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1.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805767

RESUMEN

Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.


Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Toxinas Bacterianas/antagonistas & inhibidores , Infección Hospitalaria/tratamiento farmacológico , Enterocolitis Seudomembranosa/tratamiento farmacológico , Enterotoxinas/antagonistas & inhibidores , ADP-Ribosilación/efectos de los fármacos , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestructura , Actinas/deficiencia , Actinas/genética , Antibacterianos/uso terapéutico , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/química , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Sitios de Unión , /genética , Infección Hospitalaria/metabolismo , Infección Hospitalaria/microbiología , Infección Hospitalaria/patología , Endocitosis/efectos de los fármacos , Enterocolitis Seudomembranosa/metabolismo , Enterocolitis Seudomembranosa/microbiología , Enterocolitis Seudomembranosa/patología , Enterotoxinas/química , Enterotoxinas/genética , Enterotoxinas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/ultraestructura , Humanos , Modelos Moleculares , Unión Proteica , Dominios Proteicos , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína
2.
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
3.
Int J Nanomedicine ; 16: 2443-2459, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33814909

RESUMEN

Background: Specific modifications to carriers to achieve targeted delivery of chemotherapeutics into malignant tissues are a critical point for efficient diagnosis and therapy. In this case, bovine serum albumin (BSA) was conjugated with cetuximab-valine-citrulline (vc)-doxorubicin (DOX) to target epidermal growth factor receptor (EGFR) and enable the release of drug in EGFR-overexpressed tumor cells. Methods: Maleimidocaproyl-valine-citrulline-p-aminobenzylcarbonyl-p-nitrophenol (MC-Val-Cit-PAB-PNP) and DOX were used to synthesize MC-Val-Cit-PAB-DOX, which was further linked with cetuximab to prepare antibody-drug conjugates (ADCs). Then, the ADCs were adsorbed to the surface of the BSA nanoparticles (NPs), which were prepared by a desolvation method to obtain cetuximab-vc-DOX-BSA-NPs. The cetuximab-vc-DOX conjugates adsorbed on the surface of the BSA nanoparticles were determined and optimized by size exclusion chromatography. An in vitro cytotoxicity study was conducted using a colon carcinoma cell line with different EGFR-expression levels to test the selectivity of cetuximab-vc-DOX-NPs. Results: The vc-DOX and cetuximab-vc-DOX conjugates were both synthesized successfully and their structural characteristics confirmed by 1H-NMR and SDS-PAGE. The MTT assay showed stronger cytotoxicity of cetuximab-vc-DOX-NPs versus control IgG-vc-DOX-NPs in EGFR-overexpressing RKO cells. Cellular binding and intracellular accumulation determined by flow cytometry and confocal laser scanning microscopy revealed the strong binding ability of cetuximab-vc-DOX-NPs to RKO cells. The in vivo imaging study demonstrated that cetuximab-vc-DOX-NPs exhibited higher fluorescent intensity in tumor tissues than non-decorated nanoparticles (IgG-vc-DOX-NPs). In vivo tumor inhibition and survival tests showed that cetuximab-vc-DOX-NPs revealed higher tumor inhibition efficacy and lower systemic toxicity than control IgG-vc-DOX- NPs. Conclusion: The obtained results emphasize that cetuximab-vc-DOX-NPs, with good tumor-targeting ability and low systemic toxicity, are a promising targeting system for drug delivery.


Asunto(s)
Cetuximab/uso terapéutico , Citrulina/química , Neoplasias Colorrectales/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Receptores ErbB/metabolismo , Nanopartículas/química , Albúmina Sérica Bovina/química , Valina/química , Adsorción , Animales , Bovinos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Endocitosis/efectos de los fármacos , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Tamaño de la Partícula , Espectroscopía de Protones por Resonancia Magnética , Distribución Tisular/efectos de los fármacos
4.
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
5.
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
6.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-33919762

