RESUMEN
Mesoporous silica nanoparticles (MSNs) have attracted extensive attention as drug delivery systems because of their unique meso-structural features (high specific surface area, large pore volume, and tunable pore structure), easily modified surface, high drug-loading capacity, and sustained-release profiles. However, the enduring and non-specific enrichment of MSNs in healthy tissues may lead to toxicity due to their slow degradability and hinder their clinical application. The emergence of degradable MSNs provided a solution to this problem. The understanding of strategies to regulate degradation and clearance of these MSNs for promoting clinical trials and expanding their biological applications is essential. Here, a diverse variety of degradable MSNs regarding considerations of physiochemical properties and doping strategies of degradation, the biodistribution of MSNs in vivo, internal clearance mechanism, and adjusting physical parameters of clearance are highlighted. Finally, an overview of these degradable and clearable MSNs strategies for biosafety is provided along with an outlook of the encountered challenges.
Asunto(s)
Nanopartículas , Dióxido de Silicio , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Porosidad , Nanopartículas/química , Humanos , Distribución Tisular , Animales , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Over the past few years, nanoparticles have drawn particular attention in designing and developing drug delivery systems due to their distinctive advantages like improved pharmacokinetics, reduced toxicity, and specificity. Along with other successful nanosystems, silica nanoparticles (SNPs) have shown promising effects for therapeutic and diagnostic purposes. These nanoparticles are of great significance owing to their modifiable surface with various ligands, tunable particle size, and large surface area. The rate and extent of degradation and clearance of SNPs depend on factors such as size, shape, porosity, and surface modification, which directly lead to varying toxic mechanisms. Despite SNPs' enormous potential for clinical and pharmaceutical applications, safety concerns have hindered their translation into the clinic. This review discusses the biodistribution, toxicity, and clearance of SNPs and the formulation-related factors that ultimately influence clinical efficacy and safety for treatment. A holistic view of SNP safety will be beneficial for developing an enabling SNP-based drug product.
Asunto(s)
Nanopartículas , Dióxido de Silicio , Distribución Tisular , Dióxido de Silicio/toxicidad , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/uso terapéutico , Sistemas de Liberación de Medicamentos , Nanopartículas/metabolismo , Resultado del Tratamiento , Portadores de FármacosRESUMEN
A food additive, silicon dioxide (SiO2) is commonly used in the food industry as an anti-caking agent. The presence of nanoparticles (NPs) in commercial food-grade SiO2 has raised concerns regarding their potential toxicity related to nano size. While recent studies have demonstrated the oral absorption and tissue distribution of food-additive SiO2 particles, limited information is available about their excretion behaviors and potential impact on macrophage activation. In this study, the excretion kinetics of two differently manufactured (fumed and precipitated) SiO2 particles were evaluated following repeated oral administration to rats for 28 d. The excretion fate of their intact particles, decomposed forms, or ionic forms was investigated in feces and urine, respectively. Monocyte uptake, Kupffer cell activation, and cytokine release were assessed after the oral administration of SiO2 particles. Additionally, their intracellular fates were determined in Raw 264.7 cells. The results revealed that the majority of SiO2 particles were not absorbed but directly excreted via feces in intact particle forms. Only a small portion of SiO2 was eliminated via urine, predominantly in the form of bioconverted silicic acid and slightly decomposed ionic forms. SiO2 particles were mainly present in particle forms inside cells, followed by ionic and silicic acid forms, indicating their slow conversion into silicic acid after cellular uptake. No effects of the manufacturing method were observed on excretion and fates. Moreover, no in vivo monocyte uptake, Kupffer cell polarization, or cytokine release were induced by orally administered SiO2 particles. These finding contribute to understanding the oral toxicokinetics of food-additive SiO2 and provide valuable insights into its potential toxicity.
Asunto(s)
Nanopartículas , Dióxido de Silicio , Ratas , Animales , Dióxido de Silicio/farmacocinética , Ácido Silícico , Aditivos Alimentarios , Activación de Macrófagos , Nanopartículas/toxicidad , Tamaño de la Partícula , CitocinasRESUMEN
The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with ß-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo.
