RESUMEN
pH-sensitive amphiphilic diblock polyphosphoesters containing lactic acid units were synthesized by multistep one-pot polycondensation reactions. They comprise acid-labile P(O)-O-C and C(O)-O-C bonds, the cleavage of which depends on the pH of the medium. The structure of these copolymers was characterized by 1H, 13C {H}, 31P NMR, and size exclusion chromatography (SEC). The newly synthesized polymers self-assembled into the micellar structure in an aqueous solution. The effects of the molecular weight of the copolymer and the length of the hydrophobic chain on micelle formation and stabilityand micelle size were studied via dynamic light scattering (DLS). Drug loading and encapsulation efficiency tests using doxorubicin revealed that hydrophobic drugs can be delivered by copolymers. It was established that the molecular weight of the copolymer, length of the hydrophobic chain and content of lactate units affects the size of the micelles, drug loading, and efficiency of encapsulation. A copolymer with 10.7% lactate content has drug loading (3.2 ± 0.3) and efficiency of encapsulation (57.4 ± 3.2), compared to the same copolymer with 41.8% lactate content (1.63%) and (45.8%), respectively. It was demonstrated that the poly[alkylpoly(ethylene glycol) phosphate-b-alkylpoly(ethylene glycol)lactate phosphate] DOX system has a pH-sensitive response capability in the result in which DOX was selectively accumulated into the tumor, where pH is acidic. The results obtained indicate that amphiphilic diblock polyphosphoesters have potential as drug carriers.
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Doxorrubicina , Portadores de Fármacos , Ácido Láctico , Micelas , Polímeros , Concentración de Iones de Hidrógeno , Portadores de Fármacos/química , Portadores de Fármacos/síntesis química , Doxorrubicina/química , Doxorrubicina/farmacología , Ácido Láctico/química , Polímeros/química , Polímeros/síntesis química , Humanos , Ésteres/química , Interacciones Hidrofóbicas e Hidrofílicas , Peso MolecularRESUMEN
In this study, we analyzed the properties of amphiphilic alkyldi(methoxy poly(ethylene glycol) (MePEG)350-lactate) phosphates based on ethyl lactate, the monomethyl ether of poly(ethylene glycol)350, and alkyldichloro phosphates. Interestingly, these triesters combine two biodegradable bonds, -P(O)-O-C and -C(O)-O-C-, and include hydrophilic (MePEG350-lactate) and hydrophobic (R-aliphatic chain of alcohols) moieties. The properties of these esters resemble those of phospholipids. After being placed in an aqueous solution, they self-assembled. We also determined the effects of ester composition on micelle formation, stability, and size using dynamic light scattering. Solubilization tests using Sudan III or doxorubicin hydrochloride (Dox·HCl) revealed that they could be incorporated into the hydrophobic cores of dodecyl di(MePEG350-lactate) phosphate and hexadecyl di(MePEG350-lactate) phosphate. Notably, dodecyl di(MePEG350-lactate) phosphate was stable for five days, whereas hexadecyl di(MePEG350-lactate) phosphate was stable for seven days in phosphate-buffered saline. Moreover, Dox·HCl release rates from the micelles were approximately 30-40, 70-80, and 90-100% after 1, 5, and 28 d, respectively.
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Micelas , Polietilenglicoles , Polietilenglicoles/química , Doxorrubicina/química , Doxorrubicina/farmacología , Fosfatos , Lactatos , Portadores de FármacosRESUMEN
Multistep one-pot polycondensation reactions synthesized amphiphilic diblock polyphosphoesters containing lactic acid units in the polymer backbone. At the first step was synthesized poly[poly(ethylene glycol) H-phosphonate-b-poly(ethylene glycol)lactate H-phosphonate] was converted through one pot oxidation into poly[alkylpoly(ethylene glycol) phosphate-b-alkylpoly(ethylene glycol)lactate phosphate]s. They were characterized by 1H, 13C {H},31P NMR, and size exclusion chromatography (SEC). The effects of the polymer composition on micelle formation and stability, and micelle size were studied via dynamic light scattering (DLS). The hydrophilic/hydrophobic balance of these polymers can be controlled by changing the chain lengths of hydrophobic alcohols. Drug loading and encapsulation efficiency tests using Sudan III and doxorubicin revealed that hydrophobic substances can be incorporated inside the hydrophobic core of polymer micelles. The micelle size was 72-108 nm when encapsulating Sudan III and 89-116 nm when encapsulating doxorubicin. Loading capacity and encapsulation efficiency depend on the length of alkyl side chains. Changing the alkyl side chain from 8 to 16 carbon atoms increased micelle-encapsulated Sudan III and doxorubicin by 1.6- and 1.1-fold, respectively. The results obtained indicate that these diblock copolymers have the potential as drug carriers.
