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1.
Int J Pharm ; 564: 492-498, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31022505

RESUMO

The present study aimed to develop a photochemically stabilized formulation of dacarbazine [5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide; DTIC] for reducing the production of algogenic photodegradant (5-diazoimidazole-4-carboxamide; Diazo-IC). Photochemical properties of DTIC were characterized by UV-visible light spectral analysis, reactive oxygen species (ROS) assay, and photostability testing. A pharmacokinetic study was conducted after intravenous administration of DTIC formulations (1 mg-DTIC/kg) to rats. DTIC exhibited strong absorption in the UVA range, and photoirradiated DTIC exhibited marked ROS generation. Thus, DTIC had high photoreactive potential. After exposure of DTIC (1 mM) to simulated sunlight (250 W/m2) for 3 min, remaining DTIC and yielded Diazo-IC were estimated to be ca. 230 µM and 600 µM, respectively. The addition of radical scavenger (1 mM), including l-ascorbic acid, l-cysteine (Cys), l-histidine, D-mannitol, l-tryptophan, or l-tyrosine, to DTIC (1 mM) could attenuate DTIC photoreactions, and in particular, the addition of Cys to DTIC brought ca. 34% and 86% inhibition of DTIC photodegradation and Diazo-IC photogeneration, respectively. There were no significant differences in the calculated pharmacokinetic parameters of DTIC between DTIC and DTIC with Cys (0.67 mg/kg). From these findings, the supplementary use of Cys would be an effective approach to improve the photostability of DTIC with less production of Diazo-IC.


Assuntos
Antineoplásicos Alquilantes , Compostos Azo/química , Cisteína/química , Dacarbazina , Depuradores de Radicais Livres/química , Imidazóis/química , Luz , Animais , Antineoplásicos Alquilantes/sangue , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/efeitos da radiação , Dacarbazina/sangue , Dacarbazina/química , Dacarbazina/farmacocinética , Dacarbazina/efeitos da radiação , Estabilidade de Medicamentos , Masculino , Fotólise , Ratos Sprague-Dawley
2.
Biomater Sci ; 7(3): 1161-1178, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30652182

RESUMO

Melanoma is a highly aggressive skin cancer. A paclitaxel formulation of solid lipid nanoparticles modified with Tyr-3-octreotide (PSM) is employed to treat melanoma that highly expresses somatostatin receptors (SSTRs). PSM exerts more apoptotic and anti-invasive effects in B16F10 mice melanoma cells as compared to dacarbazine (DTIC), an approved chemotherapeutic drug for treating aggressive melanoma. Besides, PSM induces one of the biomarkers of immunogenic cell death in vitro and in vivo as confirmed by calreticulin exposure on the B16F10 cell surface. We observed a significant number of CD8 positive T cells in the tumor bed of the PSM treated group. As a result, PSM effectively reduces tumor volume in vivo as compared to DTIC. PSM also induces a favorable systemic immune response as determined in the spleen and sera of the treated animals. Importantly, PSM can reduce the number of nodule formations in the experimental lung metastasis model. Our experimentations indicate that the metronomic PSM exhibits remarkable anti-melanoma activities without any observable toxicity. This immune modulation behavior of PSM can be exploited for the therapy of melanoma and probably for other malignancies.


Assuntos
Antineoplásicos Alquilantes/química , Nanopartículas/química , Paclitaxel/química , Peptídeos/química , Animais , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Calreticulina/química , Calreticulina/farmacologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Dacarbazina/química , Dacarbazina/metabolismo , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Modelos Animais de Doenças , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Taxa de Sobrevida , Distribuição Tecidual
3.
J Enzyme Inhib Med Chem ; 34(1): 117-123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30362384

