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1.
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
2.
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
3.
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
4.
AAPS PharmSciTech ; 22(3): 115, 2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33763814

RESUMEN

Nanomedicine is a highly demanded discipline. Liposomes have seen an increased attention due to their physicochemical properties that allow them to act as nanocarriers of drugs and also of radioisotopes that can be used to diagnose and treat cancer. In order to obtain a novel permeability cancer imaging agent based on 99mTc-labeled liposomes, we describe microwave-assisted synthesis of stearyl 6-(benzylidenehydrazinyl) nicotinamide lipid, which was included in two formulations: nanometric hydrazinonicotinic acid (HYNIC) liposome and its PEGylated coated analogue, HYNIC-PEG liposome. Radiolabeling with 99mTc via stearyl 6-(benzylidenehydrazinyl) nicotinamide was found to be easy, reproducible, and stable, revealing high radiochemical purity (94 ± 1.7%) for both liposomal formulations. Biodistribution at 4 h and 24 h and scintigraphic images at 4 h were performed in normal and melanoma-bearing C57BL/6 mice. Biodistribution studies at 4 h showed tumor uptake of 99mTc-HYNIC liposome and 99mTc-HYNIC-PEG liposome (1.1 ± 0.6 and 2.5 ± 0.4, respectively) and also at 24 h p.i. (1.8 ± 0.5 and 3.0 ± 1.1, respectively). Scintigraphic images showed appreciable tumor uptake in melanoma tumor-bearing mice with both liposomal formulations. Our results show that 99mTc stearyl 6-(benzylidenehydrazinyl) nicotinamide liposomes can be used as diagnostic noninvasive in vivo tumor-targeting agents capable of evaluating tumor permeability and development who can be used in personalized chemotherapy planning.


Asunto(s)
Melanoma Experimental/metabolismo , Niacinamida/farmacocinética , Radiofármacos/farmacocinética , Tecnecio/farmacocinética , Animales , Línea Celular Tumoral , Liposomas , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Niacinamida/administración & dosificación , Niacinamida/química , Permeabilidad/efectos de los fármacos , Cintigrafía/métodos , Radiofármacos/administración & dosificación , Radiofármacos/química , Tecnecio/administración & dosificación , Tecnecio/química , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiología
5.
Int J Nanomedicine ; 16: 2283-2295, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33776433

RESUMEN

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


Asunto(s)
Ácido Fólico/química , Paclitaxel/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Liberación de Fármacos , Humanos , Iminas/química , Concentración 50 Inhibidora , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/patología , Paclitaxel/sangre , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Tamaño de la Partícula , Polietilenglicoles/química , Polietilenos/química , Ratas , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Succinatos/química , Distribución Tisular/efectos de los fármacos
6.
Int J Nanomedicine ; 16: 1405-1422, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33658780

RESUMEN

Aim: Iridoid glycosides (IG) as the major active fraction of Syringa oblata Lindl. has a proven anti-inflammatory effect for ulcerative colitis (UC). However, its current commercial formulations are hampered by low bioavailability and unable to reach inflamed colon. To overcome the limitation, dual functional IG-loaded nanoparticles (DFNPs) were prepared to increase the residence time of IG in colon. The protective mechanism of DFNPs on DSS-induced colonic injury was evaluated in rats. Materials and Methods: We prepared DFNPs using the oil-in-water emulsion method. PLGA was selected as sustained-release polymer, and ES100 and EL30D-55 as pH-responsive polymers. The morphology and size distribution of NPs were measured by SEM and DLS technique. To evaluate colon targeting of DFNPs, DiR, was encapsulated as a fluorescent probe into NPs. Fluorescent distribution of NPs were investigated. The therapeutic potential and in vivo transportation of NPs in gastrointestinal tract were evaluated in a colitis model. Results: SEM images and zeta data indicated the successful preparation of DFNPs. This formulation exhibited high loading capacity. Drug release results suggested DFNPs released less than 20% at the first 6 h in simulated gastric fluid (pH1.2) and simulated small intestine fluid (pH6.8). A high amount of 84.7% sustained release from NPs in simulated colonic fluid (pH7.4) was beyond 24 h. DiR-loaded NPs demonstrated a much higher colon accumulation, suggesting effective targeting due to functionalization with pH and time-dependent polymers. DFNPs could significantly ameliorate the colonic damage by reducing DAI, macroscopic score, histological damage and cell apoptosis. Our results also proved that the potent anti-inflammatory effect of DFNPs is contributed by decrease of NADPH, gene expression of COX-2 and MMP-9 and the production of TNF-α, IL-17, IL-23 and PGE2. Conclusion: We confirm that DFNPs exert protective effects through inhibiting the inflammatory response, which could be developed as a potential colon-targeted system.


Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Colon/patología , Glicósidos Iridoides/uso terapéutico , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ácidos Polimetacrílicos/química , Animales , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Colon/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Sulfato de Dextran , Liberación de Fármacos , Fluorescencia , Concentración de Iones de Hidrógeno , Glicósidos Iridoides/sangre , Glicósidos Iridoides/farmacocinética , Glicósidos Iridoides/farmacología , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos ICR , NADPH Oxidasas/metabolismo , Nanopartículas/ultraestructura , Tamaño de la Partícula , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Distribución Tisular/efectos de los fármacos
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: 1869-1888, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33716502

RESUMEN

Background and Purpose: Around 40-50% of diffuse large-B cell lymphoma (DLBCL) patients suffer from refractory disease or relapse after R-CHOP first-line treatment. Many ongoing clinical trials for DLBCL patients involve microtubule targeting agents (MTAs), however, their anticancer activity is limited by severe side effects. Therefore, we chose to improve the therapeutic window of the MTA monomethyl auristatin E developing a nanoconjugate, T22-AUR, that selectively targets the CXCR4 receptor, which is overexpressed in many DLBCL cells (CXCR4+) and associated with poor prognosis. Methods: The T22-AUR specificity towards CXCR4 receptor was performed by flow cytometry in different DLBCL cell lines and running biodistribution assays in a subcutaneous mouse model bearing CXCR4+ DLBCL cells. Moreover, we determined T22-AUR cytotoxicity using cell viability assays, cell cycle analysis, DAPI staining and immunohistochemistry. Finally, the T22-AUR antineoplastic effect was evaluated in vivo in an extranodal CXCR4+ DLBCL mouse model whereas the toxicity analysis was assessed by histopathology in non-infiltrated mouse organs and by in vitro cytotoxic assays in human PBMCs. Results: We demonstrate that the T22-AUR nanoconjugate displays CXCR4-dependent targeting and internalization in CXCR4+ DLBCL cells in vitro as well as in a subcutaneous DLBCL mouse model. Moreover, it shows high cytotoxic effect in CXCR4+ DLBCL cells, including induction of G2/M mitotic arrest, DNA damage, mitotic catastrophe and apoptosis. Furthermore, the nanoconjugate shows a potent reduction in lymphoma mouse dissemination without histopathological alterations in non-DLBCL infiltrated organs. Importantly, T22-AUR also exhibits lack of toxicity in human PBMCs. Conclusion: T22-AUR exerts in vitro and in vivo anticancer effect on CXCR4+ DLBCL cells without off-target toxicity. Thus, T22-AUR promises to become an effective therapy for CXCR4+ DLBCL patients.


Asunto(s)
Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Nanoconjugados/uso terapéutico , Oligopéptidos/uso terapéutico , Receptores CXCR4/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Endocitosis/efectos de los fármacos , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/patología , Linfoma de Células B Grandes Difuso/genética , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Oligopéptidos/farmacología , Transducción de Señal/efectos de los fármacos , Tejido Subcutáneo/efectos de los fármacos , Tejido Subcutáneo/patología , Distribución Tisular/efectos de los fármacos
9.
Int J Nanomedicine ; 16: 1943-1960, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727808