Asunto(s)
Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Naftoquinonas/administración & dosificación , Neoplasias/tratamiento farmacológico , Estrés Oxidativo , Profármacos/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Quitosano/administración & dosificación , Quitosano/química , Quitosano/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Mitocondrias/fisiología , Nanopartículas/química , Naftoquinonas/química , Naftoquinonas/farmacocinética , Neoplasias/metabolismo , Neoplasias/patología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Oxidación-Reducción , Profármacos/química , Profármacos/farmacocinética , Especies Reactivas de Oxígeno/metabolismo , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Improving anti-cancer drug delivery performance can be achieved through designing smart and targeted drug delivery systems (DDSs). For this aim, it is important to evaluate overexpressed biomarkers in the tumor microenvironment (TME) for optimizing DDSs. MATERIALS AND METHODS: Herein, we designed a novel DDS based on magnetic mesoporous silica core-shell nanoparticles (SPION@MSNs) in which release of doxorubicin (DOX) at the physiologic pH was blocked with gold gatekeepers. In this platform, we conjugated heterofunctional polyethylene glycol (PEG) onto the outer surface of nanocarriers to increase their biocompatibility. At the final stage, an epithelial cell adhesion molecule (EpCAM) aptamer as an active targeting moiety was covalently attached (Apt-PEG-Au@NPs-DOX) for selective drug delivery to colorectal cancer (CRC) cells. The physicochemical properties of non-targeted and targeted nanocarriers were fully characterized. The anti-cancer activity, cellular internalization, and then the cell death mechanism of prepared nanocarriers were determined and compared in vitro. Finally, tumor inhibitory effects, biodistribution and possible side effects of the nanocarriers were evaluated in immunocompromised C57BL/6 mice bearing human HT-29 tumors. RESULTS: Nanocarriers were successfully synthesized with a mean final size diameter of 58.22 ± 8.54 nm. Higher cytotoxicity and cellular uptake of targeted nanocarriers were shown in the EpCAM-positive HT-29 cells as compared to the EpCAM-negative CHO cells, indicating the efficacy of aptamer as a targeting agent. In vivo results in a humanized mouse model showed that targeted nanocarriers could effectively increase DOX accumulation in the tumor site, inhibit tumor growth, and reduce the adverse side effects. CONCLUSION: These results suggest that corporation of a magnetic core, gold gatekeeper, PEG and aptamer can strongly improve drug delivery performance and provide a theranostic DDS for efficient CRC therapy.
Asunto(s)
Antineoplásicos , Neoplasias Colorrectales/metabolismo , Portadores de Fármacos , Nanopartículas , Dióxido de Silicio , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Células CHO , Cricetinae , Cricetulus , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Células HT29 , Humanos , Ratones , Ratones Endogámicos C57BL , Nanopartículas/química , Nanopartículas/metabolismo , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinéticaRESUMEN
Silica nanoparticles (SiO2 NPs) synthesized by the Stober method were used as drug delivery vehicles. Doxorubicin hydrochloride (DOX·HCl) is a chemo-drug absorbed onto the SiO2 NPs surfaces. The DOX·HCl loading onto and release from the SiO2 NPs was monitored via UV-VIS and fluorescence spectra. Alternatively, the zeta potential was also used to monitor and evaluate the DOX·HCl loading process. The results showed that nearly 98% of DOX·HCl was effectively loaded onto the SiO2 NPs' surfaces by electrostatic interaction. The pH-dependence of the process wherein DOX·HCl release out of DOX·HCl-SiO2 NPs was investigated as well. For comparison, both the free DOX·HCl molecules and DOX·HCl-SiO2 NPs were used as the labels for cultured cancer cells. Confocal laser scanning microscopy images showed that the DOX·HCl-SiO2 NPs were better delivered to cancer cells which are more acidic than healthy cells. We propose that engineered DOX·HCl-SiO2 systems are good candidates for drug delivery and clinical applications.
Asunto(s)
Antineoplásicos , Doxorrubicina , Portadores de Fármacos , Nanopartículas , Neoplasias , Dióxido de Silicio , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Humanos , Células MCF-7 , Microscopía Confocal , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/farmacologíaRESUMEN
Food additive amorphous silicon dioxide (SiO2) particles are manufactured by two different methods-precipitated and fumed procedures-which can induce different physicochemical properties and biological fates. In this study, precipitated and fumed SiO2 particles were characterized in terms of constituent particle size, hydrodynamic diameter, zeta potential, surface area, and solubility. Their fates in intestinal cells, intestinal barriers, and tissues after oral administration in rats were determined by optimizing Triton X-114-based cloud point extraction (CPE). The results demonstrate that the constituent particle sizes of precipitated and fumed SiO2 particles were similar, but their aggregate states differed from biofluid types, which also affect dissolution properties. Significantly higher cellular uptake, intestinal transport amount, and tissue accumulation of precipitated SiO2 than of fumed SiO2 was found. The intracellular fates of both types of particles in intestinal cells were primarily particle forms, but slowly decomposed into ions during intestinal transport and after distribution in the liver, and completely dissolved in the bloodstream and kidneys. These findings will provide crucial information for understanding and predicting the potential toxicity of food additive SiO2 after oral intake.