RESUMO

Drug combination represents one of the most accredited strategies of cancer therapy able to improve drug efficacy and possibly overcome drug resistance. Among the agents used to complement conventional chemotherapy, carbonic anhydrase IX (CAIX) inhibitors appear as one of the most suitable, as markers of hypoxic and acidic cancer cells which do not respond to chemo- and radiotherapy. We performed preclinical in vitro assays to evaluate whether the SLC-0111 CAIX inhibitor co-operates and potentiates the cytotoxic effects of conventional chemotherapeutic drugs in A375-M6 melanoma cells, MCF7 breast cancer cells, and HCT116 colorectal cancer cells. Here, we demonstrate that the SLC-0111 CAIX inhibitor potentiates cytotoxicity of Dacarbazine and Temozolomide currently used for advanced melanoma treatment. SLC-0111 also increases breast cancer cell response to Doxorubicin and enhances 5-Fluorouracil cytostatic activity on colon cancer cells. These findings disclose the possibility to extend the use of CAIX inhibitors in the combination therapy of various cancer histotypes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Compostos de Fenilureia/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/química , Anidrase Carbônica IX/genética , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/química , Dacarbazina/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/química , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Células MCF-7 , Estrutura Molecular , Compostos de Fenilureia/química , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Temozolomida , Células Tumorais Cultivadas
4.
Nanomedicine (Lond) ; 13(20): 2579-2596, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30334671

RESUMO

AIM: To investigate the efficacy of lactoferrin nanoparticles (LfNPs) in delivering siRNA across the blood-brain barrier to treat glioblastoma multiforme (GBM) and with an additional objective of potentiation of conventional temozolomide (TMZ) chemotherapy. METHODS: Aurora kinase B (AKB) siRNA-loaded nanoparticles (AKB-LfNPs) were prepared with milk protein, lactoferrin, by water in oil emulsion method. AKB-LfNPs were tested in cell lines and in GBM orthotopic mouse model with and without TMZ treatment. RESULTS: AKB silencing, cytotoxicity and cell cycle arrest by these LfNPs were shown to be effective on GL261 cells. Tumor growth was significantly lower in AKB-LfNPs alone and in combination with TMZ treated mice and increased the survival by 2.5-times. CONCLUSION: Treatment of AKB-LfNPs to GBM mice improves life expectancy and has potential to combine with conventional chemotherapy.


Assuntos
Aurora Quinase B/genética , Glioblastoma/tratamento farmacológico , Lactoferrina/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Aurora Quinase B/antagonistas & inibidores , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/química , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Lactoferrina/química , Camundongos , RNA Interferente Pequeno/química , Temozolomida/administração & dosagem , Temozolomida/química , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Int J Pharm ; 545(1-2): 84-92, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29715532

RESUMO

Glioblastoma multiforme is the most lethal type of brain tumor and the established therapy only extends patients survival to approximately one year. Its first-line treatment is based on of chemotherapy with the alkylating agent temozolomide (TMZ). As many other chemotherapeutic drugs, TMZ presents several limitations as high toxicity and low bioavailability. The delivery of TMZ using poly(lactic-co-glycolic acid) nanoparticles is proposed in this work. Stable nanoparticles functionalized with a OX26 type monoclonal antibody for transferrin receptor were developed, targeting the glioblastoma tumor cells, since these cells are known for overexpressing this receptor. The release profile of TMZ from the nanoparticles was studied mimicking physiological conditions, and targeted cellular internalization was also investigated. Two glioblastoma cell lines - U215 and U87 - were used to evaluate the in vitro cytotoxicity of the drug, showing that the prepared nanocarriers enhance the anticancer activity of TMZ. The functionalization with the monoclonal antibody for transferrin receptor proved to be advantageous in enhancing the cellular internalization in glioblastoma cells.


Assuntos
Anticorpos Monoclonais/metabolismo , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Portadores de Fármacos , Glioblastoma/tratamento farmacológico , Ácido Láctico/química , Nanopartículas , Ácido Poliglicólico/química , Receptores da Transferrina/metabolismo , Anticorpos Monoclonais/química , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/metabolismo , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/química , Dacarbazina/metabolismo , Dacarbazina/farmacologia , Relação Dose-Resposta a Droga , Composição de Medicamentos , Liberação Controlada de Fármacos , Glioblastoma/imunologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Cinética , Nanotecnologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Receptores da Transferrina/imunologia , Tecnologia Farmacêutica/métodos , Temozolomida
7.
Int J Biol Macromol ; 116: 1260-1267, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29775717

