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1.
Nucleosides Nucleotides Nucleic Acids ; 38(12): 980-1005, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380708

RESUMO

Two series of novel fluorinated nucleosides dimers with an unnatural 1,2,3-triazole linkage were synthesized. The obtained molecules were prepared using "click" chemistry approach based on copper(I) catalyzed Huisgen azide-alkyne cycloaddition. It was performed between 3'- and 5'-azido-nucleosides as the azide components, and the 3'-O- and 5'-O-propargyl-nucleosides as the alkyne components. Based on analysis of the 3 JHH, 3 JH1'C2 and 3 JH1'C6 we estimated conformational preferences of sugar part and orientation around glycosidic bond. All described nucleosides dimers analogs were characterized by spectroscopic methods and evaluated for their in vitro cytotoxicity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7).


Assuntos
Antineoplásicos/síntese química , Floxuridina/química , Nucleosídeos/síntese química , Timidina/química , Triazóis/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Química Click/métodos , Reação de Cicloadição/métodos , Dimerização , Células HeLa , Humanos , Células KB , Células MCF-7 , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nucleosídeos/farmacologia
2.
Chem Commun (Camb) ; 55(72): 10654-10664, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31418758

RESUMO

Some host-guest complexes of cucurbit[n]uril (CB[n]) host molecules act as supramolecular amphiphiles (SAs), which hierarchically self-assemble into various nanomaterials such as vesicles, micelles, nanorods, and nanosheets in water. The structures and functions of the nanomaterials can be controlled by supramolecular engineering of the host-guest complexes. In addition, functionalization at the periphery of CB[6] and CB[7] generates CB[n]-based molecular amphiphiles (MAs) that can also self-assemble into vesicles or micelle-like nanoparticles in water. Taking advantage of the molecular cavities of CBs and their strong guest recognition properties, the surface of the self-assembled nanomaterials can be easily decorated with various functional tags in a non-covalent manner. In this feature article, the two types (SAs and MAs) of CB-based amphiphiles, their self-assemblies and their applications for nanotherapeutics and theranostics are presented with future perspectives.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Doxorrubicina/farmacologia , Nanoestruturas/química , Tensoativos/farmacologia , Antibióticos Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Células HeLa , Humanos , Células KB , Tensoativos/química
3.
Fitoterapia ; 137: 104257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278976

RESUMO

Two new meroditerpene pyrones, chevalone F (1) and 11-hydroxychevalone E (2), a new tryptoquivaline analog, tryptoquivaline V (3) and a new brasiliamide analog, brasiliamide G (4), together with thirteen known compounds, chevalones A-C (5-7), chevalone E (8), 11-hydroxychevalone C (9), pyripyropene A (10), isochaetominine C (11), pyrrolobenzoxazine terpenoids CJ-12662 (12) and CJ-12663 (13), fischerindoline (14), eurochevalierine (15), 1,4-diacetyl-2,5-dibenzylpiperazine-3,7''-oxide (16) and lecanorin (17) were isolated from the fungus Neosartorya pseudofischeri. Their structures were established on the basis of spectroscopic evidence. Compound 2 showed weak antibacterial activity against Escherichia coli and Salmonella enterica serovar Typhimurium, whereas compounds 7, 12, 13 and 15 showed antibacterial activity against Bacillus cereus and Staphylococcus aureus. In addition, compounds 13 and 14 showed cytotoxicity against KB and MCF-7 cancer cell lines, as well as the Vero cell line.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Indóis/farmacologia , Neosartorya/química , Pironas/farmacologia , Animais , Antibacterianos/isolamento & purificação , Antineoplásicos/isolamento & purificação , Florestas , Humanos , Indóis/isolamento & purificação , Células KB , Células MCF-7 , Estrutura Molecular , Pironas/isolamento & purificação , Microbiologia do Solo , Tailândia , Células Vero
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(5): 522-527, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31303615