RESUMEN

The hemibiotrophic ascomycete fungus Colletotrichum gloeosporioides is the causal agent of anthracnose on numerous plants, and it causes considerable economic losses worldwide. Endocytosis is an essential cellular process in eukaryotic cells, but its roles in C. gloeosporioides remain unknown. In our study, we identified an endocytosis-related protein, CgEnd3, and knocked it out via polyethylene glycol (PEG)-mediated protoplast transformation. The lack of CgEnd3 resulted in severe defects in endocytosis. C. gloeosporioides infects its host through a specialized structure called appressorium, and ΔCgEnd3 showed deficient appressorium formation, melanization, turgor pressure accumulation, penetration ability of appressorium, cellophane membrane penetration, and pathogenicity. CgEnd3 also affected oxidant adaptation and the expression of core effectors during the early stage of infection. CgEnd3 contains one EF hand domain and four calcium ion-binding sites, and it is involved in calcium signaling. A lack of CgEnd3 changed the responses to cell-wall integrity agents and fungicide fludioxonil. However, CgEnd3 regulated appressorium formation and endocytosis in a calcium signaling-independent manner. Taken together, these results demonstrate that CgEnd3 plays pleiotropic roles in endocytosis, calcium signaling, cell-wall integrity, appressorium formation, penetration, and pathogenicity in C. gloeosporioides, and it suggests that CgEnd3 or endocytosis-related genes function as promising antifungal targets.


Asunto(s)
Colletotrichum/patogenicidad , Endocitosis , Proteínas Fúngicas/metabolismo , Enfermedades de las Plantas/microbiología , Populus/microbiología , Adaptación Fisiológica/efectos de los fármacos , Antifúngicos/farmacología , Señalización del Calcio/efectos de los fármacos , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Celofán , Colletotrichum/efectos de los fármacos , Colletotrichum/crecimiento & desarrollo , Colletotrichum/metabolismo , Dioxoles/farmacología , Endocitosis/efectos de los fármacos , Eliminación de Gen , Hifa/efectos de los fármacos , Melaninas/metabolismo , Oxidantes/toxicidad , Estrés Oxidativo/efectos de los fármacos , Hojas de la Planta/microbiología , Presión , Pirroles/farmacología , Virulencia/efectos de los fármacos
7.
Int J Nanomedicine ; 16: 2735-2749, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33859475

RESUMEN

Purpose: Nanocarriers, with a high drug loading content and good safety, to achieve desirable therapeutic effect are always the goals for industry and research. Methods and Results: In the present study, we developed a docetaxel loaded poly-2-oxazoline polymer micellar system which employed poly-2-butyl-2 oxazoline and poly-2-methyl-2 oxazoline as the hydrophobic chain and hydrophilic chain, respectively. This micellar system achieves a high load up to 25% against the docetaxel, and further demonstrates an IC50 as low as 40% of the commercialized docetaxel injection in vitro and a double maximum tolerated dose in MCF-7 cells in vivo. Conclusion: The high drug loading content, superior safety, and considerable anti-cancer activity make this newly developed docetaxel loaded poly(2-oxazoline) micelle go further in future clinical research.


Asunto(s)
Antineoplásicos/uso terapéutico , Docetaxel/uso terapéutico , Micelas , Neoplasias/tratamiento farmacológico , Oxazoles/química , Células A549 , Animales , Antineoplásicos/química , Apoptosis , Línea Celular Tumoral , Supervivencia Celular , Docetaxel/farmacología , Portadores de Fármacos/química , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Células MCF-7 , Masculino , Dosis Máxima Tolerada , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/patología , Tamaño de la Partícula , Tensoactivos/química , Distribución Tisular
8.
Nat Commun ; 12(1): 2174, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846342

RESUMEN

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvß3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.


Asunto(s)
Apoptosis , Artritis Reumatoide/patología , Inflamación/patología , Articulaciones/patología , Macrófagos/patología , Osteoclastos/patología , Animales , Artritis Reumatoide/diagnóstico por imagen , Huesos/diagnóstico por imagen , Huesos/patología , Endocitosis/efectos de los fármacos , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Articulaciones/diagnóstico por imagen , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Nanopartículas/química , Nanopartículas/ultraestructura , Oligopéptidos/química , Ratas , Membrana Sinovial/diagnóstico por imagen , Membrana Sinovial/patología , Distribución Tisular , Triterpenos , Microtomografía por Rayos X
9.
Int J Nanomedicine ; 16: 2761-2773, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33880022