RESUMO

The present study was designed to develop and optimize Temozolomide nano lipid chitosan hydrogel formulations (TMZNLCHG) to target the brain through nasal route. The formulation was developed using chitosan as a gelling agent and Vit E: gelucire 44/14 blend as lipid. The formulations were evaluated for particle size, encapsulation efficiency (%EE), drug loading (DL), morphology, drug release, nasal diffusion, cell line study, and histopathology study. The particle size, PDI, %EE, %DL, and drug release were found to be 134 nm, 0.177, 88.45% ±â€¯4.45%, 9.12% ±â€¯0.78%, and 84.23% ±â€¯2.78%, respectively. The enhancement ratio was more than two folds higher than TMZCHG formulation (control) suggesting the superiority of chitosan with lipid as permeability enhancer. The microscopic image of lyophilized TMZNLCHGopt displayed the spherical and rough surface morphology. IC50 was found to be 3.34 µg/ml for TMZNLCHGopt and was 160 µg/ml for pure TMZ. Further, No structural damage was observed with TMZNLCHGopt treated nasal mucosa upon histopathological examination. Overall, the present study produces encouraging findings in the formulation of a non-invasive intranasal route for brain targeting as an alternate to other route for TMZ.


Assuntos
Encéfalo/metabolismo , Dacarbazina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis , Absorção Nasal , Mucosa Nasal/metabolismo , Administração Intranasal , Animais , Encéfalo/patologia , Linhagem Celular , Linhagem Celular Tumoral , Dacarbazina/química , Dacarbazina/farmacocinética , Dacarbazina/farmacologia , Cabras , Hidrogéis/química , Hidrogéis/farmacocinética , Hidrogéis/farmacologia , Mucosa Nasal/patologia , Ratos , Ratos Wistar , Temozolomida
8.
Artif Cells Nanomed Biotechnol ; 46(sup1): 1080-1087, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29482360

RESUMO

Cancer is responsible for more than 12% of all causes of death in the world, with an annual death rate of more than 7 million people. In this scenario melanoma is one of the most aggressive ones with serious limitation in early detection and therapy. In this direction we developed, characterized and tested in vivo a new drug delivery system based on magnetic core-mesoporous silica nanoparticle that has been doped with dacarbazine and labelled with technetium 99 m to be used as nano-imaging agent (nanoradiopharmaceutical) for early and differential diagnosis and melanoma by single photon emission computed tomography. The results demonstrated the ability of the magnetic core-mesoporous silica to be efficiently (>98%) doped with dacarbazine and also efficiently labelled with 99mTc (technetium 99 m) (>99%). The in vivo test, using inducted mice with melanoma, demonstrated the EPR effect of the magnetic core-mesoporous silica nanoparticles doped with dacarbazine and labelled with technetium 99 metastable when injected intratumorally and the possibility to be used as systemic injection too. In both cases, magnetic core-mesoporous silica nanoparticles doped with dacarbazine and labelled with technetium 99 metastable showed to be a reliable and efficient nano-imaging agent for melanoma.


Assuntos
Dacarbazina/química , Imãs/química , Melanoma/diagnóstico por imagem , Nanopartículas/química , Dióxido de Silício/química , Tecnécio/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Diagnóstico Diferencial , Detecção Precoce de Câncer , Humanos , Marcação por Isótopo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Porosidade
9.
Pharm Res ; 35(1): 9, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29294212

RESUMO

PURPOSE: To establish a platform for the possibility of effective and safe delivery of Temozolomide (TMZ) to brain via surface engineered (polyamidoamine) PAMAM dendrimer for the treatment of glioblastoma. METHODS: The present study aims to investigate the efficacy of PAMAM-chitosan conjugate based TMZ nanoformulation (PCT) against gliomas in vitro as well as in vivo. The prepared nanoconjugated formulation was characterized by 1H NMR, FT-IR spectroscopy and for surface morphological parameters. The reported approach was also designed in such a way to ensure toxicity before in vivo delivery through conducting the hemolytic study. RESULT: Surface morphology was found as per nanoformulation via size, pdi and zeta potential measurement. PCT was more efficacious in terms of IC50 values compared to pure TMZ against U-251 and T-98G glioma cell lines. The in vivo pharmacokinetic parameters proved sustained release fashion such as half-life (t1/2) of 22.74 h (PCT) rather than15.35 h (TMZ) only. Higher concentration was found in heart than brain in bio-distribution studies. This study exhibits the potential applicability of dendrimer and CS in improving the anticancer activity and delivery of TMZ to brain. CONCLUSION: The attractive ex vivo cytotoxicity against two glioma cell lines; U-251 and T-98G and phase solubility studies of TMZ revealed remarkable results. In vivo studies of prepared nanoformulation were significant and promising that explored the double concentration of TMZ in brain due to surface functionality of dendrimer. The reported work is novel and non- obvious as none of such approaches using chitosan anchored dendrimer for TMZ delivery has been reported earlier.


