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1.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802613

RESUMEN

This study demonstrates the rational fabrication of a magnetic composite nanofiber mesh that can achieve mutual synergy of hyperthermia, chemotherapy, and thermo-molecularly targeted therapy for highly potent therapeutic effects. The nanofiber is composed of biodegradable poly(ε-caprolactone) with doxorubicin, magnetic nanoparticles, and 17-allylamino-17-demethoxygeldanamycin. The nanofiber exhibits distinct hyperthermia, owing to the presence of magnetic nanoparticles upon exposure of the mesh to an alternating magnetic field, which causes heat-induced cell killing as well as enhanced chemotherapeutic efficiency of doxorubicin. The effectiveness of hyperthermia is further enhanced through the inhibition of heat shock protein activity after hyperthermia by releasing the inhibitor 17-allylamino-17-demethoxygeldanamycin. These findings represent a smart nanofiber system for potent cancer therapy and may provide a new approach for the development of localized medication delivery.


Asunto(s)
Benzoquinonas/farmacología , Preparaciones de Acción Retardada/farmacología , Doxorrubicina/farmacología , Lactamas Macrocíclicas/farmacología , Nanofibras/química , Neoplasias/tratamiento farmacológico , Benzoquinonas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/química , Doxorrubicina/química , Liberación de Fármacos , Sinergismo Farmacológico , Compuestos Férricos/química , Humanos , Lactamas Macrocíclicas/química , Células MCF-7 , Magnetismo/métodos , Nanopartículas de Magnetita/química
2.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805785

RESUMEN

Osteoporosis is a worldwide chronic disease characterized by increasing bone fragility and fracture likelihood. In the treatment of bone defects, materials based on calcium phosphates (CaPs) are used due to their high resemblance to bone mineral, their non-toxicity, and their affinity to ionic modifications and increasing osteogenic properties. Moreover, CaPs, especially hydroxyapatite (HA), can be successfully used as a vehicle for local drug delivery. Therefore, the aim of this work was to fabricate hydroxyapatite-based composite beads for potential use as local carriers for raloxifene. HA powder, modified with magnesium and silicon ions (Mg,Si-HA) (both of which play beneficial roles in bone formation), was used to prepare composite beads. As an organic matrix, sodium alginate with chondroitin sulphate and/or keratin was applied. Cross-linking of beads containing raloxifene hydrochloride (RAL) was carried out with Mg ions in order to additionally increase the concentration of this element on the material surface. The morphology and porosity of three different types of beads obtained in this work were characterized by scanning electron microscopy (SEM) and mercury intrusion porosimetry, respectively. The Mg and Si released from the Mg,Si-HA powder and from the beads were measured by inductively coupled plasma optical emission spectrometry (ICP-OES). In vitro RAL release profiles were investigated for 12 weeks and studied using UV/Vis spectroscopy. The beads were also subjected to in vitro biological tests on osteoblast and osteosarcoma cell lines. All the obtained beads revealed a spherical shape with a rough, porous surface. The beads based on chondroitin sulphate and keratin (CS/KER-RAL) with the lowest porosity resulted in the highest resistance to crushing. Results revealed that these beads possessed the most sustained drug release and no burst release effect. Based on the results, it was possible to select the optimal bead composition, consisting of a mixture of chondroitin sulphate and keratin.


Asunto(s)
Alginatos/química , Conservadores de la Densidad Ósea/farmacología , Sistemas de Liberación de Medicamentos/métodos , Durapatita/química , Silicatos de Magnesio/química , Clorhidrato de Raloxifeno/farmacología , Conservadores de la Densidad Ósea/metabolismo , Regeneración Ósea/fisiología , Huesos/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sulfatos de Condroitina/química , Liberación de Fármacos , Humanos , Queratinas/química , Cinética , Nanopartículas/química , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Porosidad , Clorhidrato de Raloxifeno/metabolismo
3.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809846

RESUMEN

Phosphodiesterase 7 (PDE7) is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP), an important cellular messenger. PDE7's role in neurotransmission, expression profile in the brain and the druggability of other phosphodiesterases have motivated the search for potent inhibitors to treat neurodegenerative and inflammatory diseases. Different heterocyclic compounds have been described over the years; among them, phenyl-2-thioxo-(1H)-quinazolin-4-one, called S14, has shown very promising results in different in vitro and in vivo studies. Recently, polymeric nanoparticles have been used as new formulations to target specific organs and produce controlled release of certain drugs. In this work, we describe poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles loaded with S14. Their preparation, optimization, characterization and in vivo drug release profile are here presented as an effort to improve pharmacokinetic properties of this interesting PDE7 inhibitor.