RESUMEN

Purpose: The side effects of radiotherapy induced on healthy tissue limit its use. To overcome this issue and fully exploit the potential of radiotherapy to treat cancers, the first-in-class radioenhancer NBTXR3 (functionalized hafnium oxide nanoparticles) has been designed to amplify the effects of radiotherapy. Patients and Methods: Thanks to its physical mode of action, NBTXR3 has the potential to be used to treat any type of solid tumor. Here we demonstrate that NBTXR3 can be used to treat a wide variety of solid cancers. For this, we evaluated different parameters on a large panel of human cancer models, such as nanoparticle endocytosis, in vitro cell death induction, dispersion, and retention of NBTXR3 in the tumor tissue and tumor growth control. Results: Whatever the model considered, we show that NBTXR3 was internalized by cancer cells and persisted within the tumors throughout radiotherapy treatment. NBTXR3 activated by radiotherapy was also more effective in destroying cancer cells and in controlling tumor growth than radiotherapy alone. Beyond the effects of NBTXR3 as single agent, we show that the antitumor efficacy of cisplatin-based chemoradiotherapy treatment was improved when combined with NBTXR3. Conclusion: These data support that NBTXR3 could be universally used to treat solid cancers when radiotherapy is indicated, opening promising new therapeutic perspectives of treatment for the benefit of many patients.


Asunto(s)
Antineoplásicos/uso terapéutico , Hafnio/química , Nanopartículas/química , Neoplasias/radioterapia , Óxidos/química , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Terapia Combinada , Endocitosis/efectos de los fármacos , Humanos , Ratones Desnudos , Nanopartículas/administración & dosificación , Nanopartículas/ultraestructura , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Distribución Tisular/efectos de los fármacos , Resultado del Tratamiento
10.
Int J Nanomedicine ; 16: 2775-2787, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33880023

RESUMEN

Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment. Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation. Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9±1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96±1.88)% compared with (0.99±0.10)% in PBS group, revealing the enhanced immune response against PCa. Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.


Asunto(s)
Imidazoles/uso terapéutico , Verde de Indocianina/uso terapéutico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Endocitosis/efectos de los fármacos , Humanos , Verde de Indocianina/administración & dosificación , Rayos Láser , Masculino , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Nanopartículas/ultraestructura , Neoplasias de la Próstata/patología
11.
Int J Nanomedicine ; 16: 2789-2801, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33880024

RESUMEN

Objective: Gold nanorods (AuNRs) show great potential for versatile biomedical applications, such as stem cell therapy and bone tissue engineering. However, as an indispensable shape-directing agent for the growth of AuNRs, cetyltrimethylammonium bromide (CTAB) is not optimal for biological studies because it forms a cytotoxic bilayer on the AuNR surface, which interferes with the interactions with biological cells. Methods: Citrate-stabilized AuNRs with various aspect-ratios (Cit-NRI, Cit-NRII, and Cit-NRIII) were prepared by the combination of end-selective etching and poly(sodium 4-styrenesulfonate)-assisted ligand exchange method. Their effects on osteogenic differentiation of the pre-osteoblastic cell line (MC3T3-E1), rat bone marrow mesenchymal stem cells (rBMSCs), and human periodontal ligament progenitor cells (PDLPs) have been investigated. Potential signaling pathway of citrate-stabilized AuNRs-induced osteogenic effects was also investigated. Results: The experimental results showed that citrate-stabilized AuNRs have superior biocompatibility and undergo aspect-ratio-dependent osteogenic differentiation via expression of osteogenic marker genes, alkaline phosphatase (ALP) activity and formation of mineralized nodule. Furthermore, Wnt/ß-catenin signaling pathway might provide a potential explanation for the citrate-stabilized AuNRs-mediated osteogenic differentiation. Conclusion: These findings revealed that citrate-stabilized AuNRs with great biocompatibility could regulate the osteogenic differentiation of multiple cell types through Wnt/ß-catenin signaling pathway, which promote innovative AuNRs in the field of tissue engineering and other biomedical applications.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Ácido Cítrico/farmacología , Oro/farmacología , Nanotubos/química , Osteogénesis/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Animales , Calcificación Fisiológica/efectos de los fármacos , Células Cultivadas , Cetrimonio/farmacología , Endocitosis/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Nanotubos/ultraestructura , Osteogénesis/genética , Ligamento Periodontal/citología , Ratas , Tiazolidinas/farmacología , Vía de Señalización Wnt/efectos de los fármacos
12.
Int J Nanomedicine ; 16: 2615-2631, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33854311

