human red blood cells) was investigated. Two sterically hindered phenols (SHP-2-Bn and SHP-2-R) were loaded into L-α-phosphatidylcholine (PC) nanoparticles by varying the SHP alkyl chain length. For the brain AChE inhibition assay, PC/SHP-2-Bn/SHP-2-16 nanoparticles were administered to rats intranasally at a dose of 8 mg kg-1. The Morris water maze experiment showed that scopolamine-induced AD-like dementia in rats treated with PC/SHP-2-Bn/SHP-2-16 nanoparticles was significantly reduced. This is the first example of cationic SHP-phospholipid nanoparticles for inhibition of brain cholinesterases realized by the use of intranasal administration. This route has promising potential for the treatment of AD.

3.
Chempluschem ; 85(5): 958-962, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32412179

RESUMO

Reaction of the electrochemically in situ from elemental white phosphorus generated phosphine oxide H3 PO in a single electrochemical cell, supplied with lead cathode and aluminium anode, with cyclic ketones (cyclopentanone and cyclohexanone) results in formation of secondary phosphine oxides (bis(α-hydroxycyclopentyl)phosphine oxide 2 a, isolated yield 15 %, and bis(α-hydroxycyclohexyl)phosphine oxide 2 b, isolated yield 12 %) with two α-hydroxycycloalkyl substituents at the phosphorus atom. Bis(α-hydroxycyclopentyl)phosphine oxide reacts with [PdCl2 (COD)] (COD=1,5-cyclooctadiene) to give a new palladium complex trans-[PdCl2 {P(OH)(cyclo-C5 H8 -1-OH)2 }2 ] (3 a, isolated yield 11 %) bearing phosphinous acid as a ligand formed via tautomerization of the phosphine oxide. Finally, the cytotoxicity of the synthesized secondary phosphine oxides on tumor and healthy human cell lines was studied. It was found that at a concentration of 10-6 -10-4  M, phosphine oxides 2 a,b exhibit similar IC50 values for the M-Hela cell line (ca. 50 mM), but are non-toxic for MCF-7 cells. For human alveolar adenocarcinoma cells (A-549), only 2 a is active (ca. 35 mM), while 2 b is not toxic.

4.
Bioorg Med Chem Lett ; 30(13): 127234, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32386856

RESUMO

Here we report the synthesis and biological evaluation of a series of new 2-hydroxybenzylphosphonium salts (QPS) with antimicrobial and antitumor dual action. The most active compounds exhibit antimicrobial activity at a micromolar level against Gram-positive bacteria Sa (ATCC 209p and clinical isolates), Bc (1-2 µM) and fungi Tm and Ca, and induced no notable hemolysis at MIC. The change in nature of substituents of the same length led to a drastic change of biological activity. Self-assembly behavior of the octadecyl and oleyl derivatives was studied. QPS demonstrated self-assembly within the micromolar range with the formation of nanosized aggregates capable of the solubilizing hydrophobic probe. The synthesized phosphonium salts were tested for cytotoxicity. The most potent salt was active against on M-Hela cell line with IC50 on the level of doxorubicin and good selectivity. According to the cytofluorimetry analysis, the salts induced mitochondria-dependent apoptosis.

5.
Chem Biodivers ; 17(5): e2000147, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32349191

RESUMO

The increase in the resistance of pathogens, in particular Staphylococcus aureus, to the action of antibiotics necessitates the search for new readily available and non-toxic drugs. In solving this problem, phenolic acylhydrazones have high potential. In this communication, the synthesis of quaternary ammonium compounds containing a differently substituted phenolic moiety has been performed. An initial study of antimicrobial activity showed that these compounds are highly selective against S. aureus and B. cereus. The highest activity (MIC 2.0 µm) was shown by hydrazones containing a catechol fragment. These compounds are more than 3-fold more active against S. aureus and 3-10-fold more active against B. cereus than norfloxacin. Low hemolytic and high antioxidant activities of all new compounds were also established.