Asunto(s)
Intestinos/química , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/síntesis química , Administración Oral , Animales , Análisis Químico de la Sangre , Células CACO-2 , Línea Celular Tumoral , Precipitación Química , Femenino , Humanos , Intestinos/citología , Riñón/química , Hígado/química , Nanopartículas , Octoxinol/química , Tamaño de la Partícula , Ratas , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , SolubilidadRESUMEN
Nanomedicine has attracted increasing attention and emerged as a safer and more effective modality in cancer treatment than conventional chemotherapy. In particular, the distinction of tumor microenvironment and normal tissues is often used in stimulus-responsive drug delivery systems for controlled release of therapeutic agents at target sites. In this study, we developed mesoporous silica nanoparticles (MSNs) coated with polyacrylic acid (PAA), and pH-sensitive lipid (PSL) for synergistic delivery and dual-pH-responsive sequential release of arsenic trioxide (ATO) and paclitaxel (PTX) (PL-PMSN-PTX/ATO). Tumor-targeting peptide F56 was used to modify MSNs, which conferred a target-specific delivery to cancer and endothelial cells under neoangiogenesis. PAA- and PSL-coated nanoparticles were characterized by TGA, TEM, FT-IR, and DLS. The drug-loaded nanoparticles displayed a dual-pH-responsive (pHe = 6.5, pHendo = 5.0) and sequential drug release profile. PTX within PSL was preferentially released at pH = 6.5, whereas ATO was mainly released at pH = 5.0. Drug-free carriers showed low cytotoxicity toward MCF-7 cells, but ATO and PTX co-delivered nanoparticles displayed a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs. Furthermore, the extracellular release of PTX caused an expansion of the interstitial space, allowing deeper penetration of the nanoparticles into the tumor mass through a tumor priming effect. As a result, FPL-PMSN-PTX/ATO exhibited improved in vivo circulation time, tumor-targeted delivery, and overall therapeutic efficacy.
Asunto(s)
Antineoplásicos/uso terapéutico , Trióxido de Arsénico/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/uso terapéutico , Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/toxicidad , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Trióxido de Arsénico/farmacocinética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Cetrimonio/química , Cetrimonio/toxicidad , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células MCF-7 , Ratones Endogámicos ICR , Nanopartículas/toxicidad , Oligopéptidos/química , Oligopéptidos/farmacocinética , Oligopéptidos/toxicidad , Paclitaxel/química , Paclitaxel/farmacocinética , Porosidad , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/toxicidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Liver fibrosis, as a common and refractory disease, is challenging to treat due to the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4), which is expected to have good potential effects against liver fibrosis. However, IMB16-4 is water-insoluble and has very low bioavailability. METHODS: Mesoporous silica nanoparticles (MSNs) were selected as drug carriers for the purpose of increasing the dissolution of IMB16-4, as well as improving its oral bioavailability and inhibiting liver fibrosis. The physical states of IMB16-4 and IMB16-4-MSNs were investigated using nitrogen adsorption, thermogravimetric analysis (TGA), HPLC, UV-Vis, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). RESULTS: The results show that MSNs enhanced the dissolution rate of IMB16-4 significantly. IMB16-4-MSNs reduced cytotoxicity at high concentrations of IMB16-4 on human hepatic stellate cells LX-2 cells and improved oral bioavailability up to 530% compared with raw IMB16-4 on Sprague-Dawley (SD) rats. In addition, IMB16-4-MSNs repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers, including α-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-ß1) and matrix metalloproteinase-2 (MMP2) in LX-2 cells. CONCLUSIONS: These results provided powerful information on the use of IMB16-4-MSNs for the treatment of liver fibrosis in the future.