RESUMEN

Background: Plumbagin, a naphthoquinone extracted from the officinal leadwort presenting promising anti-cancer properties, has its therapeutic potential limited by its inability to reach tumors in a specific way at a therapeutic concentration following systemic injection. The purpose of this study is to assess whether a novel tumor-targeted, lipid-polymer hybrid nanoparticle formulation of plumbagin would suppress the growth of B16-F10 melanoma in vitro and in vivo. Methods: Novel lipid-polymer hybrid nanoparticles entrapping plumbagin and conjugated with transferrin, whose receptors are present in abundance on many cancer cells, have been developed. Their cellular uptake, anti-proliferative and apoptosis efficacy were assessed on various cancer cell lines in vitro. Their therapeutic efficacy was evaluated in vivo after tail vein injection to mice bearing B16-F10 melanoma tumors. Results: The transferrin-bearing lipid-polymer hybrid nanoparticles loaded with plumbagin resulted in the disappearance of 40% of B16-F10 tumors and regression of 10% of the tumors following intravenous administration. They were well tolerated by the mice. Conclusion: These therapeutic effects, therefore, make transferrin-bearing lipid-polymer hybrid nanoparticles entrapping plumbagin a highly promising anti-cancer nanomedicine.


Asunto(s)
Lípidos/química , Melanoma Experimental/tratamiento farmacológico , Nanopartículas/química , Naftoquinonas/administración & dosificación , Naftoquinonas/uso terapéutico , Polímeros/química , Neoplasias Cutáneas/tratamiento farmacológico , Transferrina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cumarinas/farmacología , Cumarinas/uso terapéutico , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Humanos , Inyecciones Intravenosas , Melanoma Experimental/patología , Ratones Endogámicos BALB C , Naftoquinonas/farmacología , Neoplasias Cutáneas/patología , Tiazoles/farmacología , Tiazoles/uso terapéutico
13.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669839

RESUMEN

Despite Alzheimer's disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm "one target-one drug-one disease" in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn-ibuprofen drug combination into single-molecule "codrugs." Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn-ibuprofen conjugates (4-6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aß42-amyloid self-aggregation, and their cellular neuroprotective effect against Aß42-induced neurotoxicity. The fact that 6 effectively reduced Aß-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aß42-expressing Drosophila and to improve fly locomotor performance.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cromolin Sódico/uso terapéutico , Ibuprofeno/uso terapéutico , Polifarmacología , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromolin Sódico/síntesis química , Cromolin Sódico/química , Cromolin Sódico/farmacología , Drosophila/efectos de los fármacos , Diseño de Fármacos , Endocitosis/efectos de los fármacos , Ibuprofeno/síntesis química , Ibuprofeno/química , Ibuprofeno/farmacología , Inmunomodulación/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Agregado de Proteínas/efectos de los fármacos , Ratas Wistar
14.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672484

RESUMEN

Polystyrene (PS) nanoplastic exposure has been shown to affect the viability of neuronal cells isolated from mouse embryonic brains. However, the viability of mouse embryonic fibroblasts (MEFs) was not affected although PS nanoplastics accumulated in the cytoplasm. It is currently unknown whether MEFs do not respond to PS nanoplastics or their cellular functions are altered without compromising viability. Here, we found that PS nanoplastics entered the cells via endocytosis and were then released into the cytoplasm, probably by endosomal escape, or otherwise remained in the endosome. Oxidative and inflammatory stress caused by intracellular PS nanoplastics induced the antioxidant response pathway and activated the autophagic pathway. However, colocalization of the autophagic marker LC3B and PS nanoplastics suggested that PS nanoplastics in the cytoplasm might interfere with normal autophagic function. Furthermore, autophagic flux could be impaired, probably due to accumulation of PS nanoplastic-containing lysosomes or autolysosomes. Intriguingly, the level of accumulated PS nanoplastics decreased during prolonged culture when MEFs were no longer exposed to PS nanoplastics. These results indicate that accumulated PS nanoplastics are removed or exported out of the cells. Therefore, PS nanoplastics in the cytoplasm affect cellular functions, but it is temporal and MEFs can overcome the stress caused by PS nanoplastic exposure.


