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1.
Nat Commun ; 12(1): 1689, 2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33727548

RESUMEN

Administration of drugs via the buccal route has attracted much attention in recent years. However, developing systems with satisfactory adhesion under wet conditions and adequate drug bioavailability still remains a challenge. Here, we propose a mussel-inspired mucoadhesive film. Ex vivo models show that this film can achieve strong adhesion to wet buccal tissues (up to 38.72 ± 10.94 kPa). We also demonstrate that the adhesion mechanism of this film relies on both physical association and covalent bonding between the film and mucus. Additionally, the film with incorporated polydopamine nanoparticles shows superior advantages for transport across the mucosal barrier, with improved drug bioavailability (~3.5-fold greater than observed with oral delivery) and therapeutic efficacy in oral mucositis models (~6.0-fold improvement in wound closure at day 5 compared with that observed with no treatment). We anticipate that this platform might aid the development of tissue adhesives and inspire the design of nanoparticle-based buccal delivery systems.


Asunto(s)
Biomimética , Bivalvos/química , Sistemas de Liberación de Medicamentos , Mucosa Bucal/fisiología , Adhesividad , Administración Bucal , Animales , Línea Celular , Dexametasona/farmacología , Dihidroxifenilalanina/química , Liberación de Fármacos , Humanos , Indoles/toxicidad , Masculino , Mucinas/química , Moco/química , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/toxicidad , Polímeros/toxicidad , Alcohol Polivinílico/química , Alcohol Polivinílico/toxicidad , Ratas Sprague-Dawley , Espectrofotometría Ultravioleta , Porcinos , Distribución Tisular
2.
Sci Adv ; 7(12)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33741598

RESUMEN

Vaccination against SARS-CoV-2 provides an effective tool to combat the COVID-19 pandemic. Here, we combined antigen optimization and nanoparticle display to develop vaccine candidates for SARS-CoV-2. We first displayed the receptor-binding domain (RBD) on three self-assembling protein nanoparticle (SApNP) platforms using the SpyTag/SpyCatcher system. We then identified heptad repeat 2 (HR2) in S2 as the cause of spike metastability, designed an HR2-deleted glycine-capped spike (S2GΔHR2), and displayed S2GΔHR2 on SApNPs. An antibody column specific for the RBD enabled tag-free vaccine purification. In mice, the 24-meric RBD-ferritin SApNP elicited a more potent neutralizing antibody (NAb) response than the RBD alone and the spike with two stabilizing proline mutations in S2 (S2P). S2GΔHR2 elicited twofold higher NAb titers than S2P, while S2GΔHR2 SApNPs derived from multilayered E2p and I3-01v9 60-mers elicited up to 10-fold higher NAb titers. The S2GΔHR2-presenting I3-01v9 SApNP also induced critically needed T cell immunity, thereby providing a promising vaccine candidate.


Asunto(s)
/inmunología , Nanopartículas , Glicoproteína de la Espiga del Coronavirus , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , /química , /farmacología , Células HEK293 , Humanos , Inmunogenicidad Vacunal , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/uso terapéutico , Dominios Proteicos , /inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/farmacología
3.
Int J Nanomedicine ; 16: 2107-2121, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33737808

RESUMEN

Purpose: Although anti-programmed cell death protein 1 antibody (aPD1) immunotherapy and chemotherapy has made much progress in the treatment of melanoma, the efficacy still needs to be further improved. Methods: Cancer treatment has been greatly enhanced by the use of nanotechnology. Cancer cell membrane (CCM)-camouflaged nanoparticles have shown promising potential in tumor therapy due to their excellent homologous-targeting ability, long blood circulation and immune escape. This work presents a biocompatible and tumor acidic environmental responsive CCM-camouflaged mesoporous silica nanoparticle (CMSN) that is loaded with dacarbazine (DTIC) and combined with aPD1 to achieve better antitumor efficacy. Results: In vitro cell experiments demonstrated that DTIC@CMSN exhibits a better anti-tumor killing efficiency and a stronger ability to promote the apoptosis of tumor cells than free DTIC. In vivo antitumor results demonstrated that combination therapy of DTIC@CMSN chemotherapy and aPD1 immunotherapy remarkably suppress the melanoma growth and prolong survival time due to highly selective tumor killing, activation of tumor-specific T cells, and regulation of the immunosuppressive tumor microenvironment. In addition, safety evaluation studies of DTIC@CMSN also demonstrate their increased tumor accumulation and decreased systemic toxicity. Conclusion: This study provides a promising nano-platform for the combination of chemotherapy with immunotherapy, which is potentially useful for the treatment of melanoma.