6.
IEEE Trans Biomed Eng ; 67(1): 166-176, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969914

RESUMO

OBJECTIVE: Several powered ankle-foot prostheses have demonstrated moderate reductions in energy expenditure by restoring pushoff work in late stance or by assisting with balance. However, it is possible that center of pressure trajectory modulation could provide even further improvements in user performance. Here, we describe the design of a prosthesis emulator with two torque-controlled forefoot digits and a torque-controlled heel digit. Independent actuation of these three digits can modulate the origin and magnitude of the total ground reaction force vector. METHODS: The emulator was designed to be compact and lightweight while exceeding the range of motion and torque requirements of the biological ankle during walking. We ran a series of tests to determine torque-measurement accuracy, closed-loop torque control bandwidth, torque-tracking error, and center of pressure control accuracy. RESULTS: Each of the three digits demonstrated less than 2 Nm of RMS torque measurement error, a 90% rise time of 19 ms, and a bandwidth of 33 Hz. The untethered end-effector has a mass of 1.2 kg. During walking trials, the emulator demonstrated less than 2 Nm of RMS torque-tracking error and was able to maintain full digit ground contact for 56% of stance. In fixed, standing, and walking conditions, the emulator was able to control center of pressure along a prescribed pattern with RMS errors of about 10% the length of the pattern. CONCLUSION: The proposed emulator system meets all design criteria and can effectively modulate center of pressure and ground reaction force magnitude. SIGNIFICANCE: This emulator system will enable rapid development of controllers designed to enhance user balance and reduce user energy expenditure. Experiments conducted using this emulator could identify beneficial control behaviors that can be implemented on autonomous devices, thus improving mobility and quality of life of individuals with amputation.

7.
Mol Pharm ; 17(1): 40-49, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31746611

RESUMO

The addition of specific chemical groups in a macrocycle structure influences its functional properties and, consequently, can provide new possibilities, among which are aggregation properties, water solubility, biocompatibility, stimuli response, biological activity, etc. Herein, we report synthesis of new resorcin[4]arene with N-methyl-d-glucamine groups on the upper rim and n-decyl chains on the lower rim, an investigation of its self-assembly behavior in aqueous media, and its use as a building block for the formation of drug nanocontainer. N-methyl-d-glucamine fragments in the resorcin[4]arene structure promote higher stability in solutions, simplification of self-aggregation, and increased biological activity. Antimicrobial and hemolytic activity assessment revealed that this resorcin[4]arene obtained is nontoxic. The study of cell penetration was carried out with both free and encapsulated doxorubicin (DOX). Surprisingly, DOX-loaded macrocycle aggregates are more efficient in causing apoptosis in human cancer cell line. Conceivably, this knowledge will help in the rational design of DOX combination for novel drug-administration strategies in cancer treatment.

8.
Org Biomol Chem ; 17(46): 9951-9959, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31729508

RESUMO

A water-soluble pillar[5]arene, decafunctionalized with thioether and carboxylate fragments, was synthesized as a structural analogue of Sugammadex. Its ability to restore the contraction of the diaphragm muscle by encapsulating the muscle relaxant rocuronium bromide was demonstrated. Using UV-vis, NMR and fluorescence spectroscopy, it was shown that the muscle relaxant is associated with the pillar[5]arene with an association constant of 4500 M-1 and a stoichiometry of 1 : 1. The structure of the inclusion complex of the pillar[5]arene with rocuronium bromide was additionally investigated by quantum chemical methods.

9.
Medchemcomm ; 10(8): 1488-1498, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31673312

RESUMO

A series of glycosides and glycoconjugates of diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) with various monosaccharide residues were synthesized and their cytotoxicity against some human cancer and normal cell lines was assayed. Most of the synthesized compounds demonstrated moderate to significant cytotoxicity against human cancer cell lines M-HeLa and MCF-7. Three lead compounds exhibited selective cytotoxic activities against M-HeLa (IC50 = 10.0-15.1 µM) that were three times better than the cytotoxicity of the anti-cancer drug Tamoxifen (IC50 = 28.0 µM). Moreover, the lead compounds were not cytotoxic with respect to the normal human cell line Chang liver (IC50 > 100 µM), whereas Tamoxifen inhibited the viability of normal human Chang liver cells with an IC50 value of 46.0 µM. It was determined that the cytotoxicity of the lead compounds was due to induction of apoptosis proceeding along the mitochondrial pathway. The cytotoxic activity of the synthesized compounds substantially depended on the nature of the monosaccharide residue and its position, that is, whether the monosaccharide residue was attached directly to the isosteviol skeleton or was moved away from it by means of a polymethylene linker.