Asunto(s)
Embrión de Mamíferos/patología , Fibroblastos/patología , Microplásticos/toxicidad , Nanopartículas/toxicidad , Poliestirenos/toxicidad , Estrés Fisiológico , Animales , Autofagia/efectos de los fármacos , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Endocitosis/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Espacio Intracelular/metabolismo , Ratones , Estrés Fisiológico/efectos de los fármacos
15.
Nat Nanotechnol ; 16(3): 266-276, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33712737

RESUMEN

Endocytosis is a critical step in the process by which many therapeutic nanomedicines reach their intracellular targets. Our understanding of cellular uptake mechanisms has developed substantially in the past five years. However, these advances in cell biology have not fully translated to the nanoscience and therapeutics literature. Misconceptions surrounding the role of different endocytic pathways and how to study these pathways are hindering progress in developing improved nanoparticle therapies. Here, we summarize the latest insights into cellular uptake mechanisms and pathways. We highlight limitations of current systems to study endocytosis, particularly problems with non-specific inhibitors. We also summarize alternative genetic approaches to robustly probe these pathways and discuss the need to understand how cells endocytose particles in vivo. We hope that this critical assessment of the current methods used in studying nanoparticle uptake will guide future studies at the interface of cell biology and nanomedicine.


Asunto(s)
Sistemas de Liberación de Medicamentos , Endocitosis/genética , Nanomedicina/tendencias , Nanopartículas/uso terapéutico , Transporte Biológico/genética , Endocitosis/efectos de los fármacos , Humanos , Terapia Molecular Dirigida/tendencias
16.
Int J Nanomedicine ; 16: 2123-2136, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33731994

RESUMEN

Purpose: Nanomaterial-based drug-delivery systems allowing for effective targeted delivery of smallmolecule chemodrugs to tumors have revolutionized cancer therapy. Recently, as novel nanomaterials with outstanding physicochemical properties, boron nitride nanospheres (BNs) have emerged as a promising candidate for drug delivery. However, poor dispersity and lack of tumor targeting severely limit further applications. In this study, cancer cell-membrane biomimetic BNs were designed for targeted anticancer drug delivery. Methods: Cell membrane extracted from HeLa cells (HM) was used to encapsulate BNs by physical extrusion. Doxorubicin (Dox) was loaded onto HM-BNs as a model drug. Results: The cell-membrane coating endowed the BNs with excellent dispersibility and cytocompatibility. The drug-release profile showed that the Dox@HM-BNs responded to acid pH, resulting in rapid Dox release. Enhanced cellular uptake of Dox@HM-BNs by HeLa cells was revealed because of the homologous targeting of cancer-cell membranes. CCK8 and live/dead assays showed that Dox@HM-BNs had stronger cytotoxicity against HeLa cells, due to self-selective cellular uptake. Finally, antitumor investigation using the HeLa tumor model demonstrated that Dox@HM-BNs possessed much more efficient tumor inhibition than free Dox or Dox@BNs. Conclusion: These findings indicate that the newly developed HM-BNs are promising as an efficient tumor-selective drug-delivery vehicle for tumor therapy.


Asunto(s)
Materiales Biomiméticos/química , Compuestos de Boro/química , Membrana Celular/patología , Terapia Molecular Dirigida , Nanosferas/química , Neoplasias/patología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Ratones Endogámicos BALB C , Nanosferas/ultraestructura , Neoplasias/tratamiento farmacológico , Espectrometría por Rayos X , Distribución Tisular/efectos de los fármacos
17.
Int J Nanomedicine ; 16: 1575-1586, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33664572