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Ácido Láctico , Micelas , Polietilenglicoles/química , Polímeros/química , Portadores de Fármacos/química , Doxorrubicina/químicaRESUMEN
The effect of transcutaneous immunization was studied using a combined system of poly(DL-lactide-co-glycolide) (PLGA) nanoparticles and iontophoresis (IP). Both hen egg-white lysozyme (HEL)-loaded PLGA nanoparticles coated with chitosan hydroxypropyltrimonium chloride and their fluorescent nanoparticles were prepared using an antisolvent diffusion method. Their mean volume diameters were 87.6 ± 38.9 nm and 84.9 ± 27.6 nm, respectively. It was suggested from the results of the ex vivo skin accumulation study using fluorescent nanoparticles that the HEL released from the nanoparticles to the skin surface was efficiently delivered to antigen-presenting cells. HEL-specific IgG1 and IgG2a titers were determined in an in vivo percutaneous immunoreactivity study using lysozyme-sensitized mice. As results, the group using nanoparticles and IP showed 1.33 times higher HEL-specific IgG1 titer than a sham treatment group. The HEL-specific IgG2a titer was 1.36 times higher in the nanoparticles and IP group than in the HEL solution and IP group. It was suggested from the quantification results of total IgE in serum that the combined use of PLGA nanoparticles and IP reduced the total IgE concentration. The level of cytokines may have decreased due to Th1 cell activation and relative suppression of Th2 cells. The cytokine level is presumed to be reduced by activation of Th1 cells and relative suppression of Th2 cells. The histamine amount in plasma and rectal temperature after the induction of anaphylactic shock using lysozyme-sensitized mice were also studied, which indicates that the combined use of PLGA nanoparticles and IP may provide the same therapeutic effect as an injection.
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Quitosano , Nanopartículas , Ratones , Animales , Muramidasa , Inmunización , Inmunoglobulina G , Inmunoglobulina ERESUMEN
Using a novel strategy, amphiphilic polyphosphoesters based on poly(oxyethylene H-phosphonate)s (POEHP) with different poly(ethylene glycol) segment lengths and aliphatic alcohols with various alkyl chain lengths were synthesized using polycondensation reactions. They were characterized by 1H NMR, 13C {H} NMR 31P NMR, IR, and size exclusion chromatography (SEC). The effects of the polymer structure on micelle formation and stability, micelle size, and critical micelle temperature were studied via dynamic light scattering (DLS). The hydrophilic/hydrophobic balance of these polymers can be controlled by changing the chain lengths of hydrophilic PEG and hydrophobic alcohols. A solubilizing test, using Sudan III, revealed that hydrophobic substances can be incorporated inside the hydrophobic core of polymer associates. Loading capacity depends on the length of alkyl side chains. The results obtained indicate that these structurally flexible polymers have the potential as drug carriers.
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Micelas , Organofosfonatos , Portadores de Fármacos/química , Polietilenglicoles/química , Polímeros/químicaRESUMEN
BACKGROUND/AIM: In vivo models of tuberculosis are effective tools for developing new drugs. The objective of this study was to prepare in vivo models for tuberculosis by utilizing nanocomposite particles (NCPs) containing imiquimod-loaded poly(lactic-co-glycolic acid) nanoparticles. MATERIALS AND METHODS: NCPs were prepared from dichloromethane with imiquimod and poly(lactic-co-glycolic acid) using a spray dryer. Mice were treated with NCPs in the lungs by inhalation, and then infection with Mycobacterium bovis bacille Calmette-Guerin was performed (treatment groups). The concentrations of the pro-inflammatory cytokines, tumor necrosis factor-α and interferon-γ were measured in bronchoalveolar lavage fluid using an enzyme-linked immunosorbent assay. RESULTS: When animals were treated with NCPs, the concentrations of tumor necrosis factor-α and interferon-γ in bronchoalveolar lavage fluid were significantly higher than in animals not treated with NCPs. In addition, high bacterial counts and circular granuloma were observed. CONCLUSION: NCPs prepared in this study enhanced the level of inflammation in the lungs and support the preparation of in vivo models of tuberculosis.
