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1.
Chem Commun (Camb) ; 56(18): 2759-2762, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32022003

RESUMO

We describe a colorimetric and fluorescent probe 3a to detect cellular peroxynitrite with high selectivity and sensitivity. 3a was successfully applied in the bioimaging of exogenous and endogenous peroxynitrite in living cells. The up-regulation of peroxynitrite in cancer cells and normal cells during 5-fluorouracil treatment was finally monitored.


Assuntos
Antineoplásicos/farmacologia , Corantes Fluorescentes/farmacologia , Fluoruracila/farmacologia , Ácido Peroxinitroso/biossíntese , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Fluoruracila/química , Humanos , Células MCF-7 , Estrutura Molecular , Imagem Óptica , Ácido Peroxinitroso/química , Relação Estrutura-Atividade
2.
Life Sci ; 248: 117466, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101760

RESUMO

AIMS: Nanoparticles (NPs)-based drugs have been recently introduced to improve the efficacy of current therapeutic strategies for the treatment of cancer; however, the molecular mechanisms by which a NP interacts with cellular systems still need to be delineated. Here, we utilize the autophagic potential of TiO2 NPs for improving chemotherapeutic effects of 5-fluorouracil (5-FU) in human AGS gastric cells. MATERIALS AND METHODS: Cell growth and viability were determined by trypan blue exclusion test and MTT assay, respectively. Vesicular organelles formation was evaluated by acridine orange staining of cells. Cell cycle and apoptosis were monitored by flow cytometry. Reactive oxygen species (ROS) level were measured by DCHF-DA staining. Autophagy was examined by q-PCR and western blotting. Molecular docking was used for studying NP interaction with autophagic proteins. KEY FINDINGS: TiO2 NPs increase ROS production, impair lysosomal function and subsequently block autophagy flux in AGS cells. In addition, the autophagy blockade induced by non-toxic concentrations of TiO2 NPs (1 µg/ml) can promote cytotoxic and apoptotic effects of 5-FU in AGS cells. SIGNIFICANCE: These results confirm the beneficial effects of TiO2 NPs in combination with chemotherapy in in vitro model of gastric cancer, which may pave the way to develop a possible solution to circumvent chemoresistance in cancer.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Nanopartículas/química , Titânio/farmacologia , Antimetabólitos Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Vesículas Citoplasmáticas/efeitos dos fármacos , Vesículas Citoplasmáticas/metabolismo , Sinergismo Farmacológico , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fluoruracila/química , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Nanopartículas/ultraestrutura , Conformação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Proteína Sequestossoma-1/antagonistas & inibidores , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Titânio/química , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
3.
Chemosphere ; 241: 124990, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31604197

RESUMO

The effect of substitution of iron by copper in the magnetite lattice was investigated in terms of the catalytic activity in the heterogeneous photo-Fenton process. The physicochemical properties of the Fe3-xCuxO4 nanoparticles were characterized by X-ray diffraction (XRD), X-ray fluorescence (WD-XRF), specific surface area measurements, field emission scanning electron microscopy (FEG-SEM), and X-ray photoelectron spectroscopy (XPS). Copper-modified magnetite showed higher catalytic activity for H2O2 conversion to HO• (estimated using 7-hydroxycoumarin), compared to pristine magnetite (Fe3O4). Consequently, improved degradation of the anticancer drugs 5-fluorouracil (5-FU) and cyclophosphamide (CP) was observed, with high efficiencies achieved using Fe2.75Cu0.25O4 (0.125 g L-1) and 15 mmol L-1 H2O2, at pH 6.5, which resulted in complete degradation of 7.7 µmol L-1 5-FU and CP after 150 min. Low leaching of Cu and Fe demonstrated the stability of the catalyst in the Fenton process, with high catalytic activity (>90%) maintained after use in 4 cycles. The addition of radical scavengers such as methanol, tert-butanol and iodide ions indicated that surface-bonded hydroxyl radicals played a major role in the degradation of 5-FU and CP in the Fe3-xCuxO4/H2O2 system. The substitution of octahedral Fe(II) sites of the magnetite lattice by Cu(II) and the partial oxidation of Cu(I) to Cu(II) and Fe(II) to Fe(III) on the catalyst surface after the Fenton reaction were confirmed by analysis of the XPS spectra.