Asunto(s)
Antineoplásicos/farmacología , Membrana Celular/patología , Nanopartículas/química , Dióxido de Silicio/química , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Terapia Combinada , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones Endogámicos C57BL , Tamaño de la Partícula , Porosidad , Electricidad Estática
4.
Int J Nanomedicine ; 16: 2147-2171, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33746512

RESUMEN

The use of fluorescence imaging technique for visualization, resection and treatment of cancerous tissue, attained plenty of interest once the promise of whole body and deep tissue near-infrared (NIR) imaging emerged. Why is NIR so desired? Contrast agents with optical properties in the NIR spectral range offer an upgrade for the diagnosis and treatment of cancer, by dint of the deep tissue penetration of light in the NIR region of the electromagnetic spectrum, also known as the optical window in biological tissue. Thus, the development of a new generation of NIR emitting and absorbing contrast agents able to overcome the shortcomings of the basic free dye administration is absolutely essential. Several examples of nanoparticles (NPs) have been successfully implemented as carriers for NIR dye molecules to the tumour site owing to their prolonged blood circulation time and enhanced accumulation within the tumour, as well as their increased fluorescence signal relative to free fluorophore emission and active targeting of cancerous cells. Due to their versatile structure, good biocompatibility and capability to efficiently load dyes and bioconjugate with diverse cancer-targeting ligands, the research area of developing protein-based NPs encapsulated or conjugated with NIR dyes is highly promising but still in its infancy. The current review aims to provide an up-to-date overview on the biocompatibility, specific targeting and versatility offered by protein-based NPs loaded with different classes of NIR dyes as next-generation fluorescent agents. Moreover, this study brings to light the newest and most relevant advances involving the state-of-the-art NIR fluorescent agents for the real-time interventional NIR fluorescence imaging of cancer in clinical trials.


Asunto(s)
Colorantes/química , Retroalimentación , Rayos Infrarrojos , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/cirugía , Proteínas/química , Animales , Fluorescencia , Humanos
5.
Int J Nanomedicine ; 16: 2173-2186, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33758505

RESUMEN

Background: Colon cancer is a top lethal cancer in man and women worldwide and drug resistance is the major cause of cancer-related death. Combinational therapy and drug delivery with nanoparticles have been shown to effectively overcome drug resistance in many cancers. We previously reported that nanoemulsion (NE) loaded paclitaxel (PTX) and BEZ235 could synergistically inhibit colon cancer cell growth. Purpose: To investigate whether NE loaded PTX and BEZ235 can overcome drug resistance and synergistically inhibit drug-resistant colon cancer cell growth in vitro and in vivo. Methods: The in vitro treatment effect on cell viability was assayed using CCK8 kit, cell morphological change was detected by ß-tubulin immunofluorescence staining, drug resistance-related proteins were analyzed by Western blotting, and in vivo tumor growth test was performed in nude mice xeno-transplanted with 2 drug-resistant colon cancer cell lines HCT116-LOHP and HT29-DDP. Results: Both cell lines were sensitive to PTX but relatively insensitive to BEZ235. PTX combined with BEZ235 synergistically inhibited the proliferation of both cell lines. Nanoemulsion loaded PTX (NE-PTX) reduced the IC50 of PTX to approximately 2/5 of free PTX, indicating a high inhibitory efficacy of NE-PTX. When NE-PTX combined with a low concentration of BEZ235 (50 nM), the IC50 was decreased to approximately 2/3 of free PTX. Moreover, NE-PTX+BEZ235 treatment increased apoptosis, decreased Pgp and ABCC1 expression, and reduced tumor weights compared to the single drug treatment and the control group. These results suggest that nanoemulsion loaded PTX+BEZ235 can overcome drug resistance and improve the inhibitory effect on cancer cell proliferation and tumor growth. Conclusion: Our study thus provides a possible new approach to treat colon cancer patients with drug resistance.