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Nanocompuestos , Tuberculosis , Animales , Modelos Animales de Enfermedad , Imiquimod , Interferón gamma , Ácido Láctico , Macrófagos , Ratones , Tamaño de la Partícula , Fenotipo , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Tuberculosis/tratamiento farmacológico , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND/AIM: The objective of this study was to prepare doxorubicin encapsulated in micelles (DOX-micelles) using poly(hexadecanyloxyethylene glycol-lactate phosphate), which we recently synthesized, and to evaluate the anticancer effect of DOX-micelles in vitro and in vivo. MATERIALS AND METHODS: To evaluate the anticancer effect of DOX-micelles in vitro, three-dimensional spheroids composed of B16 mouse melanoma cells and fibroblasts were prepared by changing the ratio of cancer cells to fibroblasts. In addition, for efficient doxorubicin treatment of the cells present in the center of the spheroids, tranilast, an anti-fibrotic drug was added to the spheroids before treatment with DOX-micelles, then the amount of doxorubicin and cell viability of spheroids were evaluated. Moreover, to assess the effects of the combination of DOX-micelles with tranilast in vivo, relative tumor volume was investigated in a mouse model of melanoma. RESULTS: The mean diameter and doxorubicin content of DOX-micelles were 93.3 nm and 3.5%, respectively. When the ratio of cancer cells to fibroblasts was 20:80, spheroids with spherical and rigid shapes were obtained. In addition, the amount of doxorubicin in the spheroids was increased by tranilast treatment, and an efficient anticancer effect was also observed. The anticancer effect of the combination of tranilast and DOX-micelles was confirmed in vivo. CONCLUSION: Micelles encapsulating doxorubicin are promising for cancer therapy, and their anticancer effect is improved by tranilast pretreatment in 3D spheroids in vivo.
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Melanoma , Micelas , Animales , Antibióticos Antineoplásicos/farmacología , Doxorrubicina , Portadores de Fármacos , Humanos , Melanoma/tratamiento farmacológico , Ratones , ortoaminobenzoatosRESUMEN
BACKGROUND/AIM: Serious side effects are associated with the use of doxorubicin. Nanoparticles as carriers for anticancer drugs are useful for reducing side effects and improving therapeutic effects. In this study, a polymer for preparing doxorubicin-containing nanoparticles was developed. Using a novel strategy, a biodegradable poly(oxyethylene glycol lactate H-phosphonate) based on dimethyl H-phosphonate and poly(ethylene glycol)-lactate (PEG-lactate) was synthesized. MATERIALS AND METHODS: Poly(hexadecanyloxyethylene - lactate phosphate) was obtained via chlorination of poly(oxyethylene glycol - lactate H-phosphonate) with trichloroisocyanuric acid and the addition of 1-hexadecanol. The polymer was characterized by 1H NMR and 31P NMR. RESULTS: The results of 1H NMR and 31P NMR showed that the polymer was successfully synthesized, and the yield was 46.9%. CONCLUSION: Poly(hexadecanyloxyethylene - lactate phosphate) has potential as a drug carrier.