RESUMO

OBJECTIVE: To investigate the effect of chrysin on apoptosis of oral squamous carcinoma KB cell line and the possible mechanisms, and to provide new ideas for the treatment of oral cancer.
 Methods: Oral cancer KB cells were treated with different concentrations of chrysin (1, 2, 4, 8, 16, and 32 µmol/L) for 24 h. Cell proliferation was detected by MMT assay; apoptosis was detected by flow cytometry; the activity of caspase-3/7 was detected by chemiluminescent assay; mitochondrial membrane potential in KB cells was determined by JC-1 assay; and Western blotting was used to determine the activation of protein kinase B (AKT) and phosphoinositide-3-kinase (PI3K).
 Results: Chrysin inhibited the proliferation of KB cells in a concentration-dependent manner, accompanied by increase in apoptosis of KB cells, activation of caspase-3/7, decrease in mitochondrial membrane potential, and suppression of the phosphorylation of AKT and PI3K.
 Conclusion: The effect of chrysin on KB cell apoptosis may be related to mitochondrial dysfunction and inhibition of PI3K/AKT pathway.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Apoptose , Flavonoides , Humanos , Células KB , Fosfatidilinositol 3-Quinases , Transdução de Sinais
5.
Int J Nanomedicine ; 14: 3629-3644, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190816

RESUMO

Background: A very common and simple method (known as the blending method) to formulate drug delivery systems with required properties is to physically mix amphiphilic block copolymers with different hydrophobicity. In addition to its simplicity, this blending strategy could help avoid the time and effort involved in the synthesis of block copolymers with the desired structure required for specific drug formulations. Purpose: We used the blending strategy to design a system that could overcome the problem of high hydrophobicity and be a good candidate for drug product development using PEG-PLA-PEG triblock copolymers. Methods: Two types of PEG-PLA-PEG triblock copolymers with similar (long) PLA molecular weights (MWs) and different PEG MWs were synthesized. The micellar formulations were prepared by blending the two block copolymers in various ratios. The size and stability of the blending systems were subsequently investigated to optimize the formulations for further studies. The loading properties of doxorubicin or paclitaxel into the optimized blending system were compared to that in mono systems (systems composed of only a single type of triblock copolymer). In vitro and in vivo anti-cancer effects of the preparations were evaluated to assess the use of the blending system as an optimal nanomedicine platform for insoluble anticancer agents. Results: The blending system (B20 system) with an optimized ratio of the triblock copolymers overcame the drawbacks of mono systems. Drug uptake from the drug-loaded B20 system and its anticancer effects against KB cells were superior compared to those of free drugs (doxorubicin hydrochloride and free paclitaxel). In particular, doxorubicin-loaded B20 resulted in extensive doxorubicin accumulation in tumor tissues and significantly higher in vivo anti-cancer effects compared to free doxorubicin. Conclusion: The blending system reported here could be a potential nanoplatform for drug delivery due to its simplicity and efficiency for pharmaceutical application.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Animais , Antineoplásicos/farmacologia , Coloides/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Células KB , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Paclitaxel/farmacologia , Poliésteres/química , Polietilenoglicóis/química , Solubilidade , Distribuição Tecidual/efeitos dos fármacos
6.
Eur J Med Chem ; 178: 329-340, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200235

RESUMO

A novel series of 6-substituted pyrrolo[2,3-d]pyrimidines with reversed amide moieties from the lead compound 1a were designed and synthesized as nonclassical antifolates and as potential antitumor agents. Target compounds 1-9 were successfully obtained through two sequential condensation reactions from the key intermediate 2-amino-6-(2-aminoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. In preliminary antiproliferation assay, all compounds demonstrated submicromolar to nanomolar inhibitory effects against KB tumor cells, whereas compounds 1-3 also exhibited nanomolar antiproliferative activities toward SW620 and A549 cells. In particular, compounds 1-3 were significantly more potent than the positive control methotrexate (MTX) and pemetrexed (PMX) to A549 cells. The growth inhibition induced cell cycle arrest at G1-phase with S-phase suppression. Along with the results of nucleoside protection assays, inhibition assays of dihydrofolate reductase (DHFR) clearly elucidated that the intracellular target of the designed compounds was DHFR. Molecular modeling studies suggested two binding modes of the target compounds with DHFR.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Antagonistas do Ácido Fólico/farmacologia , Ácido Fólico/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Humanos , Células KB , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
7.
Ann Nucl Med ; 33(8): 606-616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31134434