Asunto(s)
Apoptosis , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos , Imidazoles/uso terapéutico , Nanopartículas/química , Paclitaxel/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Quinolinas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Recuento de Células , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Neoplasias del Colon/patología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Emulsiones/química , Femenino , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Paclitaxel/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Quinolinas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Nat Commun ; 12(1): 1436, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664241

RESUMEN

Acute kidney injury (AKI) is a prevalent and lethal adverse event that severely affects cancer patients receiving chemotherapy. It is correlated with the collateral damage to renal cells caused by reactive oxygen species (ROS). Currently, ROS management is a practical strategy that can reduce the risk of chemotherapy-related AKI, but at the cost of chemotherapeutic efficacy. Herein, we report catalytic activity tunable ceria nanoparticles (CNPs) that can prevent chemotherapy-induced AKI without interference with chemotherapeutic agents. Specifically, in the renal cortex, CNPs exhibit catalytic activity that decomposes hydrogen peroxide, and subsequently regulate the ROS-involved genes by activating the Nrf2/Keap1 signaling pathway. These restore the redox homeostasis for the protection of kidney tubules. Under an acidic tumor microenvironment, CNPs become inert due to the excessive H+ that disrupts the re-exposure of active catalytic sites, allowing a buildup of chemotherapy-mediated ROS generation to kill cancer cells. As ROS-modulating agents, CNPs incorporated with context-dependent catalytic activity, hold a great potential for clinical prevention and treatment of AKI in cancer patients.


Asunto(s)
Lesión Renal Aguda/prevención & control , Antineoplásicos/efectos adversos , Cerio/farmacología , Túbulos Renales/patología , Especies Reactivas de Oxígeno/metabolismo , Células A549 , Animales , Antineoplásicos/uso terapéutico , Dominio Catalítico , Línea Celular Tumoral , Cerio/química , Femenino , Células Hep G2 , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Interferencia de ARN , ARN Interferente Pequeño/genética , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral
7.
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
8.
Int J Nanomedicine ; 16: 1663-1680, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33688184

RESUMEN

Background: Intracellular tension plays a crucial role in the destruction of the blood-brain barrier (BBB) in response to lesion stimuli. Tight junction structure could be primarily affected by tension activity. In this study, we aimed to determine the effects of extracellular BBB damage on intracellular tension activity, and elucidate the mechanism underlying the effects of intracellular protein nanoparticle-related osmotic pressure on BBB permeability. Methods: The intracellular tension for tight junction proteins occludin and ZO1 was evaluated using the fluorescence resonance energy transfer (FRET)-based tension probes and cpstFRET analysis. The changes in mobility ratios of occludin were evaluated via the fluorescence recovery after photobleaching (FRAP) test. The cytoplasmic osmotic pressure (OP) was measured using Osmometer. The count rate of cytoplasmic nanoparticles was detected by Nanosight NS300. The activation of cofilin and stathmin was examined by Western blot analysis. The BBB permeability in vivo was determined via the changes of Evans Blue (EB) injected into SD rats. The tight junction formation was assessed by the measurement of transendothelial electrical resistance (TEER). Intracellular calcium or chloride ions were measured using Fluo-4 AM or MQAE dyes. Results: BBB lesions were accompanied by changes in occludin/ZO1 tension. Increases in intracellular osmotic pressure were involved in alteration of BBB permeability, possibly through the depolymerization of microfilaments or microtubules and mass production of protein nanoparticles according to the Donnan effect. Recovery of protein nanoparticle-related osmotic pressure could effectively reverse the effects of changes in occludin/ZO1 tension under BBB lesions. Outward tension of intracellular osmotic potential also caused upregulation of membrane fluidity, which promoted nonselective drug influx. Conclusion: Our results suggest a crucial mechanical mechanism underlying BBB lesions, and protein nanoparticle-related osmotic pressure could be a novel therapeutic target for BBB lesion-related brain diseases.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Fluidez de la Membrana , Nanopartículas/química , Presión Osmótica , Proteínas/química , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Línea Celular , Azul de Evans/metabolismo , Humanos , Masculino , Fluidez de la Membrana/efectos de los fármacos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Ocludina/metabolismo , Presión Osmótica/efectos de los fármacos , Permeabilidad , Fitoquímicos/farmacología , Polimerizacion , Ratas Sprague-Dawley , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Proteína de la Zonula Occludens-1/metabolismo
9.
Int J Nanomedicine ; 16: 1709-1724, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33688187