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Ácido Láctico , Fosfatos , Doxorrubicina/química , Portadores de Fármacos/química , Humanos , Poliésteres/químicaRESUMEN
BACKGROUND: Inhalable nanocomposite particles using O/W emulsions were studied. The effect of the composition of the dispersed phase on the nanoparticles in the nanocomposite particles was reported, however, the effect on the inhalation characteristics of nanocomposite particles has not been investigated. OBJECTIVE: The aim of this study was to study the effects of lower alcohols in the dispersed phase of O/W emulsions on inhalable nanocomposite particles. METHODS: Nanocomposite particles were prepared using a spray dryer from O/W emulsion. A mixed solution of dichloromethane and lower alcohols in which rifampicin (RFP) and poly(L-lactide-co-glycolide) were dissolved was used as a dispersed phase, and an aqueous solution in which arginine and leucine were dissolved was used as a continuous phase. RESULTS: We succeeded in preparing non-spherical nanocomposite particles with an average diameter of 9.01-10.91 µm. The results of the fine particle fraction (FPF) measurement showed that the higher the hydrophobicity of the lower alcohol mixed in the dispersed phase, the higher the FPF value. The FPF value of the nanocomposite particles was significantly increased by using ethanol and 1-propanol. CONCLUSIONS: The results were revealed that mixing 1-propanol with the dispersed phase increased the amount of RFP delivered to the lungs.
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Alcoholes , Nanocompuestos , 1-Propanol , Emulsiones , Tamaño de la Partícula , RifampinRESUMEN
PURPOSE: Pulmonary administration of dry drug powder is a considered promising strategy in the treatment of various lung diseases such as tuberculosis and is more effective than systemic medication. However, in the pre-clinical study phase, there is a lack of devices for effective delivery of dry powders to the lungs of small rodents. In this study, an administration device which utilizes Venturi effect to deliver dry powders to the lungs homogeneously was developed. METHODS: A Venturi-effect administration device which synchronizes with breathes by use of a ventilator and aerosolizes the dry powders was created. Pulmonary distribution of inhalable dry powders prepared by spray-drying poly(lactic-co-glycolic) acid and an antituberculosis agent rifampicin and anti-tuberculosis effect of the powders on mycobacteria infected rats by administration with the Venturi-effect administration device and a conventional insufflation device were evaluated. RESULTS: Homogeneous distribution of the dry powders in the lung was achieved by the Venturi-effect administration device due to efficient and recurring aerosolization of loaded dry powders while synchronizing with breathes. Amount of rifampicin delivered to the lungs by the Venturi-effect administration device was three times higher than that by a conventional insufflation device, demonstrating three times greater antimycobacterial activity. CONCLUSIONS: The Venturi-effect administration device aerosolized inhalable antituberculosis dry powders efficiently, achieved uniform pulmonary distribution, and aided the dry powders to exert antituberculosis activity on lung-residing mycobacteria.
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Mycobacterium , Tuberculosis , Administración por Inhalación , Aerosoles , Animales , Antituberculosos , Inhaladores de Polvo Seco , Pulmón , Tamaño de la Partícula , Polvos , Ratas , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND/AIM: In order to produce an animal model for oral mucositis induced by anticancer drugs, it is necessary to maintain an immunosuppressive state. We determined the optimal dose and frequency of 5-fluorouracil for a model mouse production. In addition, we used this model to investigate the effect of GGsTop® gelation on the therapeutic effect of oral mucositis. MATERIALS AND METHODS: Changes in body weight and white blood cell count were measured to determine the optimal dosing schedule. The therapeutic effect of GGsTop® gel using chitosan was evaluated by observing changes in the ulcer area for three weeks and measuring collagen and glutathione concentrations in oral mucosal tissue. RESULTS: The optimal dose and frequency of 5-fluorouracil were found to be 50 mg/kg every four days. It was revealed that the therapeutic effect of GGsTop® was enhanced by gelation. CONCLUSION: GGsTop® gel is suggested to be a promising formulation for the treatment of oral mucositis.