RESUMO

OBJECTIVE: Folate receptor (FR) is an ideal target for cancer imaging because it is frequently overexpressed in major types of human tumor, whereas its expression in normal organs is highly limited. Combining nuclear and fluorescence-imaging techniques provides a novel approach for cancer imaging and monitoring the surgery. The objective of this study was to report the synthesis and characteristics of a dual-modality imaging agent, Tc-99m Folate-Gly-His-Glu-Gly-Glu-Cys-Gly-Lys(-5-carboxy-X-rhodamine)-NH2 (Folate-ECG-ROX), and verify its feasibility as both molecular imaging agent and intra-operative guidance. METHODS: Folate-ECG-ROX was synthesized using Fmoc solid-phase peptide synthesis. Radiolabeling of Folate-ECG-ROX with Tc-99m was done using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution and ex vivo imaging studies were performed using KB and HT-1080 tumor-bearing murine models. Tumor tissue slides were prepared and analyzed with immunohistochemistry staining and confocal microscopy. Surgical removal of tumor nodules in murine models with peritoneal carcinomatosis was performed under the fluorescence-imaging system. RESULTS: After radiolabeling procedures with Tc-99m, Tc-99m Folate-ECG-ROX complexes were prepared in high yield (> 97%). The binding affinity value (Kd) of Tc-99m Folate-ECG-ROX for KB cells was estimated to be 6.9 ± 0.9 nM. In gamma camera imaging, tumor to normal muscle uptake ratio of Tc-99m Folate-ECG-ROX increased with time (3.4 ± 0.4, 4.4 ± 0.7, and 6.6 ± 0.8 at 1, 2, and 3 h, respectively). In biodistribution study, %IA/g for KB tumor was 2.50 ± 0.80 and 4.08 ± 1.16 at 1 and 3 h, respectively. Confocal microscopy with immunohistochemistry staining detected strong Tc-99m Folate-ECG-ROX fluorescence within KB tumor tissue which is correlating with the fluorescent activity of anti-FR antibody. Under real-time optical imaging, the removal of visible nodules was successfully performed. CONCLUSIONS: In vivo and in vitro studies revealed substantial and specific uptake of Tc-99m Folate-ECG-ROX in FR-positive tumors. Thus, Tc-99m Folate-ECG-ROX could provide both pre-operative molecular imaging and fluorescence image-guidance for tumor.


Assuntos
Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/química , Ácido Fólico/metabolismo , Imagem Óptica/métodos , Neoplasias Peritoneais/diagnóstico por imagem , Neoplasias Peritoneais/cirurgia , Cirurgia Assistida por Computador , Animais , Transporte Biológico , Transformação Celular Neoplásica , Estudos de Viabilidade , Feminino , Ácido Fólico/farmacocinética , Humanos , Marcação por Isótopo , Células KB , Camundongos , Compostos de Organotecnécio/química , Distribuição Tecidual
8.
Cells ; 8(5)2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137684