Asunto(s)
Antifibrinolíticos/administración & dosificación , Benzamidas/administración & dosificación , Cirrosis Hepática/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Actinas/metabolismo , Adsorción , Animales , Antifibrinolíticos/química , Antifibrinolíticos/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Portadores de Fármacos/química , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Nanopartículas/administración & dosificación , Nanopartículas/química , Nanopartículas/metabolismo , Porosidad , Ratas , Ratas Sprague-Dawley , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Solubilidad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Factor de Crecimiento Transformador beta1/metabolismo , Agua/química , Difracción de Rayos XRESUMEN
The combination of self-microemulsifying drug delivery system (SMEDDS) and mesoporous silica materials favors the oral delivery of poorly water-soluble drugs (PWSD). However, the influence of the surface property of the mesopores towards the drug release and in vivo pharmacokinetics is still unknown. In this study, SBA-15 with hydroxyl groups (SBA-15-H), methyl groups (SBA-15-M), amino groups (SBA-15-A), or carboxyl groups (SBA-15-C) was combined with SMEDDS containing sirolimus (SRL). The diffusion and self-emulsifying of SMEDDS greatly improved the drug release over the raw SRL and SRL-SBA-15-R (R referred to as the functional groups). Results of drug absorption and X-ray photoelectron spectroscopy (XPS) showed strong hydrogen binding between SRL and the amino groups of SBA-15-A, which hindered the drug release and oral bioavailability of SRL-SMEDDS-SBA-15-A. The favorable release of SRL-SMEDDS-SBA-15-C (91.31 ± 0.57%) and SRL-SMEDDS-SBA-15-M (91.76 ± 3.72%) contributed to enhancing the maximum blood concentration (Cmax) and the area under the concentration-time curve (AUC0â48). In conclusion, the release of SRL-SMEDDS-SBA-15-R was determined by the surface affinity of the SBA-15-R and the interaction between the SRL molecules and the surface of SBA-15-R. This study suggested that the SMEDDS-SBA-15 was a favorable carrier for PWSD, and the surface property of the mesopores should be considered for the optimization of the SMEDDS-SBA-15.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos/fisiología , Absorción Intestinal/fisiología , Sirolimus/administración & dosificación , Sirolimus/farmacocinética , Administración Oral , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Antibacterianos/farmacocinética , Disponibilidad Biológica , Perros , Emulsiones/administración & dosificación , Emulsiones/química , Emulsiones/farmacocinética , Absorción Intestinal/efectos de los fármacos , Masculino , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Sirolimus/química , Solubilidad , Propiedades de SuperficieRESUMEN
In this work we adapt rare-earth-ion-doped NaYF4nanoparticles coated with a silicon oxide shell (NaYF4:20%Yb,0.2%Tm@SiO2) for biological and medical applications (for example, imaging of cancer cells and therapy at the nano level). The wide upconversion emission range under 980 nm excitation allows one to use the nanoparticles for cancer cell (4T1) photodynamic therapy (PDT) without a photosensitizer. The reactive oxygen species (ROS) are generated by Tm/Yb ion upconversion emission (blue and UV light). Thein vitroPDT was tested on 4T1 cells incubated with NaYF4:20%Yb,0.2%Tm@SiO2nanoparticles and irradiated with NIR light. After 24 h, cell viability decreased to below 10%, demonstrating very good treatment efficiency. High modification susceptibility of the SiO2shell allows for attachment of biological molecules (specific antibodies). In this work we attached the anti-human IgG antibody to silane-PEG-NHS-modified NaYF4:20%Yb,0.2%Tm@SiO2nanoparticles and a specifically marked membrane model by bio-conjugation. Thus, it was possible to perform a selective search (a high-quality optical method with a very low-level organic background) and eventually damage the targeted cancer cells. The study focuses on therapeutic properties of NaYF4:20%Yb,0.2%Tm@SiO2nanoparticles and demonstrates, upon biological functionalization, their potential for targeted therapy.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Fármacos Fotosensibilizantes , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular Tumoral , Femenino , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/farmacología , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/farmacología , Tulio/química , Tulio/farmacocinética , Tulio/farmacología , Iterbio/química , Iterbio/farmacocinética , Iterbio/farmacología , Itrio/química , Itrio/farmacocinética , Itrio/farmacologíaRESUMEN
Interaction of conventional drug delivery systems such as polymeric or lipid based nano- and microparticles with the in vivo milieu has garnered significant interest, primarily to orchestrate immune escape and/or improve targeting. Surface modification with targeting ligands has been heavily relied upon for the mentioned purpose in the recent years. However, the surface modified particles can also activate the immune system. Large-scale manufacturing can also be a challenge, as surface modification needs to be reproducible. Furthermore, in vivo, the targeting is dependent on the receptor expression density and number of target sites, which adds to the pharmacokinetic variability of the constructs. An evolving paradigm to overcome complications of surface functionalization is the incorporation of bio-inspired topographies into these conventional delivery systems to enable them to better interact with biological systems. Biomimetic delivery systems combine the unique surface composition of cells or cell membranes, and versatility of synthetic nanoparticles. In this review, we focus on one such delivery system, silica particles, and explore their interaction with different biological membranes.