Assuntos
Cobre/química , Ciclofosfamida/química , Óxido Ferroso-Férrico/química , Fluoruracila/química , Catálise , Compostos Férricos/química , Peróxido de Hidrogênio/química , Radical Hidroxila , Oxirredução
4.
Int J Nanomedicine ; 14: 9259-9273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819428

RESUMO

Purpose: The main goal of this study is to evaluate the impact of physical incorporation of polyethylene glycol (PEG) into 5-fluorouracil (5-FU)-loaded polymeric nanoparticles (NPs). Methods: The 5-FU-loaded NPs were prepared utilizing a simple double emulsion method using polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA) with or without PEG 6000. The surface charge, particle size, and shape of NPs were evaluated by standard procedures. Both Fourier Transform Infrared Spectroscopy and X-ray diffraction spectra of the 5-FU loaded NPs were compared against the pure 5-FU. The in vitro release profile of 5-FU from the NPs was monitored by the dialysis tubing method. Cell death and apoptosis induction in response to 5-FU NP exposure were measured by MTT and Annexin-V/7-amino-actinomycin D (7-AAD) assays, respectively, in Daoy, HepG2, and HT-29 cancer cell lines. Results: The 5-FU loaded NPs were found to be spherical in shape with size ranging between 176±6.7 and 253.9±8.6 nm. The zeta potential varied between -7.13± 0.13 and -27.06±3.18 mV, and the entrapment efficiency was between 31.96% and 74.09%. The in vitro release of the drug followed a two-phase mode characterized by rapid release in the first 8 hrs followed by a period of slow release up to 72 hrs with composition-based variable extents. Cells exposed to NPs demonstrated a significant cell death which correlated with the ratio of PEG in the formulations in Daoy and HepG2 cells but not in HT-29 cells. Formulations (F1-F3) significantly induced early apoptosis in HT-29 cell lines. Conclusion: The physical PEGylation significantly enhanced the entrapment and loading efficiencies of 5-FU into NPs formulated with PLGA and PCL. It also fostered the in vitro cytotoxicity of 5-FU-loaded NPs in both Daoy and HepG2 cells. Induction of early apoptosis was confirmed for some of the formulations.


Assuntos
Fluoruracila/farmacologia , Nanopartículas/química , Poliésteres/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Fluoruracila/química , Células HT29 , Humanos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Polietilenoglicóis/química , Eletricidade Estática , Difração de Raios X
5.
Molecules ; 24(20)2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31614932

RESUMO

5-Fluorouracil (5FU), a common anti-cancer drug, occurs in four tautomeric forms and possesses two potential sites of both protonation and deprotonation. Tautomeric and resonance structures of the ionized forms of 5FU create the systems of connected equilibriums. Since there are contradictory reports on the ionized forms of 5FU in the literature, complex theoretical studies on neutral, protonated and deprotonated forms of 5FU, based on the broad spectrum of DFT methods, are presented. These indicate that the O4 oxygen is more willingly protonated than the O2 oxygen and the N1 nitrogen is more willingly deprotonated than the N3 nitrogen in a gas phase. Such preferences are due to advantageous charge delocalization of the respective ions, which is demonstrated by the NBO and ESP analyses. In an aqueous phase, stability differences between respective protonated and deprotonated forms of 5FU are significantly diminished due to the competition between the mesomeric effect and solvation. The calculated pKa values of the protonated, neutral and singly deprotonated 5FU indicate that 5FU does not exist in the protonated and double-deprotonated forms in the pH range of 0-14. The neutral form dominates below pH 8 and the N1 deprotonated form dominates above pH 8.


Assuntos
Fluoruracila/química , Prótons , Água/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Estrutura Molecular , Nitrogênio/química , Oxigênio/química
6.
Eur J Med Chem ; 183: 111706, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553932

RESUMO

A series of twenty-three parthenolide-5-fluorouracil (5-FU) conjugates ware synthesized and evaluated for their anti-cancer activities against human hepatocellular carcinoma cell line Bel-7402 and 5-fluorouracil resistant human hepatocellular carcinoma cell line Bel-7402/5-FU. The preliminary structure-activity relationships were discussed. The most active compound 15d showed high activity against Bel-7402/5-FU cell line with IC50 value of 2.25 µM, which demonstrated 5.8-fold improvement compared to that of the parent compound parthenolide (IC50 = 12.98 µM). The investigation of preliminary molecular mechanism of 15d revealed that 15d could reverse drug resistance by inhibiting MDR1, ABCC1 and ABCG2 to increase the intracellular drug accumulation and induce apoptosis of Bel-7402/5-FU cells through mitochondria mediated pathway. On the base of these results, compound 15d is deserved to be further investigated as a potential anti-HCC lead compound for ultimate discovery of pathenolide-based anti-cancer drug.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Sesquiterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Núcleo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/química , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Sesquiterpenos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
Nanoscale ; 11(34): 15958-15970, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31418432