10.
J Mater Chem B ; 7(46): 7351-7362, 2019 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-31696196

RESUMO

The purpose of this work was to obtain cationic liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine noncovalently modified using alkyltriphenylphosphonium bromides (TPPB-n) with different lengths of hydrocarbon tail for targeted delivery to mitochondria. The hydrodynamic diameter and electrokinetic potential of hybrid liposomes depending on the lipid/surfactant ratio were monitored in time with the aim to optimize the composition with sufficient stability and positive charge for mitochondria-targeted delivery. It was found that increasing the alkyl tail length of the surfactant (up to TPPB-14) leads to an increase in the positive charge of the liposomes. The most optimal results of stability were obtained for hybrid liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and TPPB-12, TPPB-14. The obtained modified liposomes were loaded with hydrophilic substrates (a model probe Rhodamine B and medicines metronidazole and doxorubicin). This is one of the first examples of fabrication of liposomes noncovalently modified using an amphiphilic TPP cation, with the alkyl tail length of surfactant and TPP/lipid ratio optimized in terms of stability of the liposomes and the binding/release behavior of hydrophilic probes. Using the confocal microscopy method, it was shown that modification of liposomes with a triphenylphosphonium cation results in targeted delivery of encapsulated compounds to mitochondria.

11.
Eur J Med Chem ; 184: 111735, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610378

RESUMO

A series of 2,6-diaminopyridines was synthesized for the first time, containing phosphoryl sterically hindered phenolic fragments in the aromatic core. The antioxidant activity of these compounds was investigated, 2,6-diaminopyridine derivatives were shown to exhibit higher activity in comparison with their structural analogues. For dialkyl/diphenyl [(3,5-di-tert-butyl-4-hydroxyphenyl) (2,6-diaminopyridin-3-yl) methyl] phosphonates, their structural analogues based on meta-phenylenediamine, phosphorus-containing sterically hindered phenols and the corresponding cyclohexadienones cytotoxicity against tumor lines of epithelioid carcinoma of the cervix uteri (M-Hela) and breast adenocarcinoma (MCF-7) has been studied in vitro, as well as on normal human Chang liver cell lines. Diphenyl [(3,5-di-tert-butyl-4-hydroxyphenyl) (2,6-diaminopyridin-3-yl) methyl] phosphonate was shown to be the most active against the epithelioid line M-Hela - IC50 comprises 7.4 µM. It was shown that apoptosis induced by the lead compound proceeds along the internal pathway of caspase-9 activation. It was established that all studied compounds do not possess hemolytic activity.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Organofosfonatos/farmacologia , Piridinas/farmacologia , Amidinas/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Aspergillus niger/efeitos dos fármacos , Bacillus cereus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Células HeLa , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Organofosfonatos/química , Pseudomonas aeruginosa/efeitos dos fármacos , Piridinas/síntese química , Piridinas/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
12.
Mater Sci Eng C Mater Biol Appl ; 105: 110057, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546380

RESUMO

The present work introduces ternary Ln(III) (Ln = Eu, Yb, Lu) complexes with thenoyltriflouro1,3-diketonate (TTA-) and phosphine oxide derivative (PhO) as building blocks for core-shell nanoparticles with both Eu(III)- or Yb(III)-centered luminescence and the dual Eu(III)-Yb(III)-centered luminescence. Solvent-mediated self-assembly of the complexes is presented herein as the procedure for formation of EuLu, EuYb and YbLu heterometallic or homometallic cores coated by hydrophilic polystyrenesulfonate-based shells. Steady state and time resolved Eu-centered luminescence in homolanthanide and heterolanthanide EuLu and EuYb cores is affected by Eu → Eu and Eu → Yb energy transfer due to a close proximity of the lanthanide blocks within the core of nanoparticles. The Eu → Yb energy transfer is highlighted to be the reason for the enhancement of the NIR Yb-centered luminescence. Efficient cellular uptake, low cytotoxicity towards normal and cancer cells, and sensing ability of EuYb nanoparticles on lomefloxacin additives via both red and NIR channels make them promising as cellular imaging agents and sensors.


Assuntos
Antineoplásicos , Citotoxinas , Európio , Luminescência , Nanopartículas Metálicas , Neoplasias , Itérbio , Antineoplásicos/química , Antineoplásicos/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Európio/química , Európio/farmacologia , Células HeLa , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Itérbio/farmacologia
13.
Molecules ; 24(17)2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31450696