RESUMEN

Background: Exosomes are a type of membrane vesicles secreted by living cells. Recent studies suggest exosome-like nanovesicles (ELNVs) from fruits and vegetables are involved in tissue renewal process and functional regulation against inflammatory diseases or cancers. However, there are few reports on ELNVs derived from medicinal plants. Methods: ELNVs derived from Asparagus cochinchinensis (Lour.) Merr. (ACNVs) were isolated and characterized. Cytotoxicity, antiproliferative and apoptosis-inducing capacity of ACNVs against hepatoma carcinoma cell were assessed. The endocytosis mechanism of ACNVs was evaluated on Hep G2 cells in the presence of different endocytosis inhibitors. In vivo distribution of ACNVs was detected in healthy and tumor-bearing mice after scavenger receptors (SRs) blockade. PEG engineering of ACNVs was achieved through optimizing the pharmacokinetic profiles. In vivo antitumor activity and toxicity were evaluated in Hep G2 cell xenograft model. Results: ACNVs were isolated and purified using a differential centrifugation method accompanied by sucrose gradient ultracentrifugation. The optimized ACNVs had an average size of about 119 nm and showed a typical cup-shaped nanostructure containing lipids, proteins, and RNAs. ACNVs were found to possess specific antitumor cell proliferation activity associated with an apoptosis-inducing pathway. ACNVs could be internalized into tumor cells mainly via phagocytosis, but they were quickly cleared once entering the blood. Blocking the SRs or PEGylation decoration prolonged the blood circulation time and increased the accumulation of ACNVs in tumor sites. In vivo antitumor results showed that PEGylated ACNVs could significantly inhibit tumor growth without side effects. Conclusion: This study provides a promising functional nano platform derived from edible Asparagus cochinchinensis that can be used in antitumor therapy with negligible side effects.


Asunto(s)
Asparagaceae/química , Carcinoma Hepatocelular/patología , Exosomas/metabolismo , Neoplasias Hepáticas/patología , Nanopartículas/química , Nanotecnología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/efectos adversos , Nanopartículas/ultraestructura , Polietilenglicoles/química , Distribución Tisular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Int J Nanomedicine ; 16: 1617-1630, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33688182

RESUMEN

Introduction: The clinical use of the antitumoral drug doxorubicin (Dox) is reduced by its dose-limiting toxicity, related to cardiotoxic side effects and myelosuppression. In order to overcome these drawbacks, here we describe the synthesis, the structural characterization and the in vitro cytotoxicity assays of hydrogels (HGs) and nanogels (NGs) based on short peptide sequences loaded with Dox or with its liposomal formulation, Doxil. Methods: Fmoc-FF alone or in combination with (FY)3 or PEG8-(FY)3 peptides, at two different ratios (1/1 and 2/1 v/v), were used for HGs and NGs formulations. HGs were prepared according to the "solvent-switch" method, whereas NGs were obtained through HG submicronition by the top-down methodology in presence of TWEEN®60 and SPAN®60 as stabilizing agents. HGs gelation kinetics were assessed by Circular Dichroism (CD). Stability and size of NGs were studied using Dynamic Light Scattering (DLS) measurements. Cell viability of empty and filled Dox HGs and NGs was evaluated on MDA-MB-231 breast cancer cells. Moreover, cell internalization of the drug was evaluated using immunofluorescence assays. Results: Dox filled hydrogels exhibit a high drug loading content (DLC=0.440), without syneresis after 10 days. Gelation kinetics (20-40 min) and the drug release (16-28%) over time of HGs were found dependent on relative peptide composition. Dox filled NGs exhibit a DLC of 0.137 and a low drug release (20-40%) after 72 h. Empty HGs and NGs show a high cell viability (>95%), whereas Dox loaded ones significantly reduce cell viability after 24 h (49-57%) and 72 h (7-25%) of incubation, respectively. Immunofluorescence assays evidenced a different cell localization for Dox delivered through HGs and NGs with respect to the free drug. Discussion: A modulation of the Dox release can be obtained by changing the ratios of the peptide components. The different cellular localization of the drug loaded into HGs and NGs suggests an alternative internalization mechanism. The high DLC, the low drug release and preliminary in vitro results suggest a potential employment of peptide-based HGs and NGs as drug delivery tools.


Asunto(s)
Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Hidrogeles/química , Nanogeles/química , Péptidos/química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Portadores de Fármacos/química , Liberación de Fármacos , Dispersión Dinámica de Luz , Endocitosis/efectos de los fármacos , Humanos
19.
Int J Nanomedicine ; 16: 1743-1755, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33688189