RESUMO

P-glycoprotein (Pgp/ABCB1) overexpression is associated with multidrug resistance (MDR) phenotype and, consequently, failure in cancer chemotherapy. However, molecules involved in cell death deregulation may also support MDR. Tumor necrosis factor-alpha (TNF-α) is an important cytokine that may trigger either death or tumor growth. Here, we examined the role of cancer cells in self-maintenance and promotion of cellular malignancy through the transport of Pgp and TNF-α molecules by extracellular vesicles (membrane microparticles (MP)). By using a classical MDR model in vitro, we identified a positive correlation between endogenous TNF-α and Pgp, which possibly favored a non-cytotoxic effect of recombinant TNF-α (rTNF-α). We also found a positive feedback involving rTNF-α incubation and TNF-α regulation. On the other hand, rTNF-α induced a reduction in Pgp expression levels and contributed to a reduced Pgp efflux function. Our results also showed that parental and MDR cells spontaneously released MP containing endogenous TNF-α and Pgp. However, these MP were unable to transfer their content to non-cancer recipient cells. Nevertheless, MP released from parental and MDR cells elevated the proliferation index of non-tumor cells. Collectively, our results suggest that Pgp and endogenous TNF-α positively regulate cancer cell malignancy and contribute to changes in normal cell behavior through MP.


Assuntos
Proliferação de Células , Vesículas Extracelulares/metabolismo , Neoplasias/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Retroalimentação Fisiológica , Fibroblastos/metabolismo , Humanos , Células KB , Neoplasias/patologia , Transporte Proteico , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfa/genética
9.
Molecules ; 24(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035631

RESUMO

P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure-activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3'-OH, 4'-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Flavonoides/química , Flavonoides/farmacologia , Relação Quantitativa Estrutura-Atividade , Sobrevivência Celular , Relação Dose-Resposta a Droga , Humanos , Células KB , Modelos Moleculares , Conformação Molecular , Ligação Proteica
10.
Bioorg Med Chem ; 27(10): 1925-1931, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30992201

RESUMO

Folate receptors (FR) are frequently overexpressed in a wide variety of human cancers. The aim of this study was to develop a trivalent 99mTc(CO)3-labeled folate radiotracer containing isonitrile (CN-R) as the coordinating ligand for FR target imaging. [99mTc]Tc-10 was HPLC purified (>98% chemical purity) and evaluated in vitro and in vivo as a potential agent for targeting FR-positive KB cells. [99mTc]Tc-10 is a hydrophilic compound with partition coefficient of -2.90 ±â€¯0.13 that showed high binding affinity (0.04 ±â€¯0.002 nM) in vitro. High accumulation and retention of [99mTc]Tc-10 (5.32 ±â€¯2.99% ID/g) was observed in mice with KB tumors at 4 h after injection through the tail vein, which was significantly inhibited by co-injection of free folic acid (FA). SPECT (single photon emission tomography)/CT results were in accordance with biodistribution data at all time points.


Assuntos
Receptores de Folato com Âncoras de GPI/metabolismo , Nitrilos/química , Compostos Radiofarmacêuticos/química , Animais , Estabilidade de Medicamentos , Receptores de Folato com Âncoras de GPI/química , Humanos , Células KB , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Nitrilos/sangue , Nitrilos/metabolismo , Compostos de Organotecnécio/química , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Transplante Heterólogo
11.
Acta Medica (Hradec Kralove) ; 62(1): 30-34, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931894

RESUMO

Plants with anticancer properties are considered as cancer preventive and treatment sources, due to their some biological effects. Apoptosis induction and anti-proliferative effects of Baneh extract on various cancer cell lines have been reported. Hence, this study was designed to evaluate the cytotoxic effects of this fruit on KB and human gingival fibroblast cell lines (HGF). KB and HGF cells were treated with various concentrations of ethanolic Baneh extract and cisplatin as positive control. Cytotoxic activity and apoptosis induction were investigated using WST-1 and Annexin V assays. Data were analyzed using ANOVA and student's t-tests. IC50 after 24 and 48 hours treatment were respectively 2.6 and 1 mg/mL for KB cell line, and 1.5 and 1.6 mg/mL for HGF cell. During 48 hours Baneh extract induced apoptosis without significant necrosis, in a time- and dose-dependent manner. The induction of apoptosis in KB cells was significantly higher than HGF. It seems that ethanolic extract of Baneh contains compounds that can suppress KB cell growth through the induction of apoptosis. Within 48 hours, less cytotoxic effects were observed on normal fibroblast cells; therefore, it might be a potential anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Gengiva/citologia , Pistacia/química , Extratos Vegetais/farmacologia , Neoplasias do Colo do Útero/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gengiva/efeitos dos fármacos , Gengiva/patologia , Humanos , Células KB , Neoplasias do Colo do Útero/tratamento farmacológico
12.
Photodiagnosis Photodyn Ther ; 26: 150-156, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30885845