RESUMO

A library of novel 2-(het)arylpyrrolidine-1-carboxamides were obtained via a modular approach based on the intramolecular cyclization/Mannich-type reaction of N-(4,4-diethoxybutyl)ureas. Their anti-cancer activities both in vitro and in vivo were tested. The in vitro activity of some compounds towards M-Hela tumor cell lines was twice that of the reference drug tamoxifen, whereas cytotoxicity towards normal Chang liver cell did not exceed the tamoxifen toxicity. In vivo studies showed that the number of surviving animals on day 60 of observation was up to 83% and increased life span (ILS) was up to 447%. Additionally, some pyrrolidine-1-carboxamides possessing a benzofuroxan moiety obtained were found to effectively suppress bacterial biofilm growth. Thus, these compounds are promising candidates for further development both as anti-cancer and anti-bacterial agents.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Anti-Infecciosos/química , Antineoplásicos/química , Biofilmes/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Pirrolidinas/química , Relação Estrutura-Atividade
14.
Chem Phys Lipids ; 223: 104791, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31326390

RESUMO

The study on aggregation capacity of novel imidazolium-containing amphiphiles of 1-(2-hydroxyethyl)alkylimidazolium bromide series and their interaction with bio-objects (DNA decamer, bovine serum albumin, phospholipid) was performed. It was revealed that introduction of hydroxyethyl moiety into the surfactant molecule resulted in 1.5-2-fold decrease of critical micelle concentration. These modified amphiphiles quantitatively bind DNA decamer due to intercalation and hydrophobic interactions with lipoplex formation. The evaluation of membranotropic properties of these surfactants exhibited that initiation of disordering and compression of the model cell wall consisting of dipalmitoyl phosphocholine (regulation of permeability for various compounds) could be achieved by variation of the length of hydrophobic tail of imidazolium-containing amphiphiles. Transition from individual surfactants solutions to their mixtures with protein (bovine serum albumin) is accompanied by 8-fold decrease of aggregation thresholds and characterized by the presence of two critical points. The binding of components of surfactant/BSA binary systems took place through tryptophan amino acid residue of peptide macromolecule.

15.
Molecules ; 24(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137548

RESUMO

Deep insight of the toxicity of supramolecular systems based on macrocycles is of fundamental interest because of their importance in biomedical applications. What seems to be most interesting in this perspective is the development of the macrocyclic compounds with biocompatible fragments. Here, calix[4]resorcinarene derivatives containing N-methyl- d-glucamine moieties at the upper rim and different chemical groups at the lower rim were synthesized and investigated. These macrocycles showed a tendency to self-aggregate in aqueous solution, and their self-assembly abilities depend on the structure of the lower rim. The in vitro cytotoxic and antimicrobial activity of the calix[4]resorcinarenes revealed the relationship of biological properties with the ability to aggregate. Compared to macrocycles with methyl groups on the lower rim, calix[4]resorcinarenes with sulfonate groups appear to possess very similar antibacterial properties, but over six times less hemolytic activity. In some ways, this is the first example that reveals the dependence of the observed hemolytic and antibacterial activity on the lipophilicity of the calix[4]arene structure.


Assuntos
Calixarenos/química , Calixarenos/farmacologia , Fenilalanina/análogos & derivados , Antibacterianos/farmacologia , Calixarenos/síntese química , Morte Celular/efeitos dos fármacos , Difusão , Condutividade Elétrica , Humanos , Compostos Macrocíclicos/química , Tamanho da Partícula , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Eletricidade Estática , Tensão Superficial
16.
Colloids Surf B Biointerfaces ; 178: 317-328, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30884347

RESUMO

Multi-targeted approaches for inhibition of сervical cancer cells in vitro were developed by implementing two different strategies and drug combination for creation of new therapeutic target agents and for nanotechnological-enhancement of intracellular delivery. New 2-benzimidazolylquinoxalines derivatives were synthesized and characterized by combining two different pharmacophores - benzimidazole and quinoxaline rings directly bonded in their structures. Spectrophotometric technique for determination of content of compounds in various media was developed to evaluate their solubility in water and micellar solutions of surfactants. The bioavailability of poorly water-soluble 2-benzimidazolylquinoxalines was improved by PEGylated liposomes as antitumor drug delivery carriers. 2-benzimidazolylquinoxalines-loaded PEGylated liposomes, with size close to 100 nm and negative zeta potential ranging from -13 mV to -27 mV, were time-stable at room temperature. The design of liposomal formulations for improving cellular uptake and in vitro antitumor efficacy was performed by modification of liposome surface with the new arginine surfactant. The cell viability of 2-benzimidazolylquinoxalines-loaded arginine liposomes on human cancer M-Hela cells was 16% at the concentration 0.15 mg/ml. Moreover, these liposomes showed a lower toxicity (40%) against normal human Gang liver cells both at the lowest and highest tested concentrations.