Asunto(s)
Encéfalo/efectos de los fármacos , Preparaciones de Acción Retardada/química , Portadores de Fármacos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Quinazolinonas/química , Quinazolinonas/farmacocinética , Animales , Encéfalo/metabolismo , Supervivencia Celular/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/antagonistas & inhibidores , Composición de Medicamentos , Liberación de Fármacos , Humanos , Ratones , Estructura Molecular , Nanopartículas/ultraestructura , Tamaño de la Partícula , Permeabilidad
4.
Beijing Da Xue Xue Bao Yi Xue Ban ; 53(2): 348-354, 2021 Mar 19.
Artículo en Chino | MEDLINE | ID: mdl-33879910

RESUMEN

OBJECTIVE: To explore the feasibility of preparing gastric floating formulations by fused de-position modeling (FDM) 3D printing technology, to evaluate the in vitro properties of the prepared FDM 3D printed gastric floating formulations, and to compare the influence of different external shapes of the formulation with their in vitro properties. METHODS: Verapamil hydrochloride and polyvinyl alcohol (PVA) were used as the model drug and the excipient, respectively. The capsule-shaped and hemisphere-shaped gastric floating formulations were then prepared by FDM 3D printing. The infill percentages were 15%, the layer heights were 0.2 mm, and the roof or floor thicknesses were 0.8 mm for both the 3D printed formulations, while the number of shells was 3 and 4 for capsule-shaped and hemisphere-shaped formulation, respectively. Scanning electron microscopy (SEM) was used to observe the morpho-logy of the surface and cross section of the formulations. Gravimetric method was adopted to measure the weights of the formulations. Texture analyzer was employed to evaluate the hardness of the formulations. High performance liquid chromatography method was used to determine the drug contents of the formulations. The in vitro floating and drug release behavior of the formulations were also characterized. RESULTS: SEM showed that the appearance of the FDM 3D printed gastric floating formulations were both intact and free from defects with the filling structure which was consistent with the design. The weight variations of the two formulations were relatively low, indicating a high reproducibility of the 3D printing fabrication. Above 800.0 N of hardness was obtained in two mutually perpendicular directions for the two formulations. The drug contents of the two formulations approached to 100%, showing no drug loss during the 3D printing process. The two formulations floated in vitro without any lag time, and the in vitro floating time of the capsule-shaped and hemisphere-shaped formulation were (3.97±0.41) h and (4.48±0.21) h, respectively. The in vitro release of the two formulations was significantly slower than that of the commercially available immediate-release tablets. CONCLUSION: The capsule-shaped and hemisphere-shaped verapamil hydrochloride gastric floating formulations were prepared by FDM 3D printing technology successfully. Only the floating time was found to be influenced by the external shape of the 3D printed formulations in this study.


Asunto(s)
Excipientes , Impresión Tridimensional , Liberación de Fármacos , Reproducibilidad de los Resultados , Comprimidos
5.
AAPS PharmSciTech ; 22(3): 132, 2021 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-33851275

RESUMEN

The main objective of this study was to develop an in vivo predictive dissolution (IVPD) model for topiroxostat immediate-release (IR) formulation by the combination of mechanistic absorption model (MAM) deconvolution method with time shifting factor (TSF) adjustment. The in vitro dissolution profiles in different biorelevant dissolution media containing different concentrations of sodium lauryl sulfate (SLS) were obtained from dissolution testing with the paddle method of the US Pharmacopeia, while the human pharmacokinetic profile was taken from the published experimental results. The GastroPlus™ software was used to observe the linear relationship between in vitro drug dissolution and in vivo absorption. The pharmacokinetic profile of topiroxostat IR tablet was first deconvoluted through the MAM method to obtain the fraction absorbed in vivo. Next, Levy plot was constructed to estimate the TSF, and the time scale for both processes of dissolution and absorption was then adjusted to be superimposable. The IVPD modelling was subsequently established with data between in vitro dissolution profiles and fraction absorbed in vivo. Finally, the dissolution profiles of topiroxostat IR tablet were translated into a pharmacokinetic curve in terms of convolution method. The comparison between translated and observed pharmacokinetic data will validate the performance of the developed IVPD model. This new linear IVPD model with high predictive power for the tablet can predict the in vivo pharmacokinetic differences through in vitro dissolution data, and it can be utilized as a risk-control tool for the formulation development of the topiroxostat IR tablet and the quality control of product batches.