Assuntos
Quitosana/síntese química , Dacarbazina/análogos & derivados , Dendrímeros/química , Glioma/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Dacarbazina/administração & dosagem , Dacarbazina/química , Dacarbazina/farmacocinética , Dacarbazina/uso terapêutico , Dendrímeros/síntese química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Meia-Vida , Humanos , Microscopia de Força Atômica/métodos , Microscopia Eletrônica de Varredura/métodos , Tamanho da Partícula , Ratos , Ratos Wistar , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Propriedades de Superfície , Temozolomida , Distribuição Tecidual/efeitos dos fármacos
10.
Int J Mol Sci ; 19(2)2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29364157

RESUMO

AIM: To develop an innovative delivery system for temozolomide (TMZ) in solid lipid nanoparticles (SLN), which has been preliminarily investigated for the treatment of melanoma. MATERIALS AND METHODS: SLN-TMZ was obtained through fatty acid coacervation. Its pharmacological effects were assessed and compared with free TMZ in in vitro and in vivo models of melanoma and glioblastoma. RESULTS: Compared to the standard free TMZ, SLN-TMZ exerted larger effects, when cell proliferation of melanoma cells, and neoangiogeneis were evaluated. SLN-TMZ also inhibited growth and vascularization of B16-F10 melanoma in C57/BL6 mice, without apparent toxic effects. CONCLUSION: SLN could be a promising strategy for the delivery of TMZ, allowing an increased stability of the drug and thereby its employment in the treatment of aggressive malignacies.


Assuntos
Dacarbazina/análogos & derivados , Melanoma/patologia , Nanopartículas , Animais , Biomarcadores , Linhagem Celular Tumoral , Dacarbazina/administração & dosagem , Dacarbazina/química , Modelos Animais de Doenças , Estabilidade de Medicamentos , Feminino , Humanos , Imuno-Histoquímica , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma Experimental , Camundongos , Estrutura Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Células-Tronco Neoplásicas , Temozolomida
11.
Histochem Cell Biol ; 149(3): 219-233, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29356965

RESUMO

Glioblastoma multiforme (GBM) is a highly malignant brain tumor. Tumor stem cells have a major influence on tumor malignancy, and immunological escape mechanisms, involving the Natural Killer Group 2, member D (NKG2D) receptor-ligand-system, are key elements in tumor immuno-surveillance. We analyzed the expression profile and localization of NKG2D ligands (NKG2DL) and embryonic and neural stem cell markers in solid human GBM and stem-like cells isolated from glioma cell lines by qRT-PCR and immunohistochemistry, including quantitative analysis. We also evaluated the effect of Temozolomide (TMZ), the standard chemotherapeutic agent used in GBM therapy, on NKG2DL expression. NKG2DL-positive cells were mostly found scattered and isolated, were detectable in glial fibrillary acidic protein (GFAP)-positive tumor regions and partly in the penumbra of tumor vessels. NKG2DL were found in a distinct tumor stem-like cell subpopulation and were broadly costained with each other. Quantitative analysis revealed, that dependent on the individual NKG2DL investigated, cell portions costained with different stem cell markers varied between small (Musashi-1) and high (KLf-4) amounts. However, a costaining of NKG2DL with CD3γ, typically found in T cells, was also observable, whereas CD11b as a marker for tumor micoglia cells was only rarely costained with NKG2DL. Stem-like cells derived from the glioma cell lines T98G and U251MG showed a distinct expression pattern of NKG2DL and stem cell markers, which seemed to be balanced in a cell line-specific way. With differentiation, T98G displayed less NKG2DL, whereas in U251MG, only expression of most stem cell markers decreased. In addition, stimulation with TMZ led to a significant upregulation of NKG2DL in stem-like cells of both lines. As stem-like glioma cells tend to show a higher expression of NKG2DL than more differentiated tumor cells and TMZ treatment supports upregulation of NKG2DL, the NKG2D system might play an important role in tumor stem cell survival and in GBM therapy.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Ligantes , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Adulto , Idoso , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/química , Dacarbazina/farmacologia , Feminino , Glioma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Temozolomida , Células Tumorais Cultivadas
12.
Drug Dev Ind Pharm ; 44(6): 923-933, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29280385