RESUMO

BACKGROUND: Quantum dots (QDs) bring new insights in cancer theranostics. Exceptional brightness together with the simple possibility to modify surface with targeting molecules make QDs attractive agents in fluorescence guided surgery and photodynamic therapy. Currently, many targeted QDs have been developed for theranostic purpose. However, their targeting ability was tested mainly in two dimensional monolayer tumor cell models, while our study includes 3D tumor model reflecting the specificity of in vivo tumor environment. METHODS: Core/multilayer shell CdSe/CdS/ZnS QDs were conjugated with folic acid (FA) and characterized spectroscopically. Cytotoxicity of QDs on KB and A549 cells lines were evaluated using the MTT assay. Cellular uptake of QDs was assessed by epifluorescent microscopy. To study the distribution of QDs in tumor tissue, KB spheroids were prepared by means of the liquid overlay technique and then frozen cut of spheroids treated with QDs were imaged by epifluorescence microscopy. RESULTS: We confirmed the specificity of QD-FA for the folic acid receptor positive KB cells. In 3D tumor spheroid model we demonstrated uptake enhancement of QD-FA compared with non-targeted QD. It was demonstrated that penetration profiles were similar for both QDs with penetration depth never exceeding 100 µm. CONCLUSIONS: We have demonstrated the effectiveness of FA conjugated QDs to target tumor spheroids thus confirming the crucial role of FRα receptor as a target. Further improvement of QD-FA targeting ability could be performed using dual targeting different targeting agents, such as FA and cyclic RGD.


Assuntos
Ácido Fólico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Pontos Quânticos/uso terapêutico , Células A549 , Linhagem Celular Tumoral , Humanos , Técnicas In Vitro , Células KB , Microscopia de Fluorescência , Fármacos Fotossensibilizantes/química , Pontos Quânticos/química
13.
Drug Deliv ; 26(1): 216-225, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30843439

RESUMO

To develop proliposome formulations to improve the oral bioavailability of l-glutathione (GSH), GSH-loaded proliposomes were prepared using the granule method. Mannitol was selected as an effective excipient to achieve the desired particle size, entrapment efficiency (EE), and solubility for oral delivery of the final formulation. To evaluate the effect of surface charge of proliposomes on the oral bioavailability of GSH, negative (F1-F4) and positive proliposomes (F5-F9) were prepared. Particle size of F1 and F5 was 167.8 ± 0.9 and 175.9 ± 2.0 nm, and zeta potential of F1 and F5 was -8.1 ± 0.7 and 21.1 ± 2.0 mV, respectively. Encapsulation efficiency of F1 and F5 was 58.6% and 54.7%, respectively. Considering their particle size, zeta potential, and EE, the proliposomes F1 and F5 were adopted as the optimal formulations for further experiments. Solid state characterization of the proliposomes confirmed lipid coating on the surface of mannitol. The release of GSH from F1 and F5 formulations was prolonged until 24 h and pH independent. The total antioxidant capacity of GSH was concentration-dependent and maintained after formulation of GSH proliposomes. Circular dichroism spectroscopy confirmed that the molecular structure of GSH was maintained in the proliposome formulations. GSH proliposomes exhibited no significant changes in particle size and zeta potential for 4 weeks. An oral bioavailability study in rats revealed that F5 exhibited 1.05-, 1.08-, and 1.11-fold higher bioavailability than F1, commercial capsule formulation, and pure GSH, respectively. In conclusion, the prepared GSH proliposomes enhanced the poor bioavailability of GSH and prolonged its duration of action.