RESUMO

Oral drug delivery systems (ODDSs) have attracted considerable attention in relation to orthotopic colon cancer therapy due to certain popular advantages. Unfortunately, their clinical applications are generally limited by the side-effects caused by systemic drug exposure and poor real-time monitoring capabilities. Inspired by the characteristics of pH changes of the gastrointestinal tract (GIT) and specific enzymes secreted by the colonic microflora, we anchored polyacrylic acid (PAA) and chitosan (CS) on Gd3+-doped mesoporous hydroxyapatite nanoparticles (Gd-MHAp NPs) to realize programmed drug release and magnetic resonance imaging (MRI) at the tumor sites. In particular, the grafted PAA, as a pH-responsive switch, could effect controlled drug release in the colon. Further, CS is functionalized as the enzyme-sensitive moiety, which could be degraded by ß-glycosidase in the colon. Gadolinium is a paramagnetic lanthanide element used in chelates, working as a contrast medium agent for an MRI system. Interestingly, after oral administration, CS and PAA could protect the drug-loaded nanoparticles (NPs) against variable physiological conditions in the GIT, allowing the drug to reach the colon tumor sites, preventing premature drug release. Enhanced drug concentrations at the colon tumor sites were achieved via this programmed drug release, which subsequently ameliorated the therapeutic effect. In addition, encapsulating both chemotherapeutic (5-fluorouracil, 5-FU) and targeted therapy drug (gefitinib, Gef) within Gd-MHAp NPs produced a synergistic therapeutic effect. In summary, this study demonstrated that such a novel drug system (Gd-MHAp/5-FU/Gef/CS/PAA NPs) could protect, transport, and program drug release locally within the colonic environment; further, this system exhibited a worthwhile therapeutic effect, providing a promising novel treatment strategy for orthotopic colon cancer.


Assuntos
Neoplasias do Colo , Meios de Contraste , Fluoruracila , Gadolínio , Gefitinibe , Imagem por Ressonância Magnética , Nanopartículas , Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/farmacologia , Administração Oral , Animais , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Meios de Contraste/química , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Durapatita/química , Durapatita/farmacocinética , Durapatita/farmacologia , Fluoruracila/química , Fluoruracila/farmacocinética , Fluoruracila/farmacologia , Gadolínio/química , Gadolínio/farmacocinética , Gadolínio/farmacologia , Gefitinibe/química , Gefitinibe/farmacocinética , Gefitinibe/farmacologia , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico
8.
J Mol Model ; 25(9): 265, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444705

RESUMO

In this paper, the possible interactions between 5-fluorouracil (5FU) as an anticancer drug and gallium nitride (Ga12N12) nanocage (NC) in aqueous solution have been investigated using DFT/CPCM/B3LYP-D/6-31G(d,p) level of theory. Eleven different orientations were used to mimic the 5FU adsorbed on Ga12N12 (5FU@GaNNC). To investigate the interaction mechanism between the two components, the adsorption energies and thermodynamic parameters, the electronic properties such as the energies and orbitals distribution of the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), the HOMO-LUMO energy gaps (Eg), the density of states (DOS), partial DOS (PDOS), and the molecular electrostatic potential (MEP) have been calculated and compared. The natural bond orbitals (NBOs) and the quantum theory of atoms in molecules (QTAIM) calculations have been applied for understanding chemical interactions and chemical bonding. Additionally, some quantum molecular descriptors were calculated for the understanding of molecular reactivity. Main results revealed that (1) the key factor that leads to stabilization of the formed complex/s is the relocation of one of the H atoms that originally belonging to one of the N atoms in 5FU to one of the nearest Ga atoms in GaNNC and (2) the adsorption energies for the eleven adsorbed systems are relatively larger compared with reported similar systems indicating from a theoretical point of view, a probable chemisorption type of adsorption and the privilege of GaNNC as a carrier for 5FU drug. Graphical abstract Simulation of the most stable adsorbed system of 5-fluorouracil anticancer drug on Gallium nitride nanocage.