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Aminobutiratos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Fluorouracilo/efectos adversos , Leucocitos/efectos de los fármacos , Organofosfonatos/administración & dosificación , Estomatitis/tratamiento farmacológico , Aminobutiratos/farmacología , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Peso Corporal/efectos de los fármacos , Colágeno/metabolismo , Modelos Animales de Enfermedad , Cálculo de Dosificación de Drogas , Fluorouracilo/administración & dosificación , Geles , Glutatión/metabolismo , Masculino , Ratones , Organofosfonatos/farmacología , Estomatitis/inducido químicamente , Estomatitis/metabolismoRESUMEN
The effects of polyvinyl alcohol (PVA) on the release behavior of polymer nanoparticles from nanocomposite particles using amino acids were investigated. Rifaximin (RFX) was used as a hydrophobic drug model. RFX-loaded poly(L-lactide-co-glycolide) (PLLGA) nanoparticles were prepared using an antisolvent diffusion method. They were then spray-dried with equal amounts of amino acids to prepare the nanocomposite particles. The mean diameters of nanocomposite particles were 2.86-5.42 µm. The particle size increased as the concentration of PVA aqueous solution increased. The mean diameters of RFX-loaded PLLGA nanoparticles were 150-160 nm; however, the particle size distributions of those prepared using 0.25% (w/v) PVA aqueous solution differed significantly immediately after preparation and after redispersion from nanocomposite particles. The release test results of nanocomposite particles revealed that those prepared using 0.25% and 0.50% (w/v) aqueous PVA solutions rapidly released RFX. In contrast, particles prepared using 2.00 and 4.00% (w/v) PVA aqueous solution showed sustained drug release. The results of drug release tests of nanoparticles redispersed from nanocomposite particles showed that the nanoparticles prepared using 0.50% and 2.00% (w/v) PVA aqueous solution suppressed the initial burst. Therefore, we considered that the results of the drug release behavior of the nanoparticles in these particles reflectsreflect the release behavior of the nanoparticles from the nanocomposite particles. These results indicate that the rate of redispersion from nanocomposite particles to nanoparticles can be controlled by changing the concentration of PVA aqueous solution.
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Liberación de Fármacos , Nanocompuestos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Alcohol Polivinílico/química , Aminoácidos/química , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Rifaximina/química , Soluciones , AguaRESUMEN
BACKGROUND/AIM: To evaluate the usefulness of GGsTop® for oral mucositis, a quantitative study focusing on oral mucosal tissues is necessary. In this study, we aimed to quantify collagen and glutathione using a rat model of 5-fluorouracil-induced oral mucositis. MATERIALS AND METHODS: Changes in ulcer area and erythrocyte count were measured to confirm the usefulness of GGsTop® for oral mucositis. The effect of GGsTop on collagen was evaluated by observing oral mucosal tissue sections and measuring the collagen concentration in the tissues. The total glutathione concentration and the oxidized glutathione concentration were measured, and the concentration of the reduced form was calculated. RESULTS: GGsTop® shortened the treatment period for oral mucositis without affecting the white blood cell count. In addition, GGsTop® promoted collagen production and alleviated oxidative stress conditions. CONCLUSION: GGsTop affects collagen and glutathione in the treatment of oral mucositis.
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Fluorouracilo , Estomatitis , Aminobutiratos , Animales , Colágeno , Fluorouracilo/efectos adversos , Glutatión , Mucosa Bucal , Organofosfonatos , Ratas , Estomatitis/inducido químicamente , Estomatitis/tratamiento farmacológicoRESUMEN
Anticancer drug screening is one of the most important research and development processes to develop new drugs for cancer treatment. However, there is a problem resulting in gaps between the in vitro drug screening and preclinical or clinical study. This is mainly because the condition of cancer cell culture is quite different from that in vivo. As a trial to mimic the in vivo cancer environment, there has been some research on a three-dimensional (3D) culture system by making use of biomaterials. The 3D culture technologies enable us to give cancer cells an in vitro environment close to the in vivo condition. Cancer cells modified to replicate the in vivo cancer environment will promote the biological research or drug discovery of cancers. This review introduces the in vitro research of 3D cell culture systems with biomaterials in addition to a brief summary of the cancer environment.