Assuntos
Antioxidantes/química , Glutationa/química , Lipossomos/química , Peptídeos/química , Administração Oral , Animais , Antioxidantes/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Glutationa/farmacocinética , Humanos , Células KB , Lipídeos/química , Masculino , Tamanho da Partícula , Peptídeos/farmacocinética , Ratos , Ratos Sprague-Dawley , Solubilidade
14.
J Nanobiotechnology ; 17(1): 44, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30917812

RESUMO

BACKGROUND: The combination of multiple chemotherapeutics has been used in the clinic for enhanced cancer chemotherapy, however, frequent relapse, chemo-resistance and side effects remains therapeutic hurdles. Thus, the development of co-delivery system with enhanced targeting and synergistic different modal treatments has been proposed as promising strategies for intensive improvement of the therapeutic outcomes. RESULTS: We fabricated a nanocarrier based on gold nanorods (Au NRs), cRGD peptide-modified and multi-stimuli-responsive paclitaxel (PTX) and curcumin (CUR) release for synergistic anticancer effect and chemo-photothermal therapy (PTX/CUR/Au NRs@cRGD). The specific banding of cRGD to αvß3 integrin receptor on the tumor cell surfaces facilitated the endocytosis of PTX/CUR/Au NRs@cRGD, and the near-infrared ray (NIR) further enhanced the drug release and chemotherapeutical efficiency. Compared to single drug, single model treatment or undecorated-PTX/CUR/Au NRs, the PTX/CUR/Au NRs@cRGD with a mild NIR showed significantly enhanced apoptosis and S phase arrest in three cancer cell lines in vitro, and improved drug accumulation in tumor sites as well as tumor growth inhibition in vivo. CONCLUSIONS: The tumor targeted chemo-photothermal therapy with the synergistic effect of dual drugs provided a versatile strategy for precise cancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Curcumina/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Ouro/química , Nanotubos/química , Paclitaxel/administração & dosagem , Células A549 , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Células Hep G2 , Humanos , Raios Infravermelhos , Integrina alfaVbeta3/metabolismo , Células KB , Camundongos Endogâmicos BALB C , Paclitaxel/química , Tamanho da Partícula , Peptídeos Cíclicos/metabolismo , Fototerapia/métodos , Propriedades de Superfície
15.
Talanta ; 194: 643-648, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609585

RESUMO

Serum albumin has a wide range of applications in biochemical experiments and pharmaceutical field. We found that a cyanine dye, dimethylindole red (Dir), could selectively interact with bovine serum albumin (BSA). Dir exhibited very weak red fluorescence, while the fluorescence intensity at 630 nm was enhanced up to 130-fold upon noncovalently interacting with 30 µM BSA. Besides, Dir showed a highly selective response to BSA over human serum albumin (HSA). For the detection of BSA, a limit of detection as low as 23 nM was obtained. Then biocompatible Dir-BSA nanoparticles were prepared by the desolvation technique. The Dir-BSA nanoparticles possess excellent fluorescence properties with a quantum yield of 32%. Furthermore, folic acid as a targeting group was conjugated to Dir-BSA nanoparticles and these nanoparticles were characterized by TEM and laser particle analyzer, etc. Folic acid-modified Dir-BSA nanoparticles were successfully used for tumor cell-targeted imaging.


Assuntos
Corantes Fluorescentes/química , Ácido Fólico/química , Nanopartículas/química , Imagem Óptica/métodos , Soroalbumina Bovina/análise , Albumina Sérica Humana/análise , Animais , Bovinos , Linhagem Celular Tumoral , Humanos , Células KB , Limite de Detecção , Camundongos , Células NIH 3T3 , Soroalbumina Bovina/química , Albumina Sérica Humana/química
16.
Clin Transl Oncol ; 21(4): 479-488, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30298468