Assuntos
Sistemas de Liberação de Medicamentos , Fluoruracila/administração & dosagem , Gálio/química , Modelos Moleculares , Nanoestruturas/química , Antineoplásicos/administração & dosagem , Fluoruracila/química , Teoria Quântica , Eletricidade Estática , Termodinâmica
9.
Int J Mol Sci ; 20(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438649

RESUMO

The transforming growth factor-beta (TGF-ß) plays an important role in pathological fibrosis and cancer transformation. Therefore, the inhibition of the TGF-ß signaling pathway has therapeutic potential in the treatment of cancer. In this study, the binding modes between 47 molecules with a pyrrolotriazine-like backbone structure and transforming growth factor-beta type 1 receptor (TßR1) were simulated by molecular docking using Discovery Studio software, and their structure-activity relationships were analyzed. On the basis of the analysis of the binding modes of ligands in the active site and the structure-activity relationships, 29,254 new compounds were designed for virtual screening. According to the aforementioned analyses and Lipinski's rule of five, five new compounds (CQMU1901-1905) with potential activity were screened through molecular docking. Among them, CQMU1905 is an attractive molecule composed of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), and 5-azacytosine. Interestingly, 5-FU, 6-MP, and 5-azacytidine are often used as anti-metabolic agents in cancer treatment. Compared with existing compounds, CQMU1901-1905 can interact with target proteins more effectively and have good potential for modification, making them worthy of further study.


Assuntos
Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Citosina/análogos & derivados , Citosina/química , Citosina/farmacologia , Fluoruracila/química , Fluoruracila/farmacologia , Humanos , Mercaptopurina/química , Mercaptopurina/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
10.
Int J Pharm ; 570: 118646, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31465836

RESUMO

Gastric cancer is the third leading cause of cancer-related death worldwide, with half of patients developing metastasis within 5 years after curative treatment. Moreover, many patients cannot tolerate or complete systemic treatment due severe side-effects, reducing their effectiveness. Thus, targeted therapeutics are warranted to improve treatment outcomes and reduce toxicity. Herein, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with 5-fluorouracil (5-FU) and paclitaxel were surface-functionalized with a monoclonal antibody targeting sialyl-Lewis A (sLeA), a known glycan mediating hematogenous metastasis. Nanoparticles, ranging from 137 to 330 nm, enabled the controlled release of cytotoxic drugs at neutral and acid pH, supporting potential for intravenous and oral administration. Nanoencapsulation also reduced the initial toxicity of the drugs against gastric cells, suggesting it may constitute a safer administration vehicle. Furthermore, nanoparticle functionalization significantly enhanced targeting to sLeA cells in vitro and ex vivo (over 40% in comparison to non-targeted nanoparticles). In summary, a glycoengineered nano-vehicle was successfully developed to deliver 5-FU and paclitaxel therapeutic agents to metastatic gastric cancer cells. We anticipate that this may constitute an important milestone to establish improved targeted therapeutics against gastric cancer. Given the pancarcinomic nature of the sLeA antigen, the translation of this solution to other models may be also envisaged.


Assuntos
Fluoruracila/administração & dosagem , Fluoruracila/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Paclitaxel/administração & dosagem , Paclitaxel/química , Neoplasias Gástricas/tratamento farmacológico , Anticorpos Monoclonais/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
11.
Int J Pharm ; 568: 118491, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31276765