Asunto(s)
Simulación por Computador , Modelos Biológicos , Nitrilos/química , Nitrilos/farmacocinética , Piridinas/química , Piridinas/farmacocinética , Adulto , Liberación de Fármacos/fisiología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Femenino , Predicción , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Comprimidos , Adulto Joven
6.
Int J Nanomedicine ; 16: 2357-2372, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33790554

RESUMEN

Purpose: Non-small cell lung cancer (NSCLC) is an aggressive tumor with high mortality and poor prognosis. In this study, we designed a liposome encapsulating polymeric micelles (PMs) loaded with vinorelbine (NVB) and cis-diamminedichloroplatinum (II) (cisplatin or CDDP) for the treatment of NSCLC. Materials and Methods: Sodium poly(α-l-glutamic acid)-graft-methoxy-polyethylene glycol (PLG-G-PEG5K) was used to prepare NVB-loaded NVB-PMs and CDDP-loaded CDDP-PMs that were co-encapsulated into liposomes by a reverse evaporation method, yielding NVB and CDDP co-delivery liposomes (CoNP-lips) composed of egg phosphatidyl lipid-80/cholesterol/DPPG/DSPE-mPEG2000 at a molar ratio of 52:32:14:2. The CoNP-lips were characterized in terms of particle size, zeta potential, drug content, encapsulation efficiency, and structural properties. Drug release by the CoNP-lips as well as their stability and cytotoxicity was evaluated in vitro, and their antitumor efficacy was assessed in a mouse xenograft model of Lewis lung carcinoma cell-derived tumors. Results: CoNP-lips had a spherical shape with uniform size distribution; the average particle size was 162.97±9.06 nm, and the average zeta potential was -13.02±0.22 mV. In vitro cytotoxicity analysis and the combination index demonstrated that the CoNP-lips achieved a synergistic cytotoxic effect at an NVB:CDDP weight ratio of 2:1 in an NSCLC cell line. There was sustained release of both drugs from CoNP-lips. The pharmacokinetic analysis showed that CoNP-lips had a higher plasma half-life than NP solution, with 6.52- and 8.03-fold larger areas under the receiver operating characteristic curves of NVB and CDDP. CoNP-lips showed antitumor efficacy in tumor-bearing C57BL/6 mice and drug accumulation in tumors via the enhanced permeability and retention effect. Conclusion: CoNP-lips are a promising formulation for targeted therapy in NSCLC.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/uso terapéutico , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , Micelas , Polímeros/química , Vinorelbina/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Cisplatino/farmacología , Liberación de Fármacos , Humanos , Liposomas , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Tamaño de la Partícula , Polietilenglicoles/química , Ratas Sprague-Dawley , Distribución Tisular , Vinorelbina/farmacocinética , Vinorelbina/farmacología
7.
Int J Nanomedicine ; 16: 2373-2388, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33790555

RESUMEN

Aim: The metastasis of breast cancer is an important cause of tumor recurrence. This study highlights that tyrosine kinase inhibitors dasatinib (DAS) and rosiglitazone (ROZ) inhibit tumor growth and reduce the occurrence of tumor cell metastasis. Due to the poor water solubility, short half-time in the body of DAS and ROZ, which increases the difficulty of tumor treatment, as well as the demand for nano-drug delivery systems for organ-specific therapies. Methods: Hyaluronic acid (HA) and DAS are bonded by a pH-sensitive ester bond to form an HA-DAS polymer. Then, ROZ was added as the core, D-A-tocopherol polydiethylene glycol isosuccinate (TPGS) and HA-DAS were used as carriers to form HA-DAS and TPGS mixed micelle system loaded with ROZ (THDR-NPs). The size and structure of THDR-NPs were characterized, the drug release, stability and biosafety of THDR-NPs were studied. In vitro, the cytotoxicity, targeting effect and tumor metastasis inhibition of THDR-NPs were evaluated in human breast cancer cell lines. In addition, the selective potency of designed THDR-NPs in depleting was further verified in vivo in the tumor-bearing nude mice model. Results: The designed THDR-NPs have a particle size of less than 100 nm, good stability, biological safety and sustained release, and showed strong therapeutic effects on breast cancer models in vitro and in vivo. Moreover, it has been proved that THDR-NPs have the ability to inhibit tumor metastasis. Conclusion: DAS and ROZ were designed into micelles, the efficacy of THDR-NPs was higher than that of free drugs. These results indicate that nanoparticles have a good application prospect in the treatment of tumor metastasis.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Animales , Peso Corporal/efectos de los fármacos , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Dasatinib/administración & dosificación , Dasatinib/farmacocinética , Dasatinib/farmacología , Dasatinib/uso terapéutico , Portadores de Fármacos/química , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Hemólisis/efectos de los fármacos , Humanos , Ácido Hialurónico/química , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Espectroscopía de Protones por Resonancia Magnética , Ratas Sprague-Dawley , Rosiglitazona/farmacocinética , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Electricidad Estática , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos
8.
Int J Nanomedicine ; 16: 2405-2417, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33814907