RESUMO

OBJECTIVES: To investigate the effects of Au@Fe2O3 core-shell nanoparticle (NP), with and without conjugation to folic acid (FA) as a targeting ligand, on radiosensitization of both cancer and healthy cells. METHODS: Au@Fe2O3 NPs were first synthesized, then modified with FA, and finally characterized. Radiation dose enhancement studies were performed on KB cancer cells and L929 healthy cells. NPs at the concentration of 20 µg/ml were first incubated with both cell lines and then different doses of 6 MV X-ray radiation were examined. The end effects were evaluated via MTT assay and flow cytometry using AnnexinV/PI kit. RESULTS: It was indicated that viability of KB cells has a much lower rate than L929 cells when the cells were treated by {(FA-Au@Fe2O3) + (X-ray)} regimen. Cell viability was even decreased significantly when X-ray dose increased. Moreover, flow cytometry studies revealed that FA-targeted NPs induced higher level of apoptosis for KB cancer cells than L929 healthy cells. CONCLUSION: Our findings provide a new perspective on high ability of the synthesized FA-targeted Au@Fe2O3 NPs which may be considered as an efficient radiosensitizer in the process of targeted radiation therapy of cancer.


Assuntos
Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Ouro/química , Nanopartículas de Magnetita/química , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Células KB , Camundongos , Doses de Radiação , Radiossensibilizantes/química , Radiossensibilizantes/toxicidade , Radioterapia , Raios X
17.
Nat Prod Res ; 33(2): 212-218, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29468891

RESUMO

Two new prenylisoflavones, 3',4',5-trihydroxy-8-prenyl-dihydrofuran[2″,3″:7,6]isoflavone (1) and 4',5-dihydroxy-8-prenyl-dihydrofuran[2″,3″:7,6]isoflavone (2), along with five known prenylisoflavones (3-7), benzylalcohol-4-O-ß-d-glucoside (8) and two cinnamic acid esters (9, 10) were isolated from the leaves of Maclura cochinchinensis (Cudrania cochinchinensis). Their structures were elucidated by analysis of NMR (1H-, 13C-NMR, HSQC, HMBC), MS spectra and comparison with the published data. Compounds 4-10 were the first time isolated from this species. Prenylisoflavones 1-4 and 6-7 were evaluated for their in vitro cytotoxic activity on KB and HepG2 cancer cell lines. Compound 4 showed cytotoxic activity against both cancer cell lines with IC50 values of 26.99 and 19.95 µM, respectively. The other compounds were considered as inactive.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Furanos/química , Isoflavonas/química , Maclura/química , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Furanos/isolamento & purificação , Células Hep G2 , Humanos , Concentração Inibidora 50 , Isoflavonas/isolamento & purificação , Células KB , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Extratos Vegetais/química , Folhas de Planta/química , Prenilação , Vietnã
18.
Nat Prod Res ; 33(5): 622-627, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29126362

RESUMO

The phytochemical and biological investigation of Cissampelos pareira leads to the isolation of one new isoquinoline alkaloid (7) along with six known isoquinoline alkaloids, namely, magnoflorine (1), magnocurarine (2), cissamine (3), curine (4), hayatinine (5) and cycleanine (6). Magnoflorine (1) and magnocurarine (2) were isolated for the first time from C. pareira. A new, rapid, simple and sensitive UPLC method was developed for simultaneous quantification of five pure compounds (1-5). Seasonal variation study revealed higher content of these compounds during the rainy season. The chloroform (CPCF) and n-butanol (CPBF) fractions showed cytotoxic efficacy against KB cells. Among pure compounds, hayatinine (5) was found to be most active against KB and A549, while, cycleanine (6) against KB cells.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Cissampelos/química , Isoquinolinas/farmacologia , Células A549 , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Aporfinas , Humanos , Índia , Isoquinolinas/isolamento & purificação , Células KB , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Raízes de Plantas/química , Estações do Ano
19.
Nat Prod Res ; 33(6): 796-802, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29210295