RESUMO

Due to the toxicity and resistance to treatment with anticancer drugs, various methods are used to improve their efficacy in cancer treatment. In this present study, in order to overcome the limitation of 5-Fluorouracil (5-FU), prodrug strategy has been pursued with using density functional theory (DFT) and molecular dynamics simulation (MDs). The main objective of this study is to examine the mechanisms of drug release from its prodrug form by using the intrinsic reaction coordinate (IRC) calculations. The reaction mechanisms of 5-FU prodrug (EMC-5-FU) in the presence of lactic acid (LA) and water molecule were theoretically studied. The IRC calculations were carried out at the M06-2X/6-311G** level in the aqueous phase through the mechanism of ester hydrolysis to obtain energies, the geometry optimization of all stationary points along the potential energy surfaces (PES), and also to determine the harmonic vibrational frequencies. The results herein presented suggest that three reaction pathways and transition states TS1 to TS2 are involved along the calculated potential energy surface. We found that the drug molecule is released in the third step and this occurs by separation CH2O group in the presence of water molecule with the highest energy barrier about 25.9 kcal/mol. Since the carbon nanotubes (CNTs) can act as drug delivery vehicles and deliver anticancer drugs directly to the target cells. Therefore in DFT section, the interaction mechanism of CNTs with 5-FU prodrug is studied by means of DFT method. The atoms in molecules (AIM) and the non-covalent interactions (NCI) between the CNTs and prodrug are used in order to examine the strength and type of interaction between them. The result of negative binding energy values of CNT-prodrug interaction show the stability of these complexes. Our theoretical results show that the more favorable interaction occurs when the prodrug is located inside the carbon nanotube. Furthermore, for design and development of intracellular drug delivery systems, steered molecular dynamics (SMD) simulations was used to investigate the possibility of encapsulated prodrug-CNT penetration through a (1-palmitoyl-2-oleoyl phosphatidylcholine) POPC lipid bilayer. For this purpose, the forces of penetration and the free energies of rupture of POPC bilayer with a Prodrug-CNT were studied. Our simulation results show that encapsulated prodrug-carbon nanotube does not permanently destroy the POPC membrane structure.


Assuntos
Antineoplásicos/química , Fluoruracila/química , Maleimidas/química , Nanotubos de Carbono/química , Pró-Fármacos/química , Preparações de Ação Retardada/química , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Permeabilidade , Fosfatidilcolinas/química
12.
Asian Pac J Cancer Prev ; 20(7): 2181-2194, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350983

RESUMO

Controlled release delivery system of chemotherapeutic agents at the site of colon endorses modern drug-entrapped delivery tools, which release the entrappedagents at a controlled rate for anextended period providing patient compliance and additional protection from the degradinggastric environment. Thus, the present study was aimed to develop and optimize a novel polymeric microsphere of 5-fluorouracil (5-FU) using natural gum katira to obtain an optimal therapeutic response at the colon. Due course of experimentation, in-vivo safety profile of the gum katira in an animal model was established. Modified solvent extraction/evaporation technique wasemployed to encapsulate 5-FU in the natural polymeric microsphere and was characterized using in-vitro studies to investigate particle size, morphology, encapsulation efficiency and release of the drug from developed formulation. Formulated and optimized polymeric microsphere of 5-FU using gum katira polymer own optimal physicochemical characteristics with a fine spherical particle with size ranged from 210.37±7.50 to 314.45±7.80 µm.Targeted microsphere exhibited good cytotoxicity and also has high drug entrapment efficiency, and satisfactory release pattern of the drug within a time frame of 12 h. Finally, we foresee that the optimized polymeric gum katiramicrosphere of 5-FU could be a promising micro-carrier for efficient colon drug targeting delivery tool with improved chemotherapeutic efficacy against colon cancer.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Materiais Biocompatíveis/química , Neoplasias do Colo/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Fluoruracila/administração & dosagem , Microesferas , Gomas Vegetais/química , Animais , Antimetabólitos Antineoplásicos/química , Neoplasias do Colo/patologia , Portadores de Fármacos/química , Fluoruracila/química , Humanos , Masculino , Ratos , Ratos Wistar , Células Tumorais Cultivadas
13.
Eur J Pharm Sci ; 137: 105002, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302215

RESUMO

Here, we introduce core-shell nanofibers based on chitosan (CS)-loaded poly (ε-caprolactone) (PCL) shell and 5-fluorouracil (5-FU)-loaded Poly(N-vinyl-2-pyrrolidone) (PVP) core for synergistic therapy of melanoma skin cancer. The yielded nanofibers exhibited an average diameter of 503 nm with high drug-encapsulating efficiency and good mechanical properties. Moreover, the burst release of 5-FU significantly inhibited melanoma skin cancer cells (B16F10 cells), and the sustained release of CS exhibited "remedying effects" on normal skin cells (L929 cells) after suffering adverse effects from 5-FU treatment. For the B16F10 cells, the early apoptosis cells increased from 0.8% to 62.2% after being treated with blended films loaded with 5-FU (2 wt%) for 24 h; for the L929 cells, the vital cells increased from 68.9% to 77.0%, and the early apoptosis of stage cells decreased from 12.3% to 10.9% after being treated with blended films with CS (8 wt%) for 24 h. In conclusion, the results introduced in this work can be a promising strategy for cancer treatment and possesses synergism potential to broaden an avenue for chemotherapeutic therapy with minimum adverse effects on normal cells.