Asunto(s)
Antineoplásicos/administración & dosificación , Materiales Biomiméticos/química , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Dióxido de Silicio/química , Animales , Antineoplásicos/farmacocinética , Materiales Biomiméticos/farmacocinética , Membrana Celular/metabolismo , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Modelos Animales de Enfermedad , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Humanos , Nanopartículas/química , Dióxido de Silicio/farmacocinética , Propiedades de SuperficieRESUMEN
The human hair follicle (HF) represents a promising drug delivery target as an anatomical entity by itself, but also as a gateway enabling dermal or systemic bioavailability of active cosmetic and pharmaceutical ingredients. Due to its morphological characteristics, the HF provides a mechanically driven transport process of nanoparticles (NPs) when external forces are applied. This mechanism was presented as the so-called ratchet effect within the framework of an in silico study published recently. To investigate the influence of massage frequency on the penetration depth of NPs, and, by this, to validate the results obtained in silico, we implemented a corresponding application protocol on an ex vivo porcine skin model. In this connection, we compared three different skin massage frequencies (4.2 Hz, 50 Hz, 100 Hz) for the topical application of cyanine 5-labeled silica NPs (Cy5-SNPs). To elucidate the interplay of frequency and particle size, we furthermore applied Cy5-SNPs of three different diameters (300 nm, 676 nm, 1000 nm). Confocal laser scanning microscopy was utilized to investigate the follicular penetration depth of Cy5-SNPs on cryohistological slices. By this, we could demonstrate that the massage frequency and the follicular penetration depth exhibit an inverse relation pattern. Thus, the highest follicular penetration depth was observed within the 4.2 Hz group, while the lowest follicular penetration depth was found within the 100 Hz group for each Cy5-SNP size category. Additionally, we found that 676 nm Cy5-SNPs penetrated significantly deeper into HFs than 300 nm Cy5-SNPs and 1000 nm Cy5-SNPs, respectively. Summarizing, our results show that a low massage frequency including a dominant radial direction component leads to deeper follicular penetration depths of NPs than automated 3D-oscillation massage at 50 Hz or 100 Hz. Thus, our findings are in line with recent in silico results. Regarding translational purposes, our results are of high interest, since a massage executed at 250BPM (4.2 Hz) is within a realizable range for manual application, e.g. for the implementation into clinical routines or the domestic use of drugs or cosmetics. Furthermore, the application of different massage frequencies offers the opportunity of patho-specific targeting as different anatomical parts of the HF can be reached.
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Portadores de Fármacos/farmacocinética , Folículo Piloso/metabolismo , Masaje/métodos , Dióxido de Silicio/farmacocinética , Piel/metabolismo , Administración Cutánea , Animales , Portadores de Fármacos/administración & dosificación , Masaje/instrumentación , Nanopartículas/administración & dosificación , Dióxido de Silicio/administración & dosificación , Absorción Cutánea , PorcinosRESUMEN
The rise of antibiotic resistance and the growing number of biofilm-related infections make bacterial infections a serious threat for global human health. Nanomedicine has entered into this scenario by bringing new alternatives to design and develop effective antimicrobial nanoweapons to fight against bacterial infection. Among them, mesoporous silica nanoparticles (MSNs) exhibit unique characteristics that make them ideal nanocarriers to load, protect and transport antimicrobial cargoes to the target bacteria and/or biofilm, and release them in response to certain stimuli. The combination of infection-targeting and stimuli-responsive drug delivery capabilities aims to increase the specificity and efficacy of antimicrobial treatment and prevent undesirable side effects, becoming a ground-breaking alternative to conventional antibiotic treatments. This review focuses on the scientific advances developed to date in MSNs for infection-targeted stimuli-responsive antimicrobials delivery. The targeting strategies for specific recognition of bacteria are detailed. Moreover, the possibility of incorporating anti-biofilm agents with MSNs aimed at promoting biofilm penetrability is overviewed. Finally, a comprehensive description of the different scientific approaches for the design and development of smart MSNs able to release the antimicrobial payloads at the infection site in response to internal or external stimuli is provided.
