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1.
Biomed Pharmacother ; 139: 111494, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243595

RESUMO

This study set out to optimize simvastatin (SV) in lipid nanoparticles (SLNs) to improve bioavailability, efficacy and alleviate adverse effects. Simvastatin-loaded solid lipid nanoparticles (SV-SLNs) were prepared by hot-melt ultrasonication method and optimized by box-Behnken experimental design. Sixty Wister albino rats were randomly assigned into six groups and treated daily for 16 weeks: control group, the group fed with 20 g of high-fat diet (HFD), group treated with vehicle (20 mg/kg, P.O.) for last four weeks, group treated with HFD and SV (20 mg/kg, P.O.) / or SV-SLNs (20 mg/kg/day, P.O.) / or SV-SLNs (5 mg/kg, P.O.) at last four weeks. Blood, liver tissues, and quadriceps muscles were collected for biochemical analysis, histological and immunohistochemical assays. The optimized SV-SLNS showed a particle-size 255.2 ± 7.7 nm, PDI 0.31 ± 0.09, Zeta-potential - 19.30 ± 3.25, and EE% 89.81 ± 2.1%. HFD showed severe changes in body weight liver functions, lipid profiles, atherogenic index (AIX), albumin, glucose, insulin level, alkaline phosphatase as well as muscle injury, oxidative stress biomarkers, and protein expression of caspase-3. Simvastatin treatment in animals feed with HFD showed a significant improvement of all tested parameters, but it was associated with hepatotoxicity, myopathy, and histological changes in quadriceps muscles. SV-SLNs exhibited a significant improvement of all biochemical, histological examinations, and immunohistochemical assays. SV-SLNs (5 mg/kg) treatment returns all measured parameters to control itself. These results represent that SV-SLNs is a promising candidate as a drug carrier for delivering SV with maximum efficacy and limited adverse reaction.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Lipídeos/química , Doenças Musculares/tratamento farmacológico , Nanopartículas/química , Sinvastatina/farmacologia , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar
2.
Biomed Pharmacother ; 139: 111656, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243603

RESUMO

INTRODUCTION: Amyrins are triterpenes that have attractive pharmacological potential; however, their low water solubility and erratic stomach absorption hinders their use as a drug. The aim of this paper was to develop a novel α-amyrin-loaded nanocapsule for intestinal delivery and evaluate, preliminarily, its cytotoxic ability against leukemic cells. MATERIAL AND METHODS: Five nanocapsule formulations were designed by the solvent displacement-evaporation method. Poly-ε-caprolactone, Eudragit® E100, and Kollicoat® Mae 100 P were used as film-former materials. Particle size, polydispersity index (PdI), zeta potential, and the pH of all formulations were measured. The cytotoxic potential of the nanocapsules was evaluated in vitro using different leukemic lineages RESULTS: Nanocapsules coated with Kollicoat® Mae 100 P presented the smallest particle size (130 nm), the lowest zeta-potential (-38 mV), and the narrowest size distribution (PdI = 0.100). The entrapment efficiency was 65.47%, while the loading capacity was 2.40%. Nanocapsules release 100% of α-amyrin in 40 min (pH 7.4), by using a possible mechanism of swelling-diffusion. The formulation showed excellent on-shelf physicochemical stability during one year. Additionally, nanocapsules produced a selective cytotoxic effect on a human leukemia lineage Kasumi-1, an acute myeloid leukemia cell line, and produced cell death by apoptosis CONCLUSION: α-amyrin-loaded nanocapsules appear to be a promising nanoformulation that could be used against leukemia.


Assuntos
Leucemia/tratamento farmacológico , Nanocápsulas/química , Triterpenos Pentacíclicos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caproatos/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Células Jurkat , Células K562 , Lactonas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Tamanho da Partícula , Ácidos Polimetacrílicos/química
3.
AAPS PharmSciTech ; 22(5): 204, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34258696

RESUMO

Hirsutism is a dermatological condition that refers to the excessive growth of hair in androgen-sensitive areas in women. Recently, the enhancement of the visible signs of a hairy female has taken special concern that affected the quality of life. The present study was developed to compare the follicular targeting effect of topical spironolactone (SP) or progesterone (PG)-loaded nanostructured lipid carrier (NLC) on the management of hirsutism. Four NLC formulations were prepared using cold homogenization techniques and pharmaceutically evaluated. SP-NLC and PG-NLC topical hydrogels were prepared to explore their pharmacological effect on letrozole induced polycystic ovarian syndrome (PCOS) in rats. Inflammatory mediators, antioxidant, and hormonal parameters were assayed. Additionally, histopathological examination was carried out to confirm the successful induction of PCOS. Results confirmed that all NLC formulations have a spherical shape with particle size ranged from 225.92 ± 0.41 to 447.80 ± 0.66 nm, entrapment efficiency > 75%, and zeta potential (- 31.4 to - 36.5 mV). F1 and F3 NLCs were considered as selected formulations for SP and PG, respectively. Female Wistar rats treated with F1 formulation for 3 weeks displayed better outcomes as manifested by the measured parameters as compared to the other tested groups. A significant reduction in hair follicle diameter and density was observed after topical application of SP or PG nano-gels. Finally, the outcomes pose a strong argument that the development of topically administered SP-NLC can be explored as a promising carrier over PG-NLC for more effectual improvement in the visible sign of hirsutism.