RESUMEN

Purpose: Ciprofloxacin (CIP) has poor lung targeting after oral inhalation. This study developed optimized inhalable nanostructured lipid carriers (NLCs) for CIP to enhance deposition and accumulation in deeper parts of the lungs for treatment of noncystic fibrosis bronchiectasis (NCFB). Methods: NLC formulations based on stearic acid and oleic acid were successfully prepared by hot homogenization and in vitro-characterized. CIP-NLCs were formulated into nanocomposite micro particles (NCMPs) for administration in dry powder inhalation (DPI) formulations by spray-drying (SD) using different ratios of chitosan (CH) as a carrier. DPI formulations were evaluated for drug content and in vitro deposition, and their mass median aerodynamic diameter (MMAD), fine particle fraction (FPF), fine particle dose (FPD), and emitted dose (ED) were determined. Results: The CIP-NLCs were in the nanometric size range (102.3 ± 4.6 nm), had a low polydispersity index (0.267 ± 0.12), and efficient CIP encapsulation (98.75% ± 0.048%), in addition to a spherical and smooth shape with superior antibacterial activity. The in vitro drug release profile of CIP from CIP-NLCs showed 80% release in 10 h. SD of CIP-NLCs with different ratios of CH generated NCMPs with good yield (>65%). The NCMPs had a corrugated surface, but with increasing lipid:CH ratios, more spherical, smooth, and homogenous NCMPs were obtained. In addition, there was a significant change in the FPF with increasing lipid:CH ratios (P ˂ 0.05). NCMP-1 (lipid:CH = 1:0.5) had the highest FPD (45.0 µg) and FPF (49.2%), while NCMP-3 (lipid:CH = 1:1.5) had the lowest FPF (37.4%). All NCMP powders had an MMAD in the optimum size range of 3.9-5.1 µm. Conclusion: Novel inhalable CIP NCMP powders are a potential new approach to improved target ability and delivery of CIP for NCFB treatment.


Asunto(s)
Bronquiectasia/tratamiento farmacológico , Ciprofloxacino/uso terapéutico , Portadores de Fármacos/química , Lípidos/química , Nanoestructuras/química , Administración por Inhalación , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Quitosano/química , Ciprofloxacino/administración & dosificación , Portadores de Fármacos/administración & dosificación , Liberación de Fármacos , Inhaladores de Polvo Seco , Fibrosis , Cinética , Liposomas , Pulmón , Pruebas de Sensibilidad Microbiana , Nanoestructuras/ultraestructura , Tamaño de la Partícula , Electricidad Estática
9.
Int J Nanomedicine ; 16: 2487-2499, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33824587

RESUMEN

Purpose: Due to the shortcomings of nanocarriers, the development of carrier-free nanodelivery systems has attracted more and more attention in cancer treatment. However, there are few studies on carrier-free nanosystems that can simultaneously achieve monitoring functions. Here a multifunctional carrier-free nanosystem loaded with curcumin and irinotecan hydrochloride was established for the treatment and monitoring of gastric cancer. Methods: In this study, an irinotecan hydrochloride-curcumin nanosystem in the early stage (the system is named SICN) was prepared. Based on the fluorescence of curcumin, flow cytometry, laser confocal microscopy, and zebrafish fluorescence imaging were used to study the monitoring function of SICN in vivo and in vitro. In addition, HGC-27 human gastric cancer cells were used to study SICN cytotoxicity. Results: Flow cytometry and zebrafish fluorescence imaging monitoring results showed that the uptake of SICN was significantly higher than free curcumin, and the excretion rate was lower. SICN had higher accumulation and retention in cells and zebrafish. Laser confocal microscopy monitoring results showed that SICN was internalized into HGC-27 cells through multiple pathways, including macropinocytosis, caveolin, and clathrin-mediated and clathrin -independent endocytosis, and distributed intracellularly throughout the whole cytoplasm, including lysosomes and Golgi apparatus. In vitro cell experiments showed that SICN nanoparticles were more toxic than single components, and HGC-27 cells had more absorption and higher toxicity to nanoparticles under slightly acidic conditions. Conclusion: SICN is a promising carrier-free nanoparticle, and the combination of two single-component therapies can exert a synergistic antitumor effect. When exposed to a tumor acidic environment, SICN showed stronger cytotoxicity due to charge conversion. More importantly, the nanoparticles' self-monitoring function has been developed, opening up new ideas for combined tumor therapy.


Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Curcumina/administración & dosificación , Curcumina/farmacología , Curcumina/uso terapéutico , Portadores de Fármacos , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Fluorescencia , Humanos , Imagenología Tridimensional , Irinotecán/farmacología , Irinotecán/uso terapéutico , Tamaño de la Partícula , Pez Cebra
10.
Int J Nanomedicine ; 16: 2501-2513, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33824588

RESUMEN

Introduction: Aim to obtain a NO donor that can control released NO in vivo with the high efficacy of tumor suppression and targeting, a nanoplatform consisting of FA-Fe3O4@mSiO2-Au/DOX was constructed. Methods: In vitro, the nanoplatform catalyzed NO's release with the maximum value of 4.91 µM within 60 min at 43°C pH=5.0, which was increased by 1.14 times when the temperature was 37°C. In vivo, 11.7 µg Au in the tumor tissue was found to catalyze S-nitrosoglutathione continuously, and 54 µM NO was checked out in the urine. Results and Discussion: The high concentration of NO was found to increase the apoptotic rate and to reduce tumor proliferation. In the chemo-photothermal combination therapy, the tumor inhibition rate was increased up to 94.3%, and Au's contribution from catalyzing NO release NO was 8.17%.


Asunto(s)
Oro/química , Neoplasias/patología , Neoplasias/terapia , Óxido Nítrico/metabolismo , Catálisis , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Ácido Fólico/química , Humanos , Células MCF-7 , Fenómenos Magnéticos , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Porosidad , Silicio/química , Difracción de Rayos X
11.
Int J Nanomedicine ; 16: 2533-2553, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33824590

RESUMEN

Purpose: The present study was intended to fabricate chitosan (Ch)-tamarind gum polysaccharide (TGP) polyelectrolyte complex stabilized cubic nanoparticles of simvastatin and evaluate their potential against human breast cancer cell lines. Materials and Methods: The antisolvent precipitation method was used for formulation of nanoparticles. Factorial design (32) was utilized as a tool to analyze the effect of Ch and TGP concentration on particle size and entrapment efficiency of nanoparticles. Results: Formulated nanoparticles showed high entrapment efficiency (67.19±0.42-83.36±0.23%) and small size (53.3-383.1 nm). The present investigation involved utilization of two biological membranes (egg and tomato) as biological barriers for drug release. The study revealed that drug release from tomato membranes was retarded (as compared to egg membranes) but the release pattern matched that of egg membranes. All formulations followed the Baker-Lansdale model of drug release irrespective of the two different biological barriers. Stability studies were carried out for 45 days and exhibited less variation in particle size as well as a reduction in entrapment efficiency. Simvastatin loaded PEC stabilized nanoparticles exhibited better control on growth of human breast cancer cell lines than simple simvastatin. An unusual anticancer effect of simvastatin nanoparticles is also supported by several other research studies. Conclusion: The present study involves first-time synthesis of Ch-TGP polyelectrolyte complex stabilized nanoparticles of simvastatin against MCF-7 cells. It recommends that, in future, theoretical modeling and IVIVC should be carried out for perfect designing of delivery systems.


Asunto(s)
Quitosano/química , Nanopartículas/química , Gomas de Plantas/química , Polielectrolitos/química , Polisacáridos/química , Simvastatina/farmacología , Tamarindus/química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Humanos , Células MCF-7 , Nanopartículas/ultraestructura , Tamaño de la Partícula , Espectrofotometría Infrarroja , Electricidad Estática
12.
Molecules ; 26(5)2021 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-33673582

RESUMEN

Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned.


Asunto(s)
Antineoplásicos/química , Neoplasias Pulmonares/tratamiento farmacológico , Péptido Hidrolasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Toxinas Biológicas/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Calicheamicinas/farmacología , Proliferación Celular/efectos de los fármacos , Preparaciones de Acción Retardada/química , Portadores de Fármacos/química , Diseño de Fármacos , Liberación de Fármacos , Terapia Enzimática , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Maitansina/farmacología , Terapia Molecular Dirigida , Péptido Hidrolasas/genética , Profármacos/química , Profármacos/farmacología , Tapsigargina/farmacología , Toxinas Biológicas/farmacología
13.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33672879

