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1.
Mater Sci Eng C Mater Biol Appl ; 89: 274-282, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29752099

RESUMO

Our aim was to develop multiwalled carbon nanotubes (MWCNTs)-based nanoconstructs for the codelivery of N-desmethyl tamoxifen (N-TAM) and a mild P-gp efflux inhibitor, i.e., quercetin (QT) to treat multiple drug resistant (MDR) cancer cells. The hypothesis banks on three-tier attack on the MDR mechanisms viz. drug derivatization, MWCNT permeation and P-gp inhibition. Tamoxifen was converted to N-TAM and was conjugated to carboxylated MWCNTs mediated by a biodegradable linker, i.e., tetraethylene glycol (TEG). QT was adsorbed on the conjugate to fetch the final product, i.e., N-TAM-TEG-MWCNT-QT. Spectroscopic analysis confirmed successful conjugation of N-TAM and physical adsorption of QT. The in-vitro release of N-TAM from the N-TAM-TEG-MWCNT conjugate was minimal to that of pure drug under physiological conditions, but markedly enhanced under the acidic pH of cancer cells. The developed nanometeric formulation was found to be haemo-compatible. Reduced IC50values and better cellular uptake in drug resistant MDA-MB-231 cells were observed, followed by enhanced drug availability in the systemic circulation of rodents vis-à-vis naïve drug. The smart nanosystem conferred the desired temporal drug delivery, enhanced drug efficacy, biocompatibility and conducive pharmacokinetics, which are the crucial desired attributes to tackle the increasing concern of MDR in cancer chemotherapy.


Assuntos
Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanotubos de Carbono/química , Quercetina/química , Tamoxifeno/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meia-Vida , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Polietilenoglicóis/química , Quercetina/metabolismo , Quercetina/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia
2.
Mater Sci Eng C Mater Biol Appl ; 76: 501-508, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28482557

RESUMO

Water dispersible fullerenes were synthesized by tethering with glycine. The glycinated fullerenes were conjugated to docetaxel and characterized using FT-IR and NMR. The nanometric drug-loaded carriers were able to release drug at cancer cell pH, but resisted drug release at plasma pH. The cytotoxicity in MDA MB-231 cells was substantially enhanced as well as the system was well tolerated by erythrocytes. The confocal laser scanning microphotographs confirmed the substantial drug delivery to cytosol as well as nuclei of cancer cells. The developed system not only increased the circulation time of drug, but also decreased its protein binding and substantially enhanced AUC. The glycinated fullerenes can serve as promising "cargo vehicles" for delivery of anti-cancer drugs in safe and effective manner.


Assuntos
Taxoides/química , Linhagem Celular Tumoral , Docetaxel , Sistemas de Liberação de Medicamentos , Fulerenos , Glicina , Humanos , Espectroscopia de Infravermelho com Transformada de Fourier
3.
Nanomedicine (Lond) ; 12(9): 1011-1023, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28440713

RESUMO

AIM: Glycine-tethered C60-fullerenes were conjugated with N-desmethyl tamoxifen and evaluated for drug delivery benefits. MATERIALS & METHODS: C60-fullerenes were functionalized with glycine, and N-desmethyl tamoxifen was conjugated, employing a linker and characterized for micromeritics, drug loading, drug release and evaluated for cancer cell toxicity, cellular uptake and pharmacokinetics. RESULTS: The nanoconjugate with a drug entrapment efficiency of 82.71 ± 6.23% and a drug loading of 66.01 ± 4.98% was hemocompatibile with appreciable MCF-7 cytotoxicity. The confocal results confirmed enhanced uptake of conjugate. Interestingly, pharmacokinetic outcomes of the conjugate were superior and the area under the curve was enhanced by approximately three-times, whereas the drug clearance was reduced by around five-times, after single intravenous injection. CONCLUSION: The conjugation assured improved availability of drug in a biological system for prolonged duration as well as in the interiors of target cells with a promise of enhanced efficacy and compatibility.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Fulerenos/química , Glicina/análogos & derivados , Nanoconjugados/química , Tamoxifeno/administração & dosagem , Animais , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Ratos Wistar , Tamoxifeno/farmacocinética , Tamoxifeno/farmacologia
4.
Int J Biol Macromol ; 88: 206-12, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27037052

RESUMO

Docetaxel is one of the promising drugs and employed for the management of variety of cancers. However, challenges like poor-bioavailability, low tissue-permeability, compromised aqueous solubility and dose-dependent side-effects limit its clinical applications. Whereas, PLGA-based polymeric micelles possess the ability to enhance the tissue permeability of drugs and increase their biocompatibility. Henceforth, it was aimed to fabricate the dextran-PLGA-based polymeric-micelles loaded with docetaxel to explore the potential benefits in drug delivery. Dextran was chemically linked to PLGA and the linkage was confirmed by FT-IR, UV and NMR-spectroscopy. Critical-micelle-concentration of amphiphilic polymer was determined and drug was encapsulated by diffusion technique and erythrocyte compatibility. The system was evaluated for drug release profile and in vitro cytotoxicity studies. The pharmacokinetic profile was studied in rats. The micelles obtained were of 96.5±2.5nm and offered drug encapsulation of order of 54.85±1.21%.The cytotoxicity of drug against MCF-7 and MDA-MB-231 cell lines was enhanced by approx. 100%. The pharmacokinetic profile was substantially modified and about 16-folds enhancement in bioavailability was observed vis-à-vis plain drug. The approach was not only able to control the drug release, but also offered promise to enhance the pharmacokinetic and pharmacodynamic potential of docetaxel and similar anticancer agents.