RESUMEN

Background: Manganese Ferrite Nanoparticles (Mn-IONPs) are widely used in biomedical field and their cytotoxicity has been initially explored, but the mechanism remains obscure. The nano-bio interactions are believed to be crucial for cytotoxicity mechanism, while little data have been acquired. Methods: Mn-IONPs were synthesized by thermal decomposition of acetylacetonate precursor. After physicochemical characterization, we analyzed the metabolic conversion and removal of Mn-IONPs in RAW264.7 cells by Prussian blue staining, TEM, HRTEM and elemental quantitative analysis, followed by gene expression evaluation using quantitative RT-PCR. Results: Mn-IONPs were successfully synthesized. Both the uptake and cytotoxicity of Mn-IONPs on RAW264.7 cells were time- and dose-dependent. After internalized, Mn-IONPs were passed to daughter cells with passages on. Meanwhile, Mn-IONPs were exocytosed and digested to metal ions and further excreted out, resulted in the labeling rate and ions contents decreased gradually. As ion influx related genes, the expressions of ZIP14, IRP2, FtH and DMT1 were suppressed within 24 hours but overexpressed to a plateau at the 48th hour in a dose-dependent manner. At the 72nd hour, ZIP14 and DMT1 mRNA levels decreased toward normal, while IRP2 and FtH kept up-regulated. As efflux related genes, FPN, SLC30A10 and Hamp2 genes were up-regulated within 24-72 hours; SPCA1 was suppressed at the 24th and 72nd hour, while overexpressed at the 48th hour. All the efflux related genes' mRNA had a dose-dependent increasing manner at the corresponding time points. Conclusion: Mn-IONPs showed time- and dose-dependent cytotoxicity and cell labeling rate in RAW264.7 cells. Accompanying with the intracellular catabolic breakdown and exocytosis of Mn-IONPs, RAW264.7 cells also secreted and re-uptook manganese and iron ions to maintain intracellular homeostasis in the succeeding passages. And the metabolic conversion of Mn-IONPs in RAW264.7 cells can affect the expression of ZIP14, DMT1, FPN, SLC30A10, IRP2, FtH, Hamp2 and SPCA1 genes.


Asunto(s)
Proteínas de Transporte de Catión/genética , Compuestos Férricos/metabolismo , Regulación de la Expresión Génica , Compuestos de Manganeso/metabolismo , Nanopartículas/química , Animales , Proteínas de Transporte de Catión/metabolismo , Muerte Celular/genética , Proliferación Celular/genética , Ratones , Nanopartículas/ultraestructura , Tamaño de la Partícula , Células RAW 264.7
10.
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
11.
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
12.
Int J Nanomedicine ; 16: 1819-1836, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33707942

RESUMEN

Background: The development of vaccines is a promising and cost-effective strategy to prevent emerging multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections. The purpose of this study was to prepare a multiepitope peptide nanovaccine and evaluate its immunogenicity and protective effect in BALB/c mice. Methods: The B-cell and T-cell epitopes of Omp22 from A. baumannii were predicted using bioinformatics methods and identified by immunological experiments. The optimal epitopes were conjugated in series by 6-aminocaproic acid and chemically synthesized multiepitope polypeptide rOmp22. Then, rOmp22 was encapsulated by chitosan (CS) and poly (lactic-co-glycolic) acid (PLGA) to prepare CS-PLGA-rOmp22 nanoparticles (NPs). The immunogenicity and immunoprotective efficacy of the vaccine were evaluated in BALB/c mice. Results: CS-PLGA-rOmp22 NPs were small (mean size of 272.83 nm) with apparently spherical structures, positively charged (4.39 mV) and nontoxic to A549 cells. A high encapsulation efficiency (54.94%) and a continuous slow release pattern were achieved. Compared with nonencapsulated rOmp22, CS-PLGA-rOmp22 immunized BALB/c mice induced higher levels of rOmp22-specific IgG in serum and IFN-γ in splenocyte supernatant. Additionally, lung injury and bacterial burdens in the lung and blood were suppressed, and potent protection (57.14%-83.3%) against acute lethal intratracheal A. baumannii challenge was observed in BALB/c mice vaccinated with CS-PLGA-rOmp22. Conclusion: CS-PLGA-rOmp22 NPs elicited specific IgG antibodies, Th1 cellular immunity and protection against acute lethal intratracheal A. baumannii challenge. Our results indicate that this nanovaccine is a desirable candidate for preventing A. baumannii infection.