RESUMO

The aim of the presented study was to develop PEGylated liposomes of Temozolomide (TMZ) that provide optimum drug concentration at tumor site. Reverse phase evaporation (REV) method was used to prepare TMZ-loaded PEGylated liposomes. Formulation was optimized by using design expert software by 32 factorial design. The physicochemical properties including size, morphology, entrapment efficiency, drug loading, etc. of formulated liposomes were evaluated. Finally, the optimized formulation was selected for in vitro drug release and stability study. In vivo pharmacokinetic study in rats showed that TMZ-loaded PEGylated liposomes leads to 1.6-fold increase in AUCTotal in blood and 4.2-fold increase in brain as compared to free drug solution. This formulated PEGylated liposomes offers a promising approach for treatment of Glioblastoma Multiforme.


Assuntos
Dacarbazina/análogos & derivados , Glioblastoma/química , Lipossomos/química , Polietilenoglicóis/química , Administração Intravenosa , Animais , Encéfalo , Dacarbazina/administração & dosagem , Dacarbazina/química , Liberação Controlada de Fármacos , Ratos , Temozolomida
13.
Mater Sci Eng C Mater Biol Appl ; 83: 44-50, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29208287

RESUMO

Recently most of the researchers have turned their interest towards plant mediated synthesis of metal nanoparticles to avoid several environmental toxicants. In this manuscript, we have discussed the ecofriendly syntheses of zinc oxide nanoparticles (ZnO NPs) were achieved using Glycyrrhiza glabra (G. glabra) seed aqueous extract. The green synthesized ZnO NPs were characterized using analytical techniques like XRD, TEM, particle size histogram and Zeta potential. From the results, it was found that the green synthesized ZnO NPs were around 35nm in size with irregular spherical shape. The Zeta potential study of ZnO NPs was resulted to be high stabile with electronegative charge around -56.3mV. Further the G. glabra seed aqueous extract mediated synthesis of ZnO NPs were subjected to treat human glioblastoma cells with the help of temozolomide (TMZ) a commercially available drug by the method of MTT cell viability assay. The results stated that the ZnO NPs shows IC50 value around 30µg/mL results significantly. The plausible mechanism behind the mortality rate was also discussed in this manuscript.


Assuntos
Dacarbazina/análogos & derivados , Nanopartículas Metálicas/química , Óxido de Zinco/química , Linhagem Celular Tumoral , Dacarbazina/química , Dacarbazina/uso terapêutico , Glioma/tratamento farmacológico , Química Verde/métodos , Humanos , Extratos Vegetais/química , Folhas de Planta/química , Temozolomida , Óxido de Zinco/uso terapêutico
14.
Sci Rep ; 7(1): 16517, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29184162

RESUMO

Dacarbazine (DZ) is poorly soluble in water with the short half-life in blood circulation, low rate of response with the toxic effect which ultimately limits its utilization of the treatment of skin cancer. In view of this background current study was designed for development of dacarbazine laden nanoparticle (DZNP) and dacarbazine laden nanocream (DZNC) topical delivery system for the treatment of melanoma. Firstly DZNP was prepared. By using DZNP its cream formulation prepared for topic drug delivery for melanoma. Dacarbazine nanoparticle and its cream were evaluated for morphology, drug load capacity, efficiency of nanoencapsulation and size of particle and zeta potential, Transmission Electron Microscopy (TEM), determination of pH, spreadability and viscosity, in vitro drug release capacity and its cytotoxic potential. The particle size of DZNP and DZNC was 16.3 ± 8.1 nm and 16.9 ± 7.8 nm respectively. pH value and spreadability of nanoparticle cream were found to be 6.7 ± 0.14 g cm/sec and 55.23 ± 3.13 g cm/sec respectively. Nanoencapsulation efficiency and Drug loading capacity were 67.4 ± 3.5% and 6.73 mg/10 mg respectively. IC50 of dacarbazine nanoparticle was 0.19 mg/ml while it was 0.63 mg/ml for nanoparticle cream. It can be concluded that DZNP and its cream can be effectively used as a topical formulation for the treatment of melanoma.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Dacarbazina/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas , Administração Tópica , Animais , Antineoplásicos Alquilantes/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/química , Portadores de Fármacos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma Experimental , Camundongos , Nanopartículas/química , Tamanho da Partícula , Permeabilidade , Viscosidade
15.
J Clin Neurosci ; 45: 288-292, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28867360