Assuntos
Antineoplásicos/administração & dosagem , Quitosana/administração & dosagem , Sistemas de Liberação de Medicamentos , Fluoruracila/administração & dosagem , Nanofibras/administração & dosagem , Poliésteres/administração & dosagem , Povidona/administração & dosagem , Animais , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Fluoruracila/química , Melanoma Experimental/tratamento farmacológico , Camundongos , Nanofibras/química , Poliésteres/química , Povidona/química , Neoplasias Cutâneas/tratamento farmacológico
14.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1137-1143, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31303582

RESUMO

The aim of study was cross linking of high molecular weight chitosan nanoparticles containing 5-fluorouracil to improve dissolution rate and ultimately enhance its bioavailability by reverse emulsion/micelles method and cross-linking agent i.e. glutaraldehyde (GA 25% aqueous solution in water). The nature and outer morphologies were evaluated by scanning electron microscopy (SEM). Drug release models were functional to support way from cross linked NPs. Cross linking of 5-fluorouracil with glutaraldehyde improved dissolution rate. Mean dissolution time of 5-fluorouracil decreased significantly upon reverse emulsion/cross linking as encapsulated drug is protective and thermally stable within cross linked chitosan NPs. FTIR studies showed formation of intermolecular hydrogen bonding between 5-fluorouracil and GA-co-CHNPs. DSC studies indicated a less crystalline state of 5-fluorouracil in cross linking. SEM showed spherical nanoparticles with somewhat rough surface. 5-FU release followed Korsmeyer-Peppas model which indicate diffusion and dissociation control drug release from GA-co-CH-NPs. 5-FU cross linked chitosan nanoparticles can be safe and useful tool for other chemotherapeutic agents.


Assuntos
Quitosana/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Fluoruracila/farmacocinética , Nanopartículas/química , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Reagentes para Ligações Cruzadas/química , Estabilidade de Medicamentos , Fluoruracila/química , Glutaral/química , Ligação de Hidrogênio , Microscopia Eletrônica de Varredura , Peso Molecular , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
15.
Mater Sci Eng C Mater Biol Appl ; 103: 109828, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349496

RESUMO

New type of nanocapsules based on carboxymethyl chitosan functionalized with AS1411 aptamer and poly(N-vinylpyrrolidone-alt-itaconic anhydride) loaded with 5-Fluorouracil (5-FU) were developed, with the potential to improve the treatment of cancer. Functionalization of nanocapsules with AS1411 aptamer will enhance their recognition by tumor cells, due to the interaction with nucleolin, and subsequent endocytosis. Nanocapsules were prepared by interfacial condensation method in the absence of any toxic crosslinking agents. The condensation reaction took place at the interface between the organic and aqueous phases by opening the anhydride cycles from the copolymer, under the action of the NH2 groups from mixture of chitosan/aptamer-functionalized carboxymethyl chitosan. The nanocapsules diameter varied between 100 and 267 nm as a function of the molar ratio of the polymers. SEM images have revealed that nanocapsules were spherical and presented relatively low dimensional polydispersity. Nanocapsules swelling degree was found between 1000 and 1680% in PBS solution (pH = 7.4) and they allowed the encapsulation of an important amount of 5-Fluorouracil (5-FU). The release efficiency of 5-FU was studied, the processes being controlled by the drug diffusion through the polymeric membrane, as confirmed by the theoretical analysis of the drug release. The cytotoxicity and haemolysis tests performed on the nanocapsules proved their lack of toxicity and their excellent hemocompatibility. The obtained results were encouraging, showing that these original 5-FU-loaded nanocapsules were able to induce a more pronounced cytotoxic effect on neoplastic MCF-7 cells, the occurrence of dead cells being more rapidly than in the case of free 5-FU.