RESUMEN
Controlling the size of nanoparticles is important for drug delivery methods such as pulmonary administration, transdermal administration, and intravenous administration. In this study, we have investigated the effect of polymer conformation in organic solvents on the size of the nanoparticles. Poly(L-lactide-co-glycolide) (PLLGA), a promising nanoparticle carrier, was used as the polymer. A mixed solution of dichloromethane, which is a good solvent, and a lower alcohol (methanol, ethanol, and 1-propanol), which is a poor solvent, was used as the solvent for dissolving PLLGA. An oil-in-water emulsion was prepared by sonication using the mixed solution of organic solvents in which PLLGA was dissolved as a dispersed phase and an amino acid aqueous solution as a continuous phase. Nanocomposite particles were prepared from the emulsion using a spray dryer and redispersed in purified water to obtain the PLLGA nanoparticles. The conformation of PLLGA molecules in the organic solvents was evaluated by analyzing the results of the viscosity measurements. The polymer coil radius and the volume per polymer coil were observed to decrease with the increase in the ratio of the lower alcohol in the solvent, whereas these values tended to decrease with the use of more hydrophilic lower alcohols. In addition, based on the results of the calculated entanglement index, it was found that when the hydrophobicity of the dispersed phase is reduced, the polymers were hardly entangled with each other. These results were significant, specifically when the ratio of the lower alcohol in the solvent was low. Estimation of the Pearson's correlation coefficients indicated that there were positive correlations between these indices and the mean volume diameter of PLLGA nanoparticles. This study shows that changing the composition of the dispersed phase, in which the PLLGA is dissolved, can change the conformation of the PLLGA molecules and control the size of the PLLGA nanoparticles.
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Cloruro de Metileno/química , Nanopartículas/química , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Solventes/química , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Emulsiones , Interacciones Hidrofóbicas e Hidrofílicas , Conformación Molecular , Psicoterapia Breve , SonicaciónRESUMEN
BACKGROUND/AIM: Oral mucositis, which occurs frequently in the treatment of cancer, is a major problem. In this study, we aimed to develop a rat model of oral mucositis induced by cancer chemotherapy for quantitative measurement. MATERIALS AND METHODS: A model animal of oral mucositis was prepared by injecting an acetic acid aqueous solution into the buccal mucosa of rats to which a 5-FU solution had been previously administered. The doses of 5-FU and acetic acid were examined, and a treatment experiment using Kenalog® was performed. RESULTS: The optimal dose of the 5-FU solution and the optimal concentration of the acetic acid aqueous solution were 40 mg/kg and 25%, respectively. Treatment with Kenalog® confirmed that this model mimics immunocompromised oral mucositis. CONCLUSION: Compared with a mouse model, oral mucositis can be easily observed in this model and provides a large amount of oral mucosal tissue.
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Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Estomatitis/inducido químicamente , Animales , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Recuento de Leucocitos , Masculino , Ratas Wistar , Estomatitis/sangre , Úlcera/inducido químicamenteRESUMEN
The objective of this study is to design a cancer invasion model by making use of cancer-associated fibroblasts (CAF) or tumor-associated macrophages (TAM) and gelatin hydrogel microspheres (GM) for the sustained release of drugs. The GM containing adenosine (A) (GM-A) were prepared and cultured with TAM to obtain three-dimensional (3D) TAM aggregates incorporating GM-A (3D TAM-GM-A). The GM-A incorporation enabled TAM to enhance the secretion level of vascular endothelial growth factor. When co-cultured with HepG2 liver cancer cells in an invasion assay, the 3D TAM-GM-A promoted the invasion rate of cancer cells. In addition, the E-cadherin expression level decreased to a significantly greater extent compared with that co-cultured with TAM aggregates incorporating GM, whereas the significantly higher expression of N-cadherin and Vimentin was observed. This indicates that the epithelial-mesenchymal transition event was induced. The GM containing transforming growth factor-ß1 (TGF-ß1) were prepared to incorporate into 3D CAF (3D CAF-GM-TGF-ß1). Following a co-culture of mixed 3D CAF-GM-TGF-ß1 and 3D TAM-GM-A and every HepG2, MCF-7 breast cancer cell, or WA-hT lung cancer cell, the invasion rate of every cancer cell enhanced depending on the mixing ratio of 3D TAM-GM-A and 3D CAF-GM-TGF-ß1. The amount of matrix metalloproteinase-2 (MMP-2) secreted also enhanced, and the enhancement was well corresponded with that of cancer cell invasion rate. The higher MMP secretion assists the breakdown of basement membrane, leading to the higher rate of cancer cell invasion. This model is a promising 3D culture system to evaluate the invasion ability of various cancer cells in vitro. Impact statement This study proposes a cell culture system to enhance the tumor-associated macrophage function based on the combination of three-dimensional (3D) cell aggregates and gelatin hydrogel microspheres (GM) for adenosine delivery. An additional combination of 3D cancer-associated fibroblasts incorporating GM containing transforming growth factor-ß1 allowed cancer cells to enhance their invasion rate. This co-culture system is promising to evaluate the ability of cancer cell invasion for anticancer drug screening.