RESUMO

The current treatment of glioblastoma multiforme (GBM) is limited by the restricted arsenal of agents which effectively cross the blood brain barrier (BBB). For example, only a fraction of temozolomide (TMZ) administered systemically is available for therapeutic effect because of the BBB and the instability of TMZ under physiologic conditions. A novel approach to overcome this obstacle is to bypass the BBB and locally deliver chemotherapeutic agents directly to the tumor mass. We have explored the loading of TMZ into a novel hydrogel matrix, which can be delivered in liquid form and then solidifies in situ and releases chemotherapy as the matrix dissolves. Here, we tested the effect of amphiphilic diblock copolypeptide hydrogels (DCHs) of 180-poly-lysine and 20-poly-leucine (K180L20) on TMZ using Glioblastoma models. In both the in vitro model, which involved treatment of a human glioblastoma GSC line suspended as neurospheres, and in vivo using an orthotopic glioma xenograft mouse model, we found that K180L20 could safely enhance the efficacy of TMZ. This technique may offer the opportunity to 'coat' the inner lining of the cavity following glioma resection with a slow-release TMZ and potentially decrease recurrence. Future studies in larger animals are needed to delineate this effect.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Glioma/tratamento farmacológico , Hidrogéis/administração & dosagem , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dacarbazina/administração & dosagem , Dacarbazina/química , Dacarbazina/uso terapêutico , Modelos Animais de Doenças , Humanos , Hidrogéis/química , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Chem Commun (Camb) ; 53(62): 8739-8742, 2017 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726866

RESUMO

An acyclic cucurbit[n]uril (CB[n]) conjugated dextran is developed as a new biomaterial for drug delivery and bioimaging. This biomaterial retains the host-guest recognition properties of acyclic CB[n]s. It is able to directly encapsulate anti-tumor drugs 5-fluorouracil and temozolomide. This polymeric material can form a supramolecular assembly with polyethyleneimine (PEI). Although there is no conventional chromophore in these supramolecular systems, they exhibit aggregation-induced emission (AIE) in water with a quantum yield of 10%. This supramolecular assembly is used for bioimaging in vitro with good biocompatibility.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Dextranos/química , Portadores de Fármacos/química , Imidazóis/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Dacarbazina/análogos & derivados , Dacarbazina/química , Dextranos/síntese química , Dextranos/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Etilenodiaminas/química , Fluoruracila/química , Células HeLa , Humanos , Imidazóis/síntese química , Imidazóis/toxicidade , Substâncias Luminescentes/síntese química , Substâncias Luminescentes/química , Substâncias Luminescentes/toxicidade , Microscopia Confocal , Nanopartículas/química , Nanopartículas/toxicidade , Tamanho da Partícula , Polietilenoimina/química , Temozolomida
18.
Mol Pharm ; 14(8): 2607-2615, 2017 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-28520445

RESUMO

New therapeutics for glioblastoma multiforme and our ability to deliver them using efficient nanocarriers constitute topical areas of research. We report a comparative study of temozolomide and quercetin in the treatment of glioblastoma (GBM) in three-dimensions, and their incorporation into micelles obtained from synthetically articulated architectural copolymers, and a commercially available linear polymer poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA). A versatile synthetic methodology to telodendrimers, which can be easily adapted to the needs of other therapeutic interventions, is presented. These dendritic block copolymers self-assemble into micelles and offer a platform for single or combination drug therapy. Telodendrimer micelles loaded with quercetin did not exhibit superior cell killing effect over the free drug, but acetazolamide, an inhibitor carbonic anhydrase IX, significantly reduced GBM cell viability in 3D spheroids. Results from these studies show that high loading of drugs into telodendrimer micelles requires a physical fit between the biologically active agent and telodendrimer nanocarrier, and points toward new possibilities for incorporation of chemotherapeutic and other agents to enhance their effectiveness.