RESUMEN

Osteosarcoma has a poor survival rate due to relapse and metastasis. Zoledronic acid (ZOL), an anti-resorptive and anti-tumor agent, is used for treating osteosarcoma. Delivery of ZOL to the target region is difficult due to its high binding affinity to bone minerals. This study developed a novel treatment for osteosarcoma by delivering ZOL to the target region locally and sustainably. In this study, we fabricated a novel bone substitute by loading ZOL on ß-tricalcium phosphate (ß-TCP). The ZOL-loaded ß-TCP (ZOL/ß-TCP) would be expected to express the inhibitory effects via both bound-ZOL (bound to ß-TCP) and free-ZOL (release from ZOL/ß-TCP). To explore the ability to release ZOL from the ZOL/ß-TCP, the amount of released ZOL was measured. The released profile indicates that a small amount of ZOL was released, and most of it remained on the ß-TCP. Our data showed that ZOL/ß-TCP could successfully express the effects of ZOL via both bound-ZOL and free-ZOL. In addition, we examined the biological effects of bound/free-ZOL using osteosarcoma and osteoclasts (target cells). The results showed that two states of ZOL (bound/free) inhibit target cell activities. As a result, ZOL/ß-TCP is a promising candidate for application as a novel bone substitute.


Asunto(s)
Fosfatos de Calcio/farmacología , Proliferación Celular/efectos de los fármacos , Osteoclastos/metabolismo , Osteosarcoma/metabolismo , Ácido Zoledrónico/farmacología , Animales , Sustitutos de Huesos/química , Sustitutos de Huesos/farmacocinética , Sustitutos de Huesos/farmacología , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacocinética , Diferenciación Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Liberación de Fármacos , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Osteosarcoma/patología , Ácido Zoledrónico/química , Ácido Zoledrónico/farmacocinética
14.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33672949

RESUMEN

Two different types of ordered mesoporous nanoparticles, namely MCM-41 and MCM-48, with similar pore sizes but different pore connectivity, were loaded with aprepitant via a passive diffusion method. The percentage of the loaded active agent, along with the encapsulation efficiency, was evaluated using High-performance Liquid Chromatography (HPLC) analysis complemented by Thermogravimetric Analysis (TGA). The determination of the pore properties of the mesoporous particles before and after the drug loading revealed the presence of confined aprepitant in the pore structure of the particles, while Powder X-ray Diffractometry(pXRD), Differential Scanning Calorimetry (DSC), and FTIR experiments indicated that the drug is in an amorphous state. The release profiles of the drug from the two different mesoporous materials were studied in various release media and revealed an aprepitant release up to 45% when sink conditions are applied. The cytocompatibility of the silica nanoparticles was assessed in Caco-2 cell monolayers, in the presence and absence of the active agent, suggesting that they can be used as carriers of aprepitant without presenting any toxicity in vitro.


Asunto(s)
Aprepitant/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Dióxido de Silicio/química , Administración Oral , Antieméticos/administración & dosificación , Antieméticos/farmacocinética , Aprepitant/farmacocinética , Células CACO-2 , Rastreo Diferencial de Calorimetría , Cromatografía Líquida de Alta Presión , Difusión , Liberación de Fármacos , Humanos , Microscopía Electrónica de Rastreo , Nanopartículas/ultraestructura , Tamaño de la Partícula , Porosidad , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier
15.
Eur J Med Chem ; 216: 113297, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33677351

RESUMEN

Antibody-drug conjugates (ADCs) are currently among the most successful and important strategies for treating patients with solid tumors. ADCs are composed of a monoclonal antibody and warhead, which are conjugated via a linker. Currently, monomethyl auristatin E (MMAE) is the most widely applied warhead in the development of ADCs. However, MMAE-based ADCs are generally constructed using the MC-VC-PABC linker, and this design has limited structural diversity and some disadvantages. Accordingly, in this study, we generated three types of novel linker-MMAE (with alterations in the spacer, catabolizing area, and self-immolative compared with MC-VC-PABC-MMAE) in ADCs, termed SCT200-linker-MMAE conjugates, and then evaluated the linker-drug plasma stability and the rate of drug release by cathepsin B. The binding ability, internalization rates, and efficacy of all SCT200-linker-MMAE ADCs were systematically studied, and the expression of apoptosis-associated proteins and the therapeutic efficacies of SCT200-M-2, -C-2, and -C-4 were evaluated. The results showed that the activities of some of these ADCs were increased for epidermal growth factor receptor-positive tumors. Moreover, the novel linkers designed in this study can be linked with other antibodies to treat other types of cancer. Overall, these findings provide important insights into the application of SCT200-based linkers in ADCs.