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Antibacterianos , Bacterias/crecimiento & desarrollo , Infecciones Bacterianas/tratamiento farmacológico , Fenómenos Fisiológicos Bacterianos/efectos de los fármacos , Biopelículas/efectos de los fármacos , Portadores de Fármacos , Nanopartículas , Dióxido de Silicio , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/patología , Biopelículas/crecimiento & desarrollo , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/uso terapéutico , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapéutico , Liberación de Fármacos , Humanos , Nanopartículas/química , Nanopartículas/uso terapéutico , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/uso terapéuticoRESUMEN
Magnetic iron oxide containing MCM-41 silica (MM) with ~300 nm particle size was developed. The MM material before or after template removal was modified with NH2- or COOH-groups and then grafted with PEG chains. The anticancer drug tamoxifen was loaded into the organic groups' modified and PEGylated nanoparticles by an incipient wetness impregnation procedure. The amount of loaded drug and the release properties depend on whether modification of the nanoparticles was performed before or after the template removal step. The parent and drug-loaded samples were characterized by XRD, N2 physisorption, thermal gravimetric analysis, and ATR FT-IR spectroscopy. ATR FT-IR spectroscopic data and density functional theory (DFT) calculations supported the interaction between the mesoporous silica surface and tamoxifen molecules and pointed out that the drug molecule interacts more strongly with the silicate surface terminated by silanol groups than with the surface modified with carboxyl groups. A sustained tamoxifen release profile was obtained by an in vitro experiment at pH = 7.0 for the PEGylated formulation modified by COOH groups after the template removal. Free drug and formulated tamoxifen samples were further investigated for antiproliferative activity against MCF-7 cells.
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Proliferación Celular/efectos de los fármacos , Portadores de Fármacos , Óxido Ferrosoférrico , Polietilenglicoles , Dióxido de Silicio , Tamoxifeno , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Óxido Ferrosoférrico/química , Óxido Ferrosoférrico/farmacocinética , Óxido Ferrosoférrico/farmacología , Humanos , Células MCF-7 , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , Tamoxifeno/química , Tamoxifeno/farmacocinética , Tamoxifeno/farmacologíaRESUMEN
The major limitations of photodynamic therapy (PDT) are the poor tissue penetration of excitation light and the neutralization of reactive oxygen species (ROS) generated by overexpressed glutathione (GSH) in cancer cells. Despite tremendous efforts to design nanoplatforms, PDT still suffers from unsatisfactory effects. Furthermore, the residual of nanomaterials in the body has restricted their clinical application. To address these issues, Janus nanocomposites containing an Yb/Er codoped NaYF4 upconverting nanocrystal head and a disulfide-bridged mesoporous organosilicon body (UCN/MON) with loaded chlorin e6 (Ce6) were designed. On one hand, the upconverting nanocrystal head can convert near-infrared (NIR) light into visible light to activate Ce6 to release ROS. On the other hand, the silica body can be degraded though a redox reaction with GSH, to not only improve the tumor selectivity of the photosensitizer by redox- and pH-triggered Ce6 release, but also diminish the concentration of GSH in cancer cells to reduce the depletion of ROS. Thereby, an enhanced PDT triggered by NIR irradiation was achieved. Furthermore, UCN/MONs showed a higher clearance rate after therapeutic actions than nonbiodegradable UCN/MSNs due to their biocompatibility. Taken together, this work revealed the potential of UCN/MONs for highly efficient and NIR-induced PDT, highlighting the prospects of UCN/MONs in the clinic.