Asunto(s)
Infecciones por Acinetobacter/inmunología , Acinetobacter baumannii/inmunología , Vacunas Bacterianas/inmunología , Quitosano/química , Epítopos/inmunología , Nanopartículas/química , Péptidos/inmunología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Células A549 , Infecciones por Acinetobacter/sangre , Infecciones por Acinetobacter/microbiología , Secuencia de Aminoácidos , Animales , Anticuerpos Antibacterianos/inmunología , Carga Bacteriana , Peso Corporal , Epítopos/química , Femenino , Humanos , Inmunidad Humoral , Inmunización , Inmunoglobulina G/inmunología , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Nanopartículas/ultraestructura , Péptidos/química , Proteínas Recombinantes/aislamiento & purificación , Bazo/patología , Análisis de Supervivencia
13.
Int J Nanomedicine ; 16: 1849-1867, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33707943

RESUMEN

Background: With the development of bacterial resistance, the range of effective antibiotics is increasingly becoming more limited. The effective use of nanoscale antimicrobial peptides (AP) in therapeutic and diagnostic methods is a strategy for new antibiotics. Methods: Combining both AP and cadmium selenide (CdSe) into a composite material may result in a reagent with novel properties, such as enhanced antibacterial activity, fluorescence and favorable stability in aqueous solution. Results: AP-loaded CdSe NPs (AP-CdSe NPs) showed strong antibacterial activity against multidrug-resistant (MDR) Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) in vitro and in vivo. Colony-forming unit (CFU) and minimum inhibitory concentration (MIC) assays showed that AP-CdSe NPs have highly effective antibacterial activity. The quantitative analysis of apoptosis by flow cytometry analysis further confirmed that MDR E. coli and S. aureus treated with AP-CdSe NPs had death rates of 98.76% and 99.13%, respectively. Also, AP-CdSe NPs was found to inhibit bacterial activity in an in vivo bacteremia model in mice infected with S. aureus. In addition, the antibacterial mechanism of AP-CdSe NPs was determined by RNA sequencing analysis. Gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed the molecular mechanism of the antibacterial effect of AP-CdSe NPs. Importantly, histopathology analysis, and hematological toxicity analysis indicated that AP-CdSe NPs had few side effects. Conclusion: These results demonstrate that AP loaded on CdSe NPs had a higher water solubility, bioavailability and antibacterial effect compared with raw AP. This study reports findings that are helpful for the design and development of antibacterial treatment strategies based on AP.


Asunto(s)
Antibacterianos/farmacología , Compuestos de Cadmio/química , Luminiscencia , Nanopartículas/química , Proteínas Citotóxicas Formadoras de Poros/farmacología , Puntos Cuánticos/química , Compuestos de Selenio/química , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Bacteriemia/microbiología , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Endocitosis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/ultraestructura , Femenino , Perfilación de la Expresión Génica , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Ratones Desnudos , Pruebas de Sensibilidad Microbiana , Microscopía Fluorescente , Nanopartículas/ultraestructura , Proteínas Citotóxicas Formadoras de Poros/efectos adversos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/ultraestructura
14.
Int J Nanomedicine ; 16: 1889-1899, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33707944