Assuntos
Dacarbazina/análogos & derivados , Lactatos/química , Poliésteres/química , Polietilenoglicóis/química , Acetazolamida/química , Acetazolamida/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/química , Dacarbazina/farmacologia , Dendrímeros/química , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/metabolismo , Humanos , Micelas , Quercetina/química , Quercetina/farmacologia , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Temozolomida
19.
Mater Sci Eng C Mater Biol Appl ; 75: 165-174, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28415451

RESUMO

In the present study, the PCL-Diol-b-PU/Au nanocompsite nanofibers were fabricated via electrospinning process during two different stages to load an anticancer temozolomide (TMZ) drug into the nanofibers. The first stage was the incorporation of Au nanoparticles into the nanofibers and the second stage was coating the gold nanoparticles on the surface of PCL-Diol-b-PU/Au composite nanofibers. The prepared nanofibrous formulations were characterized using FTIR, SEM and TEM analysis. Box-Behnken-design was used to investigate the influence of electrospinning parameters including solution concentration, applied voltage to tip-collector distance ratio and collector speed on the morphology and fiber diameter of PCL-Diol-b-PU/Au nanofibers. Drug loading efficiency, in vitro release profiles of TMZ from PCL-Diol-b-PU/Au and gold-coated PCL-Diol-b-PU/Au composite nanofibers as well as in vitro antitumor efficacy against U-87 MG human glioblastoma cells were carried out. The TMZ release data were well described using Korsmayer-Peppas kinetic model in which results indicated Fickian diffusion of TMZ from nanofibers. The obtained results revealed the higher efficiency of PCL-Diol-b-PU/Au@TMZ nanofibrous implants for treatment of glioblastoma tumors.


Assuntos
Dacarbazina/análogos & derivados , Implantes de Medicamento , Glioblastoma/tratamento farmacológico , Nanocompostos/química , Nanofibras/química , Linhagem Celular Tumoral , Dacarbazina/química , Dacarbazina/farmacocinética , Dacarbazina/farmacologia , Implantes de Medicamento/química , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Temozolomida
20.
Oncotarget ; 8(22): 35639-35655, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28410193

RESUMO

Glioblastomas are characterized by amplification of EGFR. Approximately half of tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). While current treatments emphasize surgery followed by radiation and chemotherapy with Temozolomide (TMZ), acquired chemoresistance is a universal feature of recurrent GBMs. To mimic the GBM resistant state, we generated an in vitro TMZ resistant model and demonstrated that dichloroacetate (DCA), a metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1), reverses the Warburg effect. Microarray analysis conducted on the TMZ resistant cells with their subsequent treatment with DCA revealed PDK1 as its sole target. DCA treatment also induced mitochondrial membrane potential change and apoptosis as evidenced by JC-1 staining and electron microscopic studies. Computational homology modeling and docking studies confirmed DCA binding to EGFR, EGFRvIII and PDK1 with high affinity. In addition, expression of EGFRvIII was comparable to PDK1 when compared to EGFR in GBM surgical specimens supporting our in silico prediction data. Collectively our current study provides the first in vitro proof of concept that DCA reverses the Warburg effect in the setting of EGFRvIII positivity and TMZ resistance leading to GBM cytotoxicity, implicating cellular tyrosine kinase signaling in cancer cell metabolism.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Antineoplásicos Alquilantes/farmacologia , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/química , Animais , Antineoplásicos Alquilantes/química , Sítios de Ligação , Linhagem Celular Tumoral , Dacarbazina/química , Dacarbazina/farmacologia , Modelos Animais de Doenças , Receptores ErbB/química , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Glicólise/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Modelos Moleculares , Conformação Molecular , Permeabilidade , Fosforilação , Ligação Proteica , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
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