RESUMO

This study describes the chemical constituents of Oldenlandia pinifolia (Wall. Ex G. Don) Kuntze (synonym Hedyotis pinifolia Wall. Ex G. Don) and discusses their anti-proliferative activities. Thirteen compounds were isolated from the n-hexane, ethyl acetate and n-butanol extracts of whole plants O. pinifolia by chromatography method. Their structures were elucidated using MS and NMR analysis and compared with reported data. They are three anthraquinones, a carotenoid, two triterpenes, four iridoid glycosides and three flavonoid glycosides. Among them, 2-methyl-1,4,6-trihydroxy-anthraquinone is a new one, and three compounds were found for the first time in this genus. MTT assay resulted that the n-butanol extract and four isolated compounds inhibited the proliferation of chronic myelogenous leukaemia cells. The results from Hoechst 33343 staining and caspase 3-inducing exhibited that those four tested compounds induced apoptosis and activated caspase 3 (p < 0.05). One of them, isorhamnetin-3-O-ß-rutinoside showed the most activity with IC50 value of 394.68 ± 25.12 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Dissacarídeos/farmacologia , Flavonoides/farmacologia , Oldenlandia/química , Extratos Vegetais/química , Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Dissacarídeos/isolamento & purificação , Flavonoides/isolamento & purificação , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Humanos , Células K562 , Células KB , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Vietnã
20.
J Nucl Med ; 60(1): 135-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30042162

RESUMO

The aim of this study was to develop the radiosyntheses of diastereomerically pure 6R- and 6S-3'-aza-2'-18F-fluoro-5-methyltetrahydrofolate (MTHF) (6R-18F-1 and 6S-18F-1) using the integrated approach and to compare the in vitro and in vivo performance characteristics of both radioligands with the previously reported 3'-aza-2'-18F-fluorofolic acid tracer (18F-2), the oxidized form. Methods: 6R-18F-1, 6S-18F-1, and 18F-2 were radiolabeled with 18F using aromatic nucleophilic substitution reaction. In vitro cell uptake studies and binding affinity assays were performed using folate receptor (FR)-α-expressing KB cells. PET/CT imaging and biodistribution experiments were performed with KB tumor-bearing mice. Results: Reference compounds 6R-1 and 6S-1 were obtained after acidic hydrolysis of the corresponding protected intermediates 6R-3 and 6S-3 in high chemical yields (81%-87%) and chemical purities of more than 95%. 6R-18F-1, 6S-18F-1, and 18F-2 were obtained after a 2-step radiosynthetic procedure in a decay-corrected radiochemical yield of up to 5% and molar radioactivities ranging from 20 to 250 GBq/µmol. In vitro binding affinity studies using FR-α-positive KB cells gave half-maximal inhibitory concentrations of 27.1 ± 3.7 and 23.8 ± 4.0 nM for 6R-1 and 6S-1, respectively, which were higher than for the previously reported 3'-aza-2'-fluorofolic acid 2 (1.4 ± 0.5 nM). Comparably high cell uptake values in FR-α-expressing KB cells were found for all 3 radiofolates. In biodistribution studies, exceptionally high KB tumor uptake value of over 32% injected activity per gram of tissue for both 6R-18F-1 and 6S-18F-1 was observed at 180 min after injection, whereas for 18F-2 only 15% injected activity per gram was found in the KB tumors. Radioactivity uptake in the kidneys, liver, salivary glands, and spleen was substantially different for the 6R- and 6S-diastereoisomers and 18F-2 Excellent KB tumor visualization was found in PET/CT images with 6R-18F-1 and 6S-18F-1, both of which outperformed the corresponding oxidized 18F-2. Conclusion: We have successfully radiolabeled 6R- and 6S-3'-aza-2'-18F-fluoro-5-MTHF with 18F using the integrated approach. Our results suggest that both 6R- and 6S-3'-aza-2'-18F-fluoro-5-MTHF are promising reduced radiofolates for imaging FR-α-expressing cancers.


Assuntos
Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/química , Ácido Fólico/metabolismo , Animais , Transporte Biológico , Transformação Celular Neoplásica , Ácido Fólico/farmacocinética , Humanos , Células KB , Camundongos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Radioquímica , Estereoisomerismo , Distribuição Tecidual
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