RESUMEN

Introduction: Sonodynamic therapy (SDT) has good targeting and non-invasive advantages in the treatment of solid cancers, and checkpoint blockade immunotherapy is also a promising treatment to cure cancer. However, their antitumor effects are not sufficient due to some inherent factors. Some studies that combined SDT with immunotherapy or nanoparticles have managed to enhance its efficiency to treat cancers. Methods: In this work, an effective therapeutic strategy that can potentiate the antitumor efficacy of anti-PD-L1 antibody (aPD-L1) is developed by the use of cascade immuno-sonodynamic therapy (immuno-SDT). Titanium dioxide (TiO2), a nanostructured agent for SDT, sonosensitizer Chlorin e6 (Ce6), and immunological adjuvant CpG oligonucleotide (CpG ODN), are used to construct a multifunctional nanosonosensitizer (TiO2-Ce6-CpG). Then, we conducted in vitro and in vivo experiments to explore the antitumor effect of TiO2-Ce6-CpG under ultrasound (US) treatment. Results: The characterization tests showed that the nanosonosensitizers are polycrystalline structure with homogeneous sizes, resulting in a good drug loading efficiency. The innovative nanosonosensitizers (TiO2-Ce6-CpG) can not only effectively inhibit tumor growth but also stimulate the immune system to activate the adaptive immune responses, using the TiO2-Ce6 to augment SDT and the immune adjuvant CpG to enhance the immune response. After combined with the aPD-L1, the synergistic effect could not only efficiently inhibit the primary tumor growth but also lead to an inhibition of the non-irradiated pre-existing distant tumors by inducing a strong tumor-specific immune response. Conclusion: In this study, we present an effective strategy for tumor treatment by combining nanosonosensitizer-augmented SDT and aPD-L1 checkpoint blockade. This work provides a promising strategy and offers a new vision for treating malignant tumors.


Asunto(s)
/uso terapéutico , Inmunoterapia , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/terapia , Terapia por Ultrasonido , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Terapia Combinada , Células Dendríticas/efectos de los fármacos , Endocitosis/efectos de los fármacos , Femenino , Humanos , Inmunidad/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Neoplasias/patología , Oligodesoxirribonucleótidos/química , Porfirinas/química , Especies Reactivas de Oxígeno/metabolismo , Titanio/química
15.
Int J Nanomedicine ; 16: 1913-1926, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33707946

RESUMEN

Purpose: Immunologically quiescent of breast cancer cells has been recognized as the key impediment for the breast cancer immunotherapy. In this study, we aimed to investigate the role of nanoparticle-mediated sonodynamic therapy (SDT) in promoting anti-tumor immune of breast cancer cells and its potential immune mechanisms. Materials and Methods: The phase-transformation nanoparticles (LIP-PFH nanoparticles) were in-house prepared and its physiochemical characters were detected. The CCK-8 assay, apoptosis analysis and Balb/c tumor model establishment were used to explore the anti-tumor effect of LIP-PFH nanoparticles triggered by low-intensity focused ultrasound (LIFU) both in vitro and in vivo. Flow cytometry and immunohistochemistry of CD4+T, CD8+T, CD8+PD-1+T in blood, spleen and tumor tissue were performed to represent the change of immune response. Detection of immunogenic cell death (ICD) markers was examined to study the potential mechanisms. Results: LIP-PFH nanoparticles triggered by LIFU could inhibit the proliferation and promote the apoptosis of 4T1 cells both in vitro and in vivo. CD4+T and CD8+T cell subsets were significantly increased in blood, spleen and tumor tissue, meanwhile CD8+PD-1+T cells were reduced, indicating enhancement of anti-tumor immune response of breast cancer cells in the nanoparticle-mediated SDT group. Detection of ICD markers (ATP, high-mobility group box B1, and calreticulin) and flow cytometric analysis of dendritic cell (DC) maturity further showed that the nanoparticle-mediated SDT can promote DC maturation to increase the proportion of cytotoxic T cells by inducing ICD of breast cancer cells. Conclusion: The therapy of nanoparticles-mediated SDT can effectively enhance anti-tumor immune response of breast cancer.