Assuntos
Aptâmeros de Nucleotídeos , Neoplasias da Mama/tratamento farmacológico , Fluoruracila , Nanocápsulas , Oligodesoxirribonucleotídeos , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacocinética , Aptâmeros de Nucleotídeos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Feminino , Fluoruracila/química , Fluoruracila/farmacocinética , Fluoruracila/farmacologia , Humanos , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/farmacocinética , Oligodesoxirribonucleotídeos/farmacologia , Tamanho da Partícula
16.
Chem Commun (Camb) ; 55(53): 7683-7686, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31204739

RESUMO

An easy access to topical gels (both hydro- and organogels) derived from an anti-cancer prodrug namely 5-fluorouracil acetic acid (5-FuA) achieved by exploiting a simple salt formation strategy is reported for the first time. Nearly 85% of the salts synthesized were gelators. Single crystal structures of some of the gelator salts revealed an intriguing hydrogen bonding network including double stranded 1D chains stabilized through uracil-uracil complementary interactions and the crystal structures of the gelator salts corroborated well with the hypothesis based on which the gelators were designed. Studies indicated that both the hydrogel and the methyl salicylate gel of the gelator salt FuA-15 were suitable for self-drug-delivery application.


Assuntos
Ácido Acético/farmacologia , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Fluoruracila/farmacologia , Pró-Fármacos/farmacologia , Ácido Acético/síntese química , Ácido Acético/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fluoruracila/síntese química , Fluoruracila/química , Géis/síntese química , Géis/química , Géis/farmacologia , Humanos , Ligação de Hidrogênio , Estrutura Molecular , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Propriedades de Superfície
17.
Biotechnol Appl Biochem ; 66(5): 772-780, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31119802

RESUMO

Nowadays, putting forward an accurate cancer therapy method with minimal side effects is an important topic of research. Nanostructures, for their ability in controlled and targeted drug release on specific cells, are critical materials in this field. In this study, a pH-sensitive graphene oxide-l-arginine nanogel was synthesized to carry and release 5-fluorouracil. Optimized conditions using statistical analysis, based on the maximum relative viscosity of nanogel, were evaluated: 5.489 for the concentration of l-arginine and 2.404 for pH. The prepared nanogels were characterized using scanning electron microscope and transmission electron microscope images and Fourier-transform infrared spectroscopic analysis. Cytotoxicity was assessed using the sulforhodamine B (SRB) assay on MCF-7 breast cancer cells. The fluorouracil release was measured by the dialysis bag method, UV spectrophotometry, and fluorouracil calibration diagram. Results proved the successful controlled release of fluorouracil at pH 5.4 and the beneficial role of graphene-oxide- l-arginine- fluorouracil nanogel in eliminating cancer cells.


Assuntos
Arginina/farmacologia , Fluoruracila/farmacologia , Grafite/farmacologia , Nanopartículas/química , Polietilenoglicóis/farmacologia , Polietilenoimina/farmacologia , Arginina/química , Sobrevivência Celular/efeitos dos fármacos , Fluoruracila/química , Grafite/química , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoimina/química , Propriedades de Superfície
18.
Int J Pharm ; 563: 110-121, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30935913