RESUMEN

Background: As a therapeutic target for cancer treatment, HSP90 has been explored extensively. However, the significant side effects of the HSP90 inhibitor 17AAG have limited its clinical use. Methods: In this study, we used hyaluronic acid (HA)-decorated DOTAP-PLGA hybrid nanoparticles (HA-DOTAP-PLGA NPs) as 17AAG-delivery carriers for targeted colon cancer therapy. Results: Different methods were used to characterize the successful fabrication of these hybrid PLGA NPs. Our results demonstrated that internalization of HA-NPs in colon cancer cells was governed by CD44receptor-mediated endocytosis. Annexin V-propidium iodide staining experiments revealed that cell apoptosis induced by HA-NPs-17AAG in colon cancer cells was more efficient than free 17AAG. In two animal models used to screen anticancer efficacy (Luc-HT29 subcutaneous xenograft and AOM/DSS-induced orthotopic tumor model), HA-NPs-17AAG significantly inhibited xenograft and orthotopic tumor growth, demonstrating HA-NPs-17AAG had much better therapeutic efficiency than free 17AAG. It is worth noting that great biocompatibility of HA-DOTAP-PLGA NPs was observed both in vitro and in vivo. Conclusion: Our research offers a preclinical proof of concept for colon cancer therapy with DOTAP-PLGA NPs as a creative drug-delivery system.


Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Ácido Hialurónico/química , Nanopartículas/química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzoquinonas/farmacología , Materiales Biocompatibles/química , Línea Celular Tumoral , Neoplasias del Colon/patología , Endocitosis/efectos de los fármacos , Ácidos Grasos Monoinsaturados/química , Fluorescencia , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Receptores de Hialuranos/metabolismo , Lactamas Macrocíclicas/farmacología , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/ultraestructura , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Compuestos de Amonio Cuaternario/química , Tejido Subcutáneo/efectos de los fármacos , Tejido Subcutáneo/patología
20.
Int J Nanomedicine ; 16: 1775-1787, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33692622

RESUMEN

Purpose: To avoid undefined metabolic mechanisms and to eliminate potential side effects of traditional nanocarriers, new green carriers are urgently needed in cancer treatment. Carrier-free nanoparticles (NPs) based on ursolic acid (UA) have attracted significant attention, but the UA NPs targeting the folate receptor have never been explored. We designed a novel self-assembled UA-Methotrexate (MTX) NPs targeting the folate-receptor and its synergetic anticancer activity was studied in vitro and in vivo. Methods: UA-MTX NPs were prepared using the solvent precipitation method. Characterization of the UA-MTX NPs preparation was performed using a size analyzer, transmission electron microscopy, and UV-vis spectrophotometry. The in vitro pH-responsive drug release capability of UA-MTX NPs was tested at different pH values. The UA-MTX NPs targeting of folates was determined by comparing the endocytosis rates of cell lines with low or overexpression of the folate receptor (A549 and MCF-7 cells). The cytotoxicity and cell apoptosis of UA-MTX NPs were also studied to determine the in vitro synergistic effects. Combination chemotherapy of UA-MTX NPs in vivo was evaluated using MCF-7 xenografted tumor models. Results: Compared with free UA or MTX, the water solubility of UA-MTX NPs improved significantly. Drug-release from the UA-MTX NPs was faster at pH 5.0 than pH 7.4, suggesting MTX-UA NPs could rapidly release MTX in the acidic conditions of the tumor microenvironment. Confocal laser scanning microscopy revealed the excellent folate receptor targeting of UA-MTX NPs in MCF-7 cells. Cytotoxicity and cell apoptosis results demonstrated greater antiproliferative capacity of UA-MTX NPs than that of free drug in folate receptor overexpressing MCF-7 cells. Anticancer effects in vivo suggested MTX-UA NPs exhibited good biological safety and could enhance antitumor efficacy due to the combination therapy. Conclusion: Our findings indicate that the UA-MTX NPs targeting folate-receptors is an efficient strategy for combination chemotherapy.


Asunto(s)
Antineoplásicos/farmacología , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Receptores de Folato Anclados a GPI/metabolismo , Metotrexato/farmacología , Nanopartículas/química , Triterpenos/farmacología , Animales , Antineoplásicos/administración & dosificación , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Sinergismo Farmacológico , Endocitosis/efectos de los fármacos , Femenino , Ácido Fólico/química , Humanos , Células MCF-7 , Metotrexato/administración & dosificación , Metotrexato/química , Ratones Desnudos , Nanopartículas/ultraestructura , Ratas Wistar , Triterpenos/administración & dosificación , Triterpenos/química
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