Asunto(s)
Inmunidad , Muerte Celular Inmunogénica , Neoplasias Mamarias Animales/inmunología , Neoplasias Mamarias Animales/terapia , Nanopartículas/química , Terapia por Ultrasonido , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Células Dendríticas/metabolismo , Endocitosis , Femenino , Fluorocarburos/química , Inmunoterapia , Neoplasias Mamarias Animales/patología , Ratones , Ratones Endogámicos BALB C , Nanopartículas/ultraestructura , Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología
16.
Int J Nanomedicine ; 16: 1977-1992, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727810

RESUMEN

Background: Phytostanols are naturally occurring compounds that reduce blood cholesterol levels significantly. However, their aqueous insolubility poses formulation challenges. Aim: To formulate and characterize solid lipid nanoparticle carriers for phytostanol esters to enhance the bioavailability of phytostanols. Methods: Phytostanol ester solid lipid nanoparticles were formulated by the microemulsion method. They were characterized for particle size distribution, polydispersity index, shape, surface charge, entrapment efficiency, stability, chemical structure, and thermal properties. The uptake of the formulation by cell lines, HepG2 and HT-29, and its effect on cell viability were evaluated. Results: The formulation of solid lipid nanoparticles was successfully optimised by varying the type of lipids and their concentration relative to that of surfactants in the present study. The optimised formulation had an average diameter of (171 ± 9) nm, a negative surface charge of (-23.0 ± 0.8) mV and was generally spherical in shape. We report high levels of drug entrapment at (89 ± 5)% in amorphous form, drug loading of (9.1 ± 0.5)%, nanoparticle yield of (67 ± 4)% and drug excipient compatibility. The biological safety and uptake of the formulations were demonstrated on hepatic and intestinal cell lines. Conclusion: Phytostanol ester solid lipid nanoparticles were successfully formulated and characterized. The formulation has the potential to provide an innovative drug delivery system for phytostanols which reduce cholesterol and have a potentially ideal safety profile. This can contribute to better management of one of the main risk factors of cardiovascular diseases.


Asunto(s)
Composición de Medicamentos , Ésteres/química , Hipercolesterolemia/tratamiento farmacológico , Lípidos/química , Nanopartículas/química , Fitosteroles/uso terapéutico , Muerte Celular , Emulsiones/química , Endocitosis , Citometría de Flujo , Células HT29 , Células Hep G2 , Humanos , Tamaño de la Partícula , Polvos , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Temperatura
17.
Int J Nanomedicine ; 16: 2013-2044, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727812

RESUMEN

Background: Sulpiride (SUL), is a selective antidopaminergic drug that had extensive biological activities. However, its sparingly aqueous solubility and limited gastrointestinal permeability lead to scanty oral bioavailability which hinders its clinical efficacy. Objective: SUL-loaded lipospheres (SUL-LPS) were designed to serve as an oral biocompatible nanovector for improving SUL permeability as well as conquering its low oral absorption and then in turn enhancing its antidepressant action. Methods: SUL-LPS were fabricated via two processing techniques namely, melt emulsification and solvent evaporation. The impact of different lipid cores, phospholipid shells together with various surfactant concentrations and types on the lipospheres properties were screened. Detailed physicochemical elucidations were performed followed by ex vivo permeation appraisal using the non-everted intestine model. The pharmacokinetic parameters of SUL-LPS, free SUL and marketed product were assessed following oral administration to healthy rats. Reserpine-induced depression rat model was used to assess the antidepressant action of SUL-LPS on which full behavioural and biochemical analysis was conducted. Safety attributes of nanoencapsulated SUL on the brain and other internal organs were evaluated. Results: The optimum LPS revealed an excellent nanosize with a narrow PdI, negative zeta potential and acceptable entrapment efficiency of 68.62 nm, 0.242, -30.4 mV and 84.12%, respectively. SUL-LPS showed a sustained release pattern and 2.1-fold enhancement in the intestinal permeation parameters with low mucin interaction. Oral pharmacokinetic appraisal exhibited that LPS provided 3.4-fold improvement in SUL oral bioavailability together with long-circulating properties, relative to the free drug. Pharmacodynamic study confirmed the superior antidepressant action of SUL-LPS as evident by 1.6 and 1.25-fold elevation in the serotonin and dopamine expressions, respectively. Meanwhile, nanotoxicological appraisal proved the biocompatibility of SUL-LPS upon repetitive oral administration. Conclusion: Rationally designed lipospheres hold promising in vitro and in vivo characteristics for efficient delivery of SUL with high oral bioavailability, antidepressant activity together with a good safety profile.