RESUMEN

Introduction: The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC. Methods: Firstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was 99mTc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1:8 Hc-TZ) was evaluated in vivo by PET and supported by MS-based proteomics profiling of tumors. Results: SiNPs-TZ (1:8 Hc-TZ) tumor uptake was significantly greater than that of SiNPs-TZ (1:2 Hc-TZ) at 6 hours post-injection (p.i.) in ex vivo biodistribution experiment. At 24 h p.i., radioactivity values remained steady. Fluorescence microscopy, confirmed the presence of radiolabeled SiNPs-TZ (1:8 Hc-TZ) within tumor even at later times. SiNPs-TZ (1:8 Hc-TZ) nanoparticles loaded with Doxorubicin (DOX-SiNPs-TZ) showed a similar DOX delivery capability than Caelyx (at 6 h p.i.), in in vitro and ex vivo assays. Nevertheless, at the end of treatment, tumor volume was significantly reduced by DOX-SiNPs-TZ (1:8 Hc-TZ), compared to Caelyx and DOX-SiNPs treatment. Proteomics study identified 88 high stringent differentially expressed proteins comparing the three treatment groups with controls. Conclusion: These findings demonstrated a promising detection specificity and treatment efficacy for our system (SiNPs-TZ, 1:8 Hc-TZ), encouraging its potential use as a new theranostic agent for HER2-positive BC lesions. In addition, proteomic profile confirmed that a set of proteins, related to tumor aggressiveness, were positively affected by targeted nanoparticles.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Portadores de Fármacos/química , Nanopartículas/química , Radiofármacos/química , Receptor ErbB-2/metabolismo , Dióxido de Silicio/química , Tecnecio/química , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Endocitosis , Femenino , Fluoresceína-5-Isotiocianato/química , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Proteoma/metabolismo , Proteómica , Radiofármacos/farmacocinética , Tecnecio/farmacocinética , Distribución Tisular/efectos de los fármacos , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento
10.
Int J Nanomedicine ; 16: 1961-1976, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727809

RESUMEN

Introduction: Metastatic breast cancer seriously harms women's health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects. Methods: The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds. Results: The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis. Conclusion: The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Nanopartículas/química , ARN Interferente Pequeño/administración & dosificación , Dióxido de Silicio/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/uso terapéutico , Doxorrubicina/farmacología , Portadores de Fármacos/química , Endocitosis/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Invasividad Neoplásica , Metástasis de la Neoplasia , Oxidación-Reducción , Porosidad , ARN Interferente Pequeño/farmacología , Distribución Tisular/efectos de los fármacos
11.
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
12.
Int J Nanomedicine ; 16: 2187-2201, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33758506

RESUMEN

The physicochemical and optical properties of silver nanoparticles (SNPs) and gold nanoparticles (GNPs) have allowed them to be employed for various biomedical applications, including delivery, therapy, imaging, and as theranostic agents. However, since they are foreign body systems, they are usually redistributed and accumulated in some vital organs, which can produce toxic effects; therefore, this a crucial issue that should be considered for potential clinical trials. This review aimed to summarize the reports from the past ten years that have used SNPs and GNPs for in vivo studies on the diagnosis and treatment of brain diseases and those related to the central nervous system, emphasizing their toxicity as a crucial topic address. The article focuses on the effect of the nanoparticle´s size and chemical composition as relevant parameters for in vivo toxicity. At the beginning of this review, the general toxicity and distribution studies are discussed separately for SNPs and GNPs. Subsequently, this manuscript analyzes the principal applications of both kinds of nanoparticles for glioma, neurodegenerative, and other brain diseases, and discusses the advances in clinical trials. Finally, we analyze research prospects towards clinical applications for both types of metallic nanoparticles.


Asunto(s)
Enfermedades del Sistema Nervioso Central/patología , Oro/química , Nanopartículas del Metal/química , Nanopartículas del Metal/toxicidad , Tamaño de la Partícula , Plata/química , Pruebas de Toxicidad , Animales , Humanos , Nanopartículas del Metal/ultraestructura , Distribución Tisular/efectos de los fármacos
13.
Nat Commun ; 12(1): 898, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563973

RESUMEN

Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.


Asunto(s)
Tolerancia a Radiación , Proteína p53 Supresora de Tumor/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de la radiación , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Int J Nanomedicine ; 16: 1175-1187, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33623381