Asunto(s)
Anticuerpos Monoclonales/química , Antineoplásicos/síntesis química , Inmunoconjugados/química , Oligopéptidos/química , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Catepsina B/metabolismo , Línea Celular Tumoral , Liberación de Fármacos , Estabilidad de Medicamentos , Receptores ErbB/genética , Receptores ErbB/inmunología , Receptores ErbB/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoconjugados/sangre , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Oligopéptidos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Molecules ; 26(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33672071

RESUMEN

Twelve derivatives of biguanide-derived 1,3,5-triazines, a promising class of anticancer agent, were synthesised and evaluated for their anticancer activity against two colorectal cancer cell lines-HCT116 and SW620. 2c and 3c which are the derivatives containing o-hydroxyphenyl substituents exhibited the highest activity with IC50 against both cell lines in the range of 20-27 µM, which is comparable to the IC50 of cisplatin reference. Moreover, the potential use of the calcium citrate nanoparticles (CaCit NPs) as a platform for drug delivery system was studied on a selected 1,3,5-triazine derivative 2a. Condition optimisation revealed that the source of citrate ions and reaction time significantly influence the morphology, size and %drug loading of the particles. With the optimised conditions, "CaCit-2a NPs" were successfully synthesised with the size of 148 ± 23 nm and %drug loading of up to 16.3%. Furthermore, it was found that the release of 2a from the synthesised CaCit-2a NPs is pH-responsive, and 2a could be control released under the acidic cancer environment. The knowledge from this study is perceptive for further development of the 1,3,5-triazine-based anticancer drugs and provide the platform for the incorporation of other drugs in the CaCit NPs in the future.


Asunto(s)
Antineoplásicos/farmacología , Biguanidas/química , Citrato de Calcio/química , Nanopartículas/química , Triazinas/síntesis química , Triazinas/farmacología , Línea Celular Tumoral , Liberación de Fármacos , Humanos , Nanopartículas/ultraestructura , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría , Triazinas/química
17.
Molecules ; 26(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33672078

RESUMEN

The development of controlled drug delivery systems based on bio-renewable materials is an emerging strategy. In this work, a controlled drug delivery system based on mesoporous oxidized cellulose beads (OCBs) was successfully developed by a facile and green method. The introduction of the carboxyl groups mediated by the TEMPO(2,2,6,6-tetramethylpiperidine-1-oxyradical)/NaClO/NaClO2 system presents the pH-responsive ability to cellulose beads, which can retain the drug in beads at pH = 1.2 and release at pH = 7.0. The release rate can be controlled by simply adjusting the degree of oxidation to achieve drug release at different locations and periods. A higher degree of oxidation corresponds to a faster release rate, which is attributed to a higher degree of re-swelling and higher hydrophilicity of OCBs. The zero-order release kinetics of the model drugs from the OCBs suggested a constant drug release rate, which is conducive to maintaining blood drug concentration, reducing side effects and administration frequency. At the same time, the effects of different model drugs and different drug-loading solvents on the release behavior and the physical state of the drugs loaded in the beads were studied. In summary, the pH-responsive oxidized cellulose beads with good biocompatibility, low cost, and adjustable release rate have shown great potential in the field of controlled drug release.


Asunto(s)
Celulosa Oxidada/química , Óxidos N-Cíclicos/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Tracto Gastrointestinal/fisiología , Rastreo Diferencial de Calorimetría , Liberación de Fármacos , Fenofibrato/farmacología , Concentración de Iones de Hidrógeno , Indometacina/farmacología , Cinética , Polvos , Difracción de Rayos X
18.
Int J Nanomedicine ; 16: 2283-2295, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33776433