Asunto(s)
Antidepresivos/farmacología , Lípidos/química , Nanopartículas/química , Sulpirida/administración & dosificación , Sulpirida/farmacología , Administración Oral , Animales , Materiales Biocompatibles/química , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Composición de Medicamentos , Liberación de Fármacos , Liofilización , Masculino , Mucinas/química , Nanopartículas/ultraestructura , Neurotransmisores/metabolismo , Especificidad de Órganos/efectos de los fármacos , Tamaño de la Partícula , Permeabilidad , Ratas Sprague-Dawley , Ratas Wistar , Sulpirida/química , Sulpirida/farmacocinética , Porcinos
18.
J Vis Exp ; (168)2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33645554

RESUMEN

Scanning electrochemical microscopy (SECM) is used to measure the local electrochemical behavior of liquid/solid, liquid/gas and liquid/liquid interfaces. Atomic force microscopy (AFM) is a versatile tool to characterize micro- and nanostructure in terms of topography and mechanical properties. However, conventional SECM or AFM provides limited laterally resolved information on electrical or electrochemical properties at nanoscale. For instance, the activity of a nanomaterial surface at crystal facet levels is difficult to resolve by conventional electrochemistry methods. This paper reports the application of a combination of AFM and SECM, namely, AFM-SECM, to probe nanoscale surface electrochemical activity while acquiring high-resolution topographical data. Such measurements are critical to understanding the relationship between nanostructure and reaction activity, which is relevant to a wide range of applications in material science, life science and chemical processes. The versatility of the combined AFM-SECM is demonstrated by mapping topographical and electrochemical properties of faceted nanoparticles (NPs) and nanobubbles (NBs), respectively. Compared to previously reported SECM imaging of nanostructures, this AFM-SECM enables quantitative assessment of local surface activity or reactivity with higher resolution of surface mapping.


Asunto(s)
Electroquímica/métodos , Microscopía de Fuerza Atómica , Microscopía Electroquímica de Rastreo , Nanoestructuras/ultraestructura , Cobre/química , Electrólitos/química , Nanopartículas/química , Nanopartículas/ultraestructura , Nanoestructuras/química , Oxidación-Reducción , Silicio/química , Programas Informáticos
19.
mBio ; 12(2)2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33653891

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the CoV disease 2019 (COVID-19) pandemic, enters host cells via the interaction of its receptor-binding domain (RBD) of the spike protein with host angiotensin-converting enzyme 2 (ACE2). Therefore, the RBD is a promising vaccine target to induce protective immunity against SARS-CoV-2 infection. In this study, we report the development of an RBD protein-based vaccine candidate against SARS-CoV-2 using self-assembling Helicobacter pylori-bullfrog ferritin nanoparticles as an antigen delivery system. RBD-ferritin protein purified from mammalian cells efficiently assembled into 24-mer nanoparticles. Sixteen- to 20-month-old ferrets were vaccinated with RBD-ferritin nanoparticles (RBD nanoparticles) by intramuscular or intranasal inoculation. All vaccinated ferrets with RBD nanoparticles produced potent neutralizing antibodies against SARS-CoV-2. Strikingly, vaccinated ferrets demonstrated efficient protection from SARS-CoV-2 challenge, showing no fever, body weight loss, or clinical symptoms. Furthermore, vaccinated ferrets showed rapid clearance of infectious virus in nasal washes and lungs as well as of viral RNA in respiratory organs. This study demonstrates that spike RBD-nanoparticles are an effective protein vaccine candidate against SARS-CoV-2.


Asunto(s)
/prevención & control , Nanopartículas/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Vacunas Virales/uso terapéutico , /química , Animales , Celulosa/química , Coronavirus/inmunología , Coronavirus/patogenicidad , Hurones , Ferritinas , Vacunas Virales/química
20.
Sci Transl Med ; 13(583)2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658355

RESUMEN

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.


Asunto(s)
Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Vacunas contra la Influenza/inmunología , Primates/inmunología , Animales , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/química , Complejo Antígeno-Anticuerpo/química , Anticuerpos ampliamente neutralizantes/biosíntesis , Anticuerpos ampliamente neutralizantes/química , Ferritinas/química , Ferritinas/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Humanos , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/química , Gripe Humana/inmunología , Gripe Humana/virología , Macaca fascicularis , Modelos Moleculares , Nanopartículas/química , Pandemias , Primates/virología , Estructura Cuaternaria de Proteína , Investigación en Medicina Traslacional
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