RESUMO

This research attempts to bring together the positive aspects of lipid nanoparticles and Quality by Design (QbD) approach for developing a novel drug delivery system for skin cancers and aktinic keratosis. Lipid nanoparticles which is one of the most efficacious options for topical treatment of skin diseases were prepared due to their ability to overcome the complex structure of skin barrier and to enhance the skin penetration. Since the formulation development contains complex variables of active ingredients, raw materials or production method; all the variables of the product should be elaborated. QbD approach which refers to design and develop formulations and manufacturing processes to maintain the prescribed product quality was also successfully adopted to achieve a time- and cost-saving process ensuring a high-quality product. 5-Fluorouracil (5-FU) loaded lipid nanoparticles, both solid lipid nanoparticles and nanostructured lipid carriers, were developed and characterized by following QbD steps. Optimal lipid nanoparticle formulation with guaranteed quality which was within the design space has been reached through the artificial neural networks. The optimal lipid nanoparticle formulation which is a NLC formulation with a mean particle size of 205,8 ±â€¯9,34 nm, narrow size distribution (0.279 ±â€¯0.01) and negative zeta potantial -30,20 ±â€¯0,92 was produced by high pressure homogenization method. Cytotoxicity profiles of the optimal NLC was determined by cell culture studies on epidermoid carcinoma cells and human keratinocyte cells. Optimal NLC showed significantly higher anticancer effect on epidermoid carcinoma cells than free 5-FU and also less cytotoxicity towards human keratinocyte cells. Optimal NLC was formulated in hydrogel formulation for ease of application which has suitable occlusive and mechanical properties, viscocity and pH for patient complience. The cumulative amount of 5-FU in dermal tissues of rat skin was found 20.11 ±â€¯2.14 µg/cm2 and 9.73 ±â€¯0.87 µg/cm2 after application of NLC enriched hydrogel and 5-FU hydrogel respectively. In conclusion, this study showed that a time and cost saving process ensuring a high-quality product can be obtained by QbD guided formulation development study with the help of artificial neural networks. A novel semisolid dosage form enriched by NLC which is promising for topical treatment of skin cancers was developed.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos/métodos , Fluoruracila/administração & dosagem , Hidrogéis/administração & dosagem , Lipídeos , Nanopartículas , Animais , Antimetabólitos Antineoplásicos/química , Linhagem Celular , Composição de Medicamentos , Liberação Controlada de Fármacos , Fluoruracila/química , Humanos , Hidrogéis/química , Ceratose Actínica/tratamento farmacológico , Lipídeos/administração & dosagem , Lipídeos/química , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Pressão , Ratos Sprague-Dawley , Pele/metabolismo , Absorção Cutânea , Neoplasias Cutâneas/tratamento farmacológico
19.
Int J Biol Macromol ; 132: 506-513, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30951773

RESUMO

In most cancer treatments, chemotherapy is currently necessary; hence, more attention was devoted to developing new methods for designing drug delivery systems (DDS) with controlled drug release. For this aim, anticancer 5­fluorouracil (5-FU) drug was loaded into chitosan/polyacrylic acid/Fe3O4 magnetic nanocomposite hydrogel (CS/PAA/Fe3O4) through immersing in the drug solution. The prepared CS/PAA/Fe3O4 was characterized using FT-IR, XRD, VSM, TGA and SEM analysis. For demonstrating the efficiency of the prepared novel nanocomposite carrier as a controlled DDS, in-vitro the drug delivery tests were carried out in mimicking the colon and rectal conditions. The drug release tests showed that the CS/PAA/Fe3O4 enhanced the stability of drug dosing for a long time with controlled releases in the colon and rectal conditions. According to the obtained results, the prepared nanocomposite hydrogel could potentially to be used in DDS as a colon and rectal administration of 5-FU.


Assuntos
Resinas Acrílicas/química , Antineoplásicos/química , Quitosana/química , Fluoruracila/química , Hidrogéis/química , Nanopartículas de Magnetita/química , Nanocompostos/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Campos Magnéticos , Modelos Moleculares , Conformação Molecular
20.
Lab Chip ; 19(10): 1764-1771, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30942234

RESUMO

An integrated microfluidic system combining 1) an optically-induced-dielectrophoresis (ODEP) module for manipulation of drug-containing particles and 2) an ultraviolet (UV) "direct writing" module capable of patterning hydrogels was established herein for automatic formulation of customized digital drug cocktails. Using the ODEP module, the drug-containing particles were assembled by using moving light patterns generated from a digital projector. The hydrogel, poly(ethylene glycol) diacrylate (PEGDA), was used as the medium in the ODEP module such that the assembled drug-containing particles could be UV-cured and consequently encapsulated in "pills" of specific sizes and shapes by using the UV direct writing module. At an optimal ODEP force of 335 pN, which was achieved in a solution of 15% PEGDA in 0.2 M sucrose, it was possible to manipulate and UV-cure the drug-containing particles. Furthermore, with a digital micromirror device inside the UV direct writing module, different UV patterns could be designed and projected, allowing for the digital drug cocktails to be packaged into different shapes in <60 s. As a demonstration, emulsion droplets containing two different anti-cancer drugs were further tested to show the capability of the developed device. This represents an automatic digital drug cocktail formulating device which stands to revolutionize personalized medicine.


Assuntos
Acrilatos/química , Antineoplásicos/química , Hidrogéis/química , Técnicas Analíticas Microfluídicas , Polietilenoglicóis/química , Eletroforese , Etoposídeo/química , Fluoruracila/química , Humanos , Imagem Óptica , Tamanho da Partícula , Processos Fotoquímicos , Medicina de Precisão , Propriedades de Superfície , Raios Ultravioleta
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