RESUMEN

Background: Paclitaxel (PTX) has interesting anticancer activity. However, it is insoluble in water, which seriously hinders its use in clinical. Superparamagnetic iron oxide nanoparticles (SPIONs) are used as an ideal drug delivery system. Therefore, we proposed a folic acid (FA) targeting drug-loaded SPIONs to reduce its adverse reaction. Methods: To improve the hydrophilicity of PTX, the structure of PTX was modified by succinic anhydride to obtain 2'-succinate paclitaxel (SPTX). FA conjugated Polyethylene glycol (PEG)/polyethyleneimine (PEI)-SPIONs SPTX-loaded nanoparticles (SPTX@FA@PEG/PEI-SPIONs) were prepared by solvent volatilization and hydrogen bond adsorption, and the nano-formulation was optimized by response surface methodology (RSM). The characteristics, antitumor effect in vitro, pharmacokinetics, and biodistribution of SPTX@FA@PEG/PEI-SPIONs were evaluated. Results: SPTX was successfully loaded on the surface of FA@PEG/PEI-SPIONs. The formation of SPTX@FA@PEG/PEI-SPIONs was exhibited water-dispersive monodispersity with high stability by RSM, and dynamic light scattering (DLS) was 178.1±3.12 nm, particle size observed in the transmission electron microscope (TEM) was 13.01±1.10 nm, and the encapsulation efficiency (EE) and loading efficiency (LE) were 81.1±1.66% and 14.8±1.46%, respectively. It enhanced the stability in normal physiological condition, accelerated drug release at tumorous pH, and preferentially prolonged the circulation time. In vitro, the SPTX@FA@PEG/PEI-SPIONs significantly targeted to folate receptor (FR) positive cancers cell (HNE-1) via the receptor-ligand mediated pathway, resulting in effective cytotoxic activity. Pharmacokinetic results demonstrated that SPTX@FA@PEG/PEI-SPIONs (t1/2=3.41 h) had longer than free SPTX or PTX (t1/2=1.67 h) in rats in vivo. Tissue distribution studies showed that SPTX@FA@PEG/PEI-SPIONs were present at high levels in the liver and help in targeting the folate receptors present on the kidneys. Conclusion: These results suggest that SPTX@FA@PEG/PEI-SPIONs offer a highly promising approach to control drug release, improve drug pharmacokinetics and actively target the nasopharyngeal carcinoma.


Asunto(s)
Ácido Fólico/química , Paclitaxel/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Liberación de Fármacos , Humanos , Iminas/química , Concentración 50 Inhibidora , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/patología , Paclitaxel/sangre , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Tamaño de la Partícula , Polietilenglicoles/química , Polietilenos/química , Ratas , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Succinatos/química , Distribución Tisular/efectos de los fármacos
19.
Food Chem ; 352: 129400, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-33691213

RESUMEN

The microbial transglutaminase (mTG) was used to improve the stability of the naringenin-loaded ß-casein micelles (CNMs). The formation of cross-linked CNMs was confirmed by SDS-PAGE electrophoresis, showing a decrease in monomeric ß-CN levels with increasing crosslinking time. Dynamic light scattering (DLS) showed that after crosslinking the particle size distribution did not change upon dilution, suggesting occurrence of intra-crosslinking. Fluorescence spectroscopy and circular dichroism (CD) showed that crosslinking induced only minor changes in the structure. Finally, release of naringenin in buffer at pH 7.4 demonstrated a slower release from the cross-linked micelles compared to the untreated micelles. In addition, the cross-linked micelles exhibited a partial resistance to pepsin enzyme. We conclude that crosslinking with mTG is a suitable method to modulate naringenin release kinetics from ß-CN micelles and improves the potential of these micelles as delivery systems targeted to the small intestine.


Asunto(s)
Caseínas/química , Digestión , Portadores de Fármacos/química , Liberación de Fármacos , Flavanonas/química , Micelas , Transglutaminasas/metabolismo , Concentración de Iones de Hidrógeno
20.
Carbohydr Polym ; 260: 117794, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712142

RESUMEN

Hydrogel beads composed of oxidized gellan gum (OGG) and resistant starch (RS) were successfully fabricated by ionic cross-linking and used as delivery carriers for resveratrol. Firstly, OGG with different degrees of oxidation were prepared through 2, 2, 6, 6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation, and characterized by Fourier transform infrared spectroscopy and carbon-13 nuclear magnetic resonance to prove that carboxyl groups were successfully introduced into the gellan gum molecules. Molecular weight, thermal stability, zeta potential and gelation temperature of OGG were also investigated. Subsequently, resveratrol was encapsulated into OGG/RS hydrogel beads in the form of resveratrol/ß-cyclodextrins inclusion complexes. The addition of RS significantly influenced the morphological structure and swelling capacity of OGG/RS hydrogel beads. The OGG/RS hydrogel beads exhibited a pH-sensitivity and high encapsulation efficiency of resveratrol (84.95 %-90.73 %). Furthermore, the in-vitro release behaviors demonstrated that OGG/RS hydrogel beads showed good stability in simulated gastric fluids and sustained release of resveratrol in simulated intestinal fluids. The obtained results indicate that OGG/RS hydrogel beads show a potential as delivery system for resveratrol in the food industry.


Asunto(s)
Hidrogeles/química , Polisacáridos Bacterianos/química , Resveratrol/química , Óxidos N-Cíclicos/química , Portadores de Fármacos/química , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Peso Molecular , Oxidación-Reducción , Resveratrol/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría
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