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Fibroblastos Asociados al Cáncer , Movimiento Celular , Técnicas de Cocultivo , Macrófagos Asociados a Tumores/citología , Fibroblastos Asociados al Cáncer/citología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Células Hep G2 , Humanos , Células MCF-7 , Metaloproteinasa 2 de la Matriz , Factor de Crecimiento Transformador beta1/farmacología , Factor A de Crecimiento Endotelial VascularRESUMEN
INTRODUCTION: The objective of this study is to design a cancer invasion model where the cancer invasion rate can be regulated in vitro. METHODS: Cancer-associated fibroblasts (CAF) aggregates incorporating gelatin hydrogel microspheres (GM) containing various concentrations of transforming growth factor-ß1 (TGF-ß1) (CAF-GM-TGF-ß1) were prepared. Alpha-smooth muscle actin (α-SMA) for the CAF aggregates was measured to investigate the CAF activation level by changing the concentration of TGF-ß1. An invasion assay was performed to evaluate the cancer invasion rate by co-cultured of cancer cells with various CAF-GM-TGF-ß1. RESULTS: The expression level of α-SMA for CAF increased with an increased in the TGF-ß1 concentration. When co-cultured with various types of CAF-GM-TGF-ß1, the cancer invasion rate was well correlated with the α-SMA level. It is conceivable that the TGF-ß1 concentration could modify the level of CAF activation, leading to the invasion rate of cancer cells. In addition, at the high concentrations of TGF-ß1, the effect of a matrix metalloproteinase (MMP) inhibitor on the cancer invasion rate was observed. The higher invasion rate would be achieved through the higher MMP production. CONCLUSIONS: The present model is promising to realize the cancer invasion whose rate can be modified by changing the TGF-ß1 concentration.
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BACKGROUND/AIM: Nanocomposite particles are suitable for inhalation; however, their systemic migration has not been confirmed. The aim of this study was to compare drug concentrations in lungs and blood after inhalation of nanocomposite particles. MATERIALS AND METHODS: Rifampicin (RFP) was used as a model drug. Nanocomposite particles were prepared from dichloromethane with RFP and poly(DL-lactic acid-co-glycolic acid) (PLGA) dissolved in an amino acid aqueous solution using a spray dryer. Measurement of RFP concentrations in lung and blood of mice was performed by in vivo tests. RESULTS: Compared with the oral administration group as a control, the RFP concentration in the lungs was significantly higher in the inhalation group. In addition, studies with a fluorescent substance suggested sustained release of drugs from nanocomposite particles in the lungs. CONCLUSION: Nanocomposite particles deliver pulmonary drug in an efficient and sustained manner.
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Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Nanocompuestos/química , Nanopartículas/química , Administración por Inhalación , Animales , Ratones , Nanocompuestos/ultraestructura , Nanopartículas/ultraestructura , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Rifampin/administración & dosificación , Rifampin/farmacocinética , Distribución TisularRESUMEN
BACKGROUND/AIM: Oral mucositis is a significant side effect in cancer treatment. In this study, we aimed to develop a rebamipide-containing film using chitosan and hydroxypropyl methylcellulose (HPMC) to efficiently treat oral mucositis. MATERIALS AND METHODS: A 0.1% (w/v) rebamipide aqueous solution, a 1.4% (w/v) chitosan aqueous solution containing Pluronic® F-127, and a 1.0% (w/v) HPMC aqueous solution were mixed and dried using a square silicon frame to form a film. Cumulative release ratios of rebamipide from sample films were measured in a phosphate buffer (pH 6.8) at 37°C. RESULTS: Chitosan suppressed the release of rebamipide from the film for up to 30 min. HPMC contributed to the sustained release of the film over a relatively long period of time and the maintenance of its shape. CONCLUSION: The combined use of chitosan and HPMC is suitable as a base material for rebamipide-containing films.