Assuntos
Antineoplásicos/farmacocinética , Dextranos/química , Portadores de Fármacos , Ácido Láctico/química , Nanopartículas/química , Ácido Poliglicólico/química , Taxoides/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Composição de Medicamentos , Liberação Controlada de Fármacos , Eritrócitos , Humanos , Células MCF-7 , Micelas , Nanopartículas/ultraestrutura , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Wistar , Taxoides/química , Taxoides/farmacologia
5.
Mol Cell Neurosci ; 43(4): 341-52, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20083202

RESUMO

AMPA receptor binding protein (ABP) is a multi-PDZ domain scaffold that binds and stabilizes AMPA receptor (AMPAR) GluR2/3 subunits at synapses. A palmitoylated N-terminal splice variant (pABP-L) concentrates in spine heads, whereas a non-palmitoylated form (ABP-L) is intracellular. We show that postsynaptic Sindbis viral expression of pABP-L increased AMPAR mediated mEPSC amplitude and frequency and elevated surface levels of GluR1 and GluR2, suggesting an increase in AMPA receptors at individual synapses. Spines were enlarged and more numerous and nerve terminals contacting these cells displayed enlarged synaptophysin puncta. A non-palmitoylated pABP-L mutant (C11A) did not change spine density or size. Exogenous pABP-L and endogenous GRIP, a related scaffold, colocalized with NPRAP (delta-catenin), to which ABP and GRIP bind, and with cadherins, which bind NPRAP. Thus postsynaptic pABP-L induces pre and postsynaptic changes that are dependent on palmitoylation and likely achieved through ABP association with a multi-molecular cell surface signaling complex.


Assuntos
Proteínas de Transporte/metabolismo , Lipoilação/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Animais , Caderinas/metabolismo , Forma Celular , Células Cultivadas , Espinhas Dendríticas/metabolismo , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/citologia , Hipocampo/metabolismo , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Neurônios/citologia , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Sinaptofisina/metabolismo
6.
J Neurosci ; 27(13): 3445-55, 2007 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-17392461

RESUMO

Postsynaptic nitric oxide (NO) production affects synaptic plasticity and neuronal cell death. Ca2+ fluxes through the NMDA receptor (NMDAR) stimulate the production of NO by neuronal nitric oxide synthase (nNOS). However, the mechanisms by which nNOS activity is regulated are poorly understood. We evaluated the effect of neuronal stimulation with glutamate on the phosphorylation of nNOS. We show that, in cortical neurons, a low glutamate concentration (30 microM) induces rapid and transient NMDAR-dependent phosphorylation of S1412 by Akt, followed by sustained phosphorylation of S847 by CaMKII (calcium-calmodulin-dependent kinase II). We demonstrate that phosphorylation of S1412 by Akt is necessary for activation of nNOS by the NMDAR. nNOS mutagenesis confirms that these phosphorylations respectively activate and inhibit nNOS and, thus, transiently activate NO production. A constitutively active (S1412D), but not a constitutively repressed (S847D) nNOS mutant elevated surface glutamate receptor 2 levels, demonstrating that these phosphorylations can control AMPA receptor trafficking via NO. Notably, an excitotoxic stimulus (150 microM glutamate) induced S1412, but not S847 phosphorylation, leading to deregulated nNOS activation. S1412D did not kill neurons; however, it enhanced the excitotoxicity of a concomitant glutamate stimulus. We propose a swinging domain model for the regulation of nNOS: S1412 phosphorylation facilitates electron flow within the reductase module of nNOS, increasing nNOS sensitivity to Ca2+-calmodulin. These findings suggest a critical role for a kinetically complex and novel series of regulatory nNOS phosphorylations induced by the NMDA receptor for the in vivo control of nNOS.


Assuntos
Morte Celular/fisiologia , Neurônios/enzimologia , Óxido Nítrico Sintase/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/embriologia , Hipocampo/metabolismo , Fosforilação , Transporte Proteico/fisiologia , Ratos
8.
J Neurosci ; 23(12): 4958-66, 2003 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12832518

RESUMO

NMDA receptors (NMDARs) are thought to be tetrameric assemblies composed of NR1 and at least one type of NR2 subunit. The identity of the NR2 subunit (NR2A, -B, -C, -D) is critical in determining many of the functional properties of the receptor, such as channel conductance and deactivation time. Further diversity may arise from coassembly of more than one type of NR2 subunit, if the resulting triheteromeric assembly (NR1 plus two types of NR2) displays distinct functional properties. We have used gene-ablated mice (NR2D -/-) to examine the effects of the NR2D subunit on NMDAR channels and NMDAR EPSCs in cerebellar Golgi cells. These cells are thought to express both NR2B and NR2D subunits, a combination that occurs widely in the developing nervous system. Our experiments provide direct evidence that the low conductance NMDAR channels in Golgi cells arise from diheteromeric NR1/NR2D assemblies. To investigate whether a functionally distinct triheteromeric assembly was also expressed, we analyzed the kinetic and pharmacological properties of single-channel currents in isolated extrasynaptic patches. We found that after the loss of the NR2D subunit, the properties of the 50 pS NMDAR channels were altered. This result is consistent with the presence of a triheteromeric assembly (NR1/NR2B/NR2D) in cells from wild-type mice. However, we could find no difference in the properties of NMDAR-mediated EPSCs between wild-type and NR2D subunit ablated mice. Our experiments suggest that although both diheteromeric and triheteromeric NR2D-containing receptors are expressed in cerebellar Golgi cells, neither receptor type participates in parallel fiber to Golgi cell synaptic transmission. The presence of the NR2D subunit within an assembly may therefore result in its restriction to extrasynaptic sites.


Assuntos
Cerebelo/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Técnicas In Vitro , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/genética , Sinapses/metabolismo
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