RESUMEN

Purpose: Although the neutrophil membrane (NM)-based nanoparticulate delivery system has exhibited rapid advances in tumor targeting stemmed from the inherited instinct, the antitumor effect requires further improvement due to inefficient cellular internalization in the absence of specific interactions between NM-coated nanoparticles and tumor cells. Methods: Herein, we fabricated drug-paclitaxel loaded NM camouflaging nanoparticles (TNM-PN) modified with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), favorable for the cellular internalization. Results: The results showed that TNM-PN exerted a significant cytotoxicity to tumor cells by TRAIL-mediated endocytosis and strong adhesion to inflamed endothelial cells in vitro. Due to TRAIL modification as well as the adhesive interactions between neutrophil and inflamed tumor vascular endothelial cells, tumors in TNM-PN group exhibited almost 2-fold higher fluorescence intensities than that of NM camouflaging nanoparticles and 3-fold higher than that of bare nanoparticles, respectively. Significant tumor inhibition and survival rates of mice were achieved in TNM-PN group as a consequence of prolonged blood circulations to 48 h and preferential tumor accumulations, which was ascribed to targeting adhesion originated from NM to immune evasion and subsequent excellent cellular internalization. Conclusion: The research unveiled a novel strategy of amplifying cellular internalization based on NM coating nanotechnology to boost antitumor efficacy.


Asunto(s)
Membrana Celular/metabolismo , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Nanotecnología/métodos , Neoplasias/tratamiento farmacológico , Neutrófilos/citología , Albúminas/farmacología , Albúminas/uso terapéutico , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Humanos , Evasión Inmune/efectos de los fármacos , Inflamación/patología , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/ultraestructura , Neoplasias/patología , Neutrófilos/efectos de los fármacos , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Células RAW 264.7 , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Distribución Tisular/efectos de los fármacos
15.
Nat Commun ; 12(1): 1124, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602928

RESUMEN

Clay-based nanomaterials, especially 2:1 aluminosilicates such as vermiculite, biotite, and illite, have demonstrated great potential in various fields. However, their characteristic sandwiched structures and the lack of effective methods to exfoliate two-dimensional (2D) functional core layers (FCLs) greatly limit their future applications. Herein, we present a universal wet-chemical exfoliation method based on alkali etching that can intelligently "capture" the ultrathin and biocompatible FCLs (MgO and Fe2O3) sandwiched between two identical tetrahedral layers (SiO2 and Al2O3) from vermiculite. Without the sandwich structures that shielded their active sites, the obtained FCL nanosheets (NSs) exhibit a tunable and appropriate electron band structure (with the bandgap decreased from 2.0 eV to 1.4 eV), a conductive band that increased from -0.4 eV to -0.6 eV, and excellent light response characteristics. The great properties of 2D FCL NSs endow them with exciting potential in diverse applications including energy, photocatalysis, and biomedical engineering. This study specifically highlights their application in cancer theranostics as an example, potentially serving as a prelude to future extensive studies of 2D FCL NSs.


Asunto(s)
Silicatos de Aluminio/química , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/terapia , Nanomedicina Teranóstica , Animales , Antineoplásicos/farmacología , Células Hep G2 , Humanos , Luz , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Neoplasias/patología , Fotoquimioterapia , Polietilenglicoles/química , Especies Reactivas de Oxígeno/química , Temperatura , Distribución Tisular/efectos de los fármacos
16.
Int J Nanomedicine ; 16: 683-700, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33536754

RESUMEN

Purpose: To develop an externally triggered rapid-release targeted system for treating ovarian cancer, gemcitabine (GMC) was entrapped into sonosensitive (SoS) folate (Fo)-modified liposomes (LPs). Methods: GMC-loaded LPs (GMC LPs), GMC-loaded Fo-targeted LPs (GMC-Fo LPs), and GMC-loaded Fo-targeted SoS LPs (GMC-SoS Fo LPs) were prepared utilizing a film-hydration technique and evaluated based on particle size, ζ-potential, and percentage entrapped drug. Cellular uptake of the fluorescent delivery systems in Fo-expressing ovarian cancer cells was quantified using flow cytometry. Finally, tumor-targeting ability, in vivo evaluation, and pharmacokinetic studies were performed. Results: GMC LPs, GMC-Fo LPs, and GMC-SoS Fo LPs were successfully prepared, with sizes of <120.3±2.4 nm, 39.7 mV ζ-potential, and 86.3%±1.84% entrapped drug. Cellular uptake of GMC-SoS Fo LPs improved 6.51-fold over GMC LPs (under ultrasonic irradiation - p<0.05). However, cellular uptake of GMC-Fo LPs improved just 1.24-fold over GMC LPs (p>0.05). Biodistribution study showed that of GMC concentration in tumors treated with GMC-SoS-Fo LPs (with ultrasound) improved 2.89-fold that of free GMC (p<0.05). In vivo, GMC-SoS Fo LPs showed the highest antiproliferative and antitumor action on ovarian cancer. Conclusion: These findings showed that externally triggered rapid-release SoS Fo-modified LPs are a promising system for delivering rapid-release drugs into tumors.