Asunto(s)
Antineoplásicos/uso terapéutico , Glutatión/metabolismo , Nanocompuestos/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Clorofilidas , Erbio/química , Erbio/efectos de la radiación , Erbio/uso terapéutico , Femenino , Fluoruros/química , Fluoruros/farmacocinética , Fluoruros/efectos de la radiación , Fluoruros/uso terapéutico , Humanos , Rayos Infrarrojos , Ratones Endogámicos BALB C , Nanocompuestos/química , Nanocompuestos/efectos de la radiación , Nanopartículas/química , Nanopartículas/efectos de la radiación , Nanopartículas/uso terapéutico , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/efectos de la radiación , Dióxido de Silicio/química , Dióxido de Silicio/metabolismo , Dióxido de Silicio/farmacocinética , Oxígeno Singlete/metabolismo , Iterbio/química , Iterbio/efectos de la radiación , Iterbio/uso terapéutico , Itrio/química , Itrio/farmacocinética , Itrio/efectos de la radiación , Itrio/uso terapéuticoRESUMEN
Mesoporous silica with uniform 2-D hexagonal pores has been newly employed as facile reservoir to impove the dissolution rate of water insoluble drugs. However, rapid drug release from mesoporous silica is usually accompanied by the generation of supersaturated solution, which leads to the drug precipitation and compromised absorption. To address this issue, a supersaturated ternary hybrid system was constructed in this study by utilizing inorganic mesoporous silica and organic precipitation inhibitor. Vinylprrolidone-vinylacetate copolymer (PVP VA64) with similar solubility parameter to model drug fenofibrate (FNB) was expected to well inhibit the precipitation. Mesoporous silica Santa Barbara amorphous-15 (SBA-15) was synthesized in acidic media and hybrid matrix was produced by hot melt extrusion technique. The results of in vitro supersaturation dissolution test obviously revealed that the presence of PVP VA64 could effectively sustain a higher apparent concentration. PVP VA64 was suggested to simultaneously reduce the rate of nucleation and crystal growth and subsequently maintain a metastable supersaturated state. The absorption of FNB delivered by the organic-inorganic hybrid matrix was remarkably enhanced in beagle dogs, and its AUC value was 1.92-fold higher than that of FNB loaded mesoporous silica without PVP VA 64. In conclusion, the supersaturated organic-inorganic hybrid matrix can serve as a modular strategy to enhance the oral availability of water insoluble drugs.
Asunto(s)
Preparaciones Farmacéuticas , Dióxido de Silicio , Animales , Perros , Disponibilidad Biológica , Estudios Cruzados , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/metabolismo , Porosidad , Dióxido de Silicio/síntesis química , Dióxido de Silicio/farmacocinética , Solubilidad , Agua/química , Agua/metabolismoRESUMEN
Poly (lactic-co-glycolic acid) (PLGA) in situ-forming implants are well-established drug delivery systems for controlled drug release over weeks up to months. To prevent initial burst release, which is still a major issue associated with PLGA-based implants, drugs attached to particulate carriers have been encapsulated. Unfortunately, former studies only investigated the resulting release of the soluble drugs and hence missed the potential offered by particulate drug release. In this study, we developed a system capable of releasing functional drug-carrying particles over a prolonged time. First, we evaluated the feasibility of our approach by encapsulating silica particles of different sizes (500 nm and 1 µm) and surface properties (OH or NH2 groups) into in situ-forming PLGA implants. In this way, we achieved sustained release of particles over periods ranging from 30 to 70 days. OH-carrying particles were released much more quickly when compared to NH2-modified particles. We demonstrated that the underlying release mechanisms involve size-dependent diffusion and polymer-particle interactions. Second, particles that carried covalently-attached ovalbumin (OVA) on their surfaces were incorporated into the implant. We demonstrated that OVA was released in association with the particles as functional entities over a period of 30 days. The released particle-drug conjugates maintained their colloidal stability and were efficiently taken up by antigen presenting cells. This system consisting of particles incorporated into PLGA-based in situ-forming implants offers the dual advantage of sustained and particulate release of drugs as a functional unit and has potential for future use in many applications, particularly in single-dose vaccines.