Assuntos
Arginina/química , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Quinoxalinas/química , Células HeLa , Humanos , Tensoativos/química
17.
Chem Biodivers ; 16(5): e1900039, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30817850

RESUMO

A versatile two-step pathway to the synthesis of triaryl(2,5-dihydroxy-6-methyl-3-(propan-2-yl)phenyl)- and triaryl(1,4-dihydroxynaphthyl)phosphonium salts from triarylphosphonium trifluoroacetates was developed. The reaction proceeds under mild conditions (20 °C, CH2 Cl2 ) with high yields (88-95 %). Some representatives of this series possess low hemolytic and high bactericidal activity against Gram-positive bacteria.


Assuntos
Anti-Infecciosos/síntese química , Compostos Organofosforados/química , Anti-Infecciosos/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Naftoquinonas/química , Compostos Organofosforados/farmacologia , Sais/química
18.
Colloids Surf B Biointerfaces ; 175: 351-357, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30554013

RESUMO

In this work, the dicationic surfactants containing viologen and vinylbipyridinium moieties and hexadecyl chains were synthesized, and their aggregation behavior in water solutions was investigated by surface tension, conductivity measurements, hydrophobic probe solubilization, dynamic light scattering and electrophoretic measurements. Effect of UV-light on cis-trans isomerism of vinylbipyridinium derivative was determined. Antimicrobial activity and the influence of these surfactants on cell viability depended on the concentration and type of surfactant used. The results obtained established the structure-property (physicochemical properties and biological activity) relationship of the surfactant molecule namely the primary role of pyridinium head group structure.


Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Cátions/química , Fungos/efeitos dos fármacos , Piridinas/química , Tensoativos/farmacologia , Anti-Infecciosos/química , Tensoativos/química
19.
Chempluschem ; 84(10): 1560-1566, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31943934

RESUMO

A nanocarrier (p(6SRA-5B)) for glucose-controlled insulin delivery consists of sulfonated resorcinarenes (SRA) that are assembled into a spherical shell and are attached to each other with phenylboronate linkers. p(6SRA-5B) is stable in water and blood plasma at normal glucose concentrations. At high glucose levels (>5 mM), p(6SRA-5B) dissociates into SRA and phenylboronates through competitive interaction with excess glucose. Insulin was successfully encapsulated into the cavity of p(6SRA-5B) and its release was investigated in water and blood plasma by NMR, UV, CD, and fluorescence spectroscopy. The results show that the dissociation of the nanocarrier and the insulin release occurs with an increase in glucose concentration. At 5 mM glucose, the nanocarrier is stable, and the insulin release does not exceed 10 %. Increasing the glucose concentration to 7.5-10 mM results in a 40-100 % insulin release. p(6SRA-5B) is thus a promising insulin nanocarrier for the treatment of type 1 diabetes.

20.
Soft Matter ; 14(38): 7916-7925, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30246848

RESUMO

The present work introduces Gd3+ complexes with giant keplerate polyanions as a promising basis for MRI contrast agents. The impact of Gd3+ binding with different building blocks of keplerates on the magnetic relaxivity of the complexes is revealed by comparative study of the keplerates [{Mo6O21}12{Mo2O4(OAc)}30]42-, [{Mo6O21}12{Mo2O4(HPO4)}30]72-, and [{Mo6O21}12{Mo2O2S2(OAc)}30]42-. Unprecedentedly high longitudinal and transverse relaxivity values (up to 250 and 300 mM-1 s-1 correspondingly) are achieved for the keplerates possessing edl{Mo2O4(OAc)} and {Mo2O4(HPO42-)} moieties under their 1 : 1 complex formation with Gd3+. The transformation of the external pores from Mo9O9 to Mo9O6S3 in the {Mo2O2S2(OAc)}-keplerate and an increase in the Gd3+-to-keplerate ratio are the factors that decrease the relaxivity. The rapid degradation of the free keplerates in aqueous solutions restricts the use of the Gd3+-bound keplerates with 1 : 1 stoichiometry as MRI contrast agents. In this work, the optimized stoichiometry of the complexes, their self-assembly into ultra-small nanoparticles and their hydrophilic coating by a triblock copolymer are highlighted as tools for increasing both the colloid and chemical stability of the keplerate complexes. Optimal keplerate compositions have been identified to achieve a compromise of low cytotoxicity and high stability; these Gd3+-bound keplerates exhibit longitudinal and transverse relaxivity values (95 and 114 mM-1 s-1, respectively), well within the region of interest for MRI techniques.

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