Asunto(s)
Desoxicitidina/análogos & derivados , Ácido Fólico/química , Ultrasonido , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Desoxicitidina/farmacología , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Humanos , Liposomas , Neoplasias Ováricas/sangre , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Tamaño de la Partícula , Ratas Sprague-Dawley , Distribución Tisular/efectos de los fármacos
17.
Am J Physiol Endocrinol Metab ; 320(3): E641-E652, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33427052

RESUMEN

Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (n = 7) and ADI-PEG20 treated (n = 8) pigs during the postprandial period. In addition, blood pressure was monitored by telemetry, and multiple tissues were collected to determine arginine concentration. Plasma arginine was depleted immediately after ADI-PEG20 administration, with an increase in plasma citrulline concentration (P < 0.01). The depletion of arginine did not affect (P > 0.10) blood pressure, whole body protein synthesis, or urea production. Despite the lack of circulating arginine in ADI-PEG20-treated pigs, most tissues were able to maintain concentrations similar (P > 0.10) to those in Control animals. The kinetics of citrulline and arginine indicated the high citrulline turnover and regeneration of arginine through the citrulline recycling pathway. ADI-PEG20 administration resulted in an absolute and almost instantaneous depletion of circulating arginine, thus reducing global availability without affecting cardiovascular parameters and protein metabolism. The citrulline produced from the deimination of arginine was in turn utilized by the citrulline recycling pathway restoring local tissue arginine availability.NEW & NOTEWORTHY Pegylated arginine deiminase depletes circulating arginine, but the citrulline generated is utilized by multiple tissues to regenerate arginine and sustain local arginine availability. Preempting the arginine depletion that occurs as result of sepsis and trauma with arginine deiminase offers the possibility of maintaining tissue arginine availability despite negligible plasma arginine concentrations.


Asunto(s)
Arginina/sangre , Arginina/farmacocinética , Hidrolasas/farmacología , Polietilenglicoles/farmacología , Animales , Disponibilidad Biológica , Citrulina/sangre , Femenino , Cinética , Masculino , Porcinos , Distribución Tisular/efectos de los fármacos
18.
Int J Nanomedicine ; 15: 10183-10197, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33363374

RESUMEN

Purpose: Nanoparticle (NP)-based chemo-photothermal therapy (CPT) has been shown to be a promising non-invasive approach for antitumor treatment. However, NPs must overcome the limitations of opsonization, clearance of the reticuloendothelial system, and ineffective targeting of tumor tissue sites. To solve these problems, stem cell membrane (SCM)-camouflaged polydopamine nanoparticles (PDA@SCM NPs) carrying the hydrophobic anticancer drug 7-ethyl-10-hydroxycamptothecin (SN38) were constructed for CPT of malignant bone tumors. Methods: We developed umbilical-cord mesenchymal stem cell membrane-coated polydopamine nanoparticles encapsulating SN38 (PDA-SN38@SCM NPs) as an efficient tumor-targeting drug-delivery platform for CPT of malignant bone tumors. We characterized PDA@SCM NPs and evaluated the biocompatibility and anti-phagocytosis properties of PDA@SCM NPs. The antitumor activity of PDA-SN38@SCM NPs was evaluated in MG63 lines and an MG63 xenograft model in mice. Results: Synthesized PDA-SN38@SCM NPs retained an excellent photothermal effect after SN38 loading. The drug release of PDA-SN38@SCM NPs could be triggered by near-infrared irradiation and an acidic stimulus. PDA@SCM NPs exhibited lower nonspecific macrophage uptake, longer retention in blood, and more effective accumulation at tumor sites than that shown by PDA NPs. Confocal laser scanning microscopy (CLSM) and flow cytometry showed that MG63 cells took up more PDA-SN38@SCM NPs than PDA-SN38 NPs. In vitro and in vivo antitumor studies demonstrated the outstanding performance of PDA-SN38@SCM NPs in synergistic CPT for bone tumors. Conclusion: PDA-SN38@SCM NPs demonstrated an extraordinary synergistic CPT effect and could be a promising strategy for the treatment of malignant bone tumors.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas/terapia , Membrana Celular/metabolismo , Indoles/química , Nanopartículas/química , Polímeros/química , Células Madre/metabolismo , Animales , Antineoplásicos/farmacología , Materiales Biocompatibles/química , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Línea Celular Tumoral , Liberación de Fármacos , Femenino , Humanos , Evasión Inmune/efectos de los fármacos , Irinotecán/farmacocinética , Irinotecán/farmacología , Irinotecán/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Células RAW 264.7 , Distribución Tisular/efectos de los fármacos
19.
Int J Nanomedicine ; 15: 6385-6399, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32922007