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Sistemas de Liberación de Medicamentos/métodos , Implantes de Medicamentos/farmacocinética , Liberación de Fármacos , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/farmacocinética , Dióxido de Silicio/farmacocinética , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/farmacocinética , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/síntesis química , Portadores de Fármacos/farmacocinética , Implantes de Medicamentos/administración & dosificación , Implantes de Medicamentos/síntesis química , Liberación de Fármacos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/administración & dosificación , Ovalbúmina/síntesis química , Ovalbúmina/farmacocinética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/síntesis química , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/síntesis químicaRESUMEN
BACKGROUND: Talc, a hydrous magnesium silicate, often used for genital hygiene purposes, is associated with ovarian carcinoma in case-control studies. Its potential to cause inflammation, injury, and functional changes in cells has been described. A complication of such studies is that talc preparations may be contaminated with other materials. A previous study by (Beck et al. Toxicol Appl Pharmacol 87:222-34, 1987) used a hamster model to study talc and granite dust exposure effects on various biochemical and cellular inflammatory markers. Our current study accessed key materials used in that 1987 study; we re-analyzed the original talc dust with contemporary scanning electron microscopy and energy dispersive x-ray analysis (SEM/EDX) for contaminants. We also examined the original bronchoalveolar lavage (BAL) cells with polarized light microscopy to quantify cell-associated birefringent particles to gain insight into the talc used. RESULTS: SEM/EDX analyses showed that asbestos fibers, quartz, and toxic metal particulates were below the limits of detection in the original talc powder. However, fibers with aspect ratios ≥3:1 accounted for 22% of instilled material, mostly as fibrous talc. Talc (based on Mg/Si atomic weight % ratio) was the most abundant chemical signature, and magnesium silicates with various other elements made up the remainder. BAL cell counts confirmed the presence of acute inflammation, which followed intratracheal instillation. Measurements of cell associated birefringent particles phagocytosis revealed significant differences among talc, granite, and control exposures with high initial uptake of talc compared to granite, but over the 14-day experiment, talc phagocytosis by lavaged cells was significantly less than that of granite. Phagocytosis of talc fibers by macrophages was observed, and birefringent particles were found in macrophages, neutrophils, and multinucleate giant cells in lavaged cells from talc-exposed animals. CONCLUSION: Our data support the contention that talc, even without asbestos and other known toxic contaminants, may elicit inflammation and contribute to lung disease. Our findings support the conclusions of (Beck et al. Toxicol Appl Pharmacol 87:222-34, 1987) study. By analyzing particulate exposures with polarized light microscopy and SEM/EDX, fibrous talc was identified and a distinctive pattern of impaired particulate ingestion was demonstrated.
Asunto(s)
Exposición por Inhalación/efectos adversos , Pulmón/efectos de los fármacos , Macrófagos/efectos de los fármacos , Silicatos de Magnesio/toxicidad , Neutrófilos/efectos de los fármacos , Talco/toxicidad , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Células Cultivadas , Cricetinae , Polvo , Exposición por Inhalación/análisis , Pulmón/metabolismo , Pulmón/patología , Macrófagos/metabolismo , Macrófagos/ultraestructura , Silicatos de Magnesio/química , Silicatos de Magnesio/farmacocinética , Masculino , Microscopía Electrónica de Rastreo , Neutrófilos/metabolismo , Neutrófilos/ultraestructura , Tamaño de la Partícula , Cuarzo/química , Cuarzo/farmacocinética , Cuarzo/toxicidad , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/toxicidad , Espectrometría por Rayos X , Propiedades de Superficie , Talco/química , Talco/farmacocinéticaRESUMEN
The balance between tumor accumulation and renal clearance has severely limited the efficacy of mesoporous silica-based drug nanocarriers in cancer therapy. Herein, a pH-responsive dissociable mesoporous silica-based nanoplatform with efficient dual-drug co-delivery, tumor accumulation and rapid clearance for cancer therapy is achieved by adjusting the wetting of the mesoporous silica surface. At pH 7.4, the synthesized spiropyran- and fluorinated silane-modified ultrasmall mesoporous silica nanoparticles (SP-FS-USMSN) self-assemble to form larger nanoclusters (denoted as SP-FS-USMSN cluster) via hydrophobic interactions, which can effectively co-deliver anticancer drugs, doxorubicin hydrochloride (Dox) and curcumin (Cur), based on the mesopores within SP-FS-USMSN and the voids among the stacked SP-FS-USMSN. At pH 4.5-5.5, the conformational conversion of spiropyran from a "closed" state to an "open" state causes the wetting of the SP-FS-USMSN surface, leading to the dissociation of the SP-FS-USMSN cluster for drug release and renal clearance. The in vitro and in vivo studies demonstrate that the Cur and Dox co-loaded SP-FS-USMSN cluster (Cur-Dox/SP-FS-USMSN cluster) possesses great combined cytotoxicity, and can accumulate into tumor tissue by its large size-favored EPR effect and potently suppress tumor growth in HepG2-xenografted mice. This research demonstrates that the SP-FS-USMSN cluster may be a promising drug delivery system for cancer therapy and lays the foundation for practical mesoporous silica-based nanomedicine designs in the future.