RESUMEN

Purpose: The mononuclear phagocyte system (MPS) presents a formidable obstacle that hampers the delivery of various nanopreparations to tumors. Therefore, there is an urgent need to improve the off-MPS targeting ability of nanomedicines. In the present study, we present a novel preconditioning strategy to substantially increase the circulation times and tumor targeting of nanoparticles by regulating nanocarrier-MPS interactions. Methods: In vitro, the effect of different vacuolar H+-ATPase inhibitors on macrophage uptake of targeted or nontargeted lipid vesicles was evaluated. Specifically, the clinically approved proton-pump inhibitor esomeprazole (ESO) was selected as a preconditioning agent. Then, we further investigated the blocking effect of ESO on the macrophage endocytosis of nanocarriers. In vivo, ESO was first intravenously administered into A549-tumor-bearing nude mice, and 24 h later, the c(RGDm7)-modified vesicles co-loaded with doxorubicin and gefitinib were intravenously injected. Results: In vitro, ESO was found to reduce the interactions between macrophages and c(RGDm7)-modified vesicles by interfering with the latter's lysosomal trafficking. Studies conducted in vivo confirmed that ESO pretreatment greatly decreased the liver and spleen distribution of the targeted vesicles, enhanced their tumor accumulation, and improved the therapeutic outcome of the drug-loaded nanomedicines. Conclusion: Our findings indicate that ESO can regulate the nanoparticle-MPS interaction, which provides a feasible option for enhancing the off-MPS targeting of nanomedicines.


Asunto(s)
Portadores de Fármacos/química , Esomeprazol/farmacología , Sistema Mononuclear Fagocítico/citología , Nanopartículas/química , Células A549 , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transporte Biológico , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Endocitosis , Esomeprazol/farmacocinética , Esomeprazol/uso terapéutico , Humanos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Células MCF-7 , Ratones , Ratones Desnudos , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Células RAW 264.7 , Distribución Tisular/efectos de los fármacos , ATPasas de Translocación de Protón Vacuolares/metabolismo
20.
AAPS PharmSciTech ; 21(6): 234, 2020 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-32794077

RESUMEN

We investigated the pharmacokinetics of nimodipine (NMD) in rats plasma and tissues following intraocular (io), intragastric (ig), and intravenous (iv) administration at doses of 5.0 mg/kg io and iv and 10.0 mg/kg ig. After a single dose of NMD, plasma, heart, liver, spleen, lung, kidney, and brain samples were collected at the scheduled time points. The concentration of NMD in rat plasma and tissues was determined by high-performance liquid chromatography, and the main pharmacokinetic parameters were calculated and compared. NMD was rapidly absorbed and reached the maximum plasma concentration in approximately 5 min after io administration. The absolute bioavailability after io administration was higher than that after ig administration (40.05% vs. 5.67%). There were significant differences in the tissue distribution of NMD with different administration routes. After io administration, NMD was distributed more in the lung, spleen, and brain tissues, and less in the kidney. The maximum drug concentration after io administration in the heart, liver, spleen, lung, kidney, and brain was 1.00, 0.47, 2.02, 1.47, 0.22, and 5.79 times higher than that after via ig administration, and the area under the curve value was 0.59, 0.78, 1.71, 1.84, 0.25, and 4.59 times greater, respectively. Nimodipine appears to achieve systemic effects via io administration. Compared with ig, io administration could significantly increase NMD distribution in the brain tissue, indicating that NMD could be delivered to the brain via io administration.


Asunto(s)
Encéfalo/metabolismo , Inyecciones Intraoculares/métodos , Nimodipina/administración & dosificación , Nimodipina/sangre , Administración Intravenosa , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/sangre , Antihipertensivos/farmacocinética , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Nimodipina/farmacocinética , Ratas , Ratas Sprague-Dawley , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiología
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