Assuntos
Portadores de Fármacos/administração & dosagem , Hirsutismo/sangue , Hirsutismo/tratamento farmacológico , Nanoestruturas/administração & dosagem , Progesterona/administração & dosagem , Espironolactona/administração & dosagem , Animais , Portadores de Fármacos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Hidrogéis/administração & dosagem , Hidrogéis/síntese química , Inflamação/tratamento farmacológico , Inflamação/patologia , Nanoestruturas/química , Tamanho da Partícula , Progesterona/síntese química , Ratos , Ratos Wistar , Espironolactona/síntese química
4.
Mikrochim Acta ; 188(8): 262, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34282508

RESUMO

COVID-19 is now a severe threat to global health. Facing this pandemic, we developed a space-encoding microfluidic biochip for high-throughput, rapid, sensitive, simultaneous quantitative detection of SARS-CoV-2 antigen proteins and IgG/IgM antibodies in serum. The proposed immunoassay biochip integrates the advantages of graphene oxide quantum dots (GOQDs) and microfluidic chip and is capable of conducting multiple SARS-CoV-2 antigens or IgG/IgM antibodies of 60 serum samples simultaneously with only 2 µL sample volume of each patient. Fluorescence intensity of antigens and IgG antibody detection at emission wavelength of ~680 nm was used to quantify the target concentration at excitation wavelength of 632 nm, and emission wavelength of ~519 nm was used during the detection of IgM antibodies at excitation wavelength of 488 nm. The method developed has a large linear quantification detection regime of 5 orders of magnitude, an ultralow detection limit of ~0.3 pg/mL under optimized conditions, and less than 10-min qualitative detection time. The proposed biosensing platform will not only greatly facilitate the rapid diagnosis of COVID-19 patients, but also provide a valuable screening approach for infected patients, medical therapy, and vaccine recipients.


Assuntos
Antígenos Virais/sangue , Imunoensaio , Imunoglobulina G/sangue , Imunoglobulina M/sangue , SARS-CoV-2/isolamento & purificação , Reações Antígeno-Anticorpo , Antígenos Virais/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Nanopartículas/química , Tamanho da Partícula , SARS-CoV-2/imunologia , Sensibilidade e Especificidade
5.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198523

RESUMO

It is crucial to establish relationship between nanoparticle structures (or properties) and nanotoxicity. Previous investigations have shown that a nanoparticle's size, shape, surface and core materials all impact its toxicity. However, the relationship between the redox property of nanoparticles and their toxicity has not been established when all other nanoparticle properties are identical. Here, by synthesizing an 80-membered combinatorial gold nanoparticle (GNP) library with diverse redox properties, we systematically explored this causal relationship. The compelling results revealed that the oxidative reactivity of GNPs, rather than their other physicochemical properties, directly caused cytotoxicity via induction of cellular oxidative stress. Our results show that the redox diversity of nanoparticles is regulated by GNPs modified with redox reactive ligands.


Assuntos
Técnicas de Química Combinatória/métodos , Citotoxinas/farmacologia , Ouro/química , Nanopartículas Metálicas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Células A549 , Proliferação de Células/efeitos dos fármacos , Citotoxinas/química , Humanos , Nanopartículas Metálicas/química , Oxirredução , Tamanho da Partícula
6.
Artigo em Inglês | MEDLINE | ID: mdl-34198698

RESUMO

Manufacturing sites, such as welding, casting, and asphalt production (fumes), generate vast numbers of ultrafine particles of <0.1 µm in size and submicron particles close to the ultrafine range (0.1-0.5 µm). Although cumulative masses of these particles are negligible in comparison to the larger particles, the health effects are more severe due to the higher penetration in the human lower respiratory tract, other body parts crossing the respiratory epithelial layers, and the larger surface area. This research investigates the effectiveness of two common commercially available N95 filtering facepieces and N95 pleated particulate respirator models against ultrafine and submicron particles. Two specific types of respirators, the N95 filtering facepiece and the N95 pleated particulate models, in both sealed and unsealed conditions to the manikin face, were tested at various commercial and academic manufacturing sites, a welding and foundry site, and an asphalt production plant. Two TSI Nanoscan SMPS nanoparticle counters were used simultaneously to collect data for particles of 10-420 nm in size from inside and outside of the respirators. While one of them represented the workplace exposure levels, the other one accounted for the exposure upon filtration through the respiratory surfaces. The results showed the particles generated by these manufacturing operations were mostly within the range of from 40 to 200 nm. Results also indicated that while the percentage of filtration levels varied based on the particle size, it remained mostly within the desired protection level of 95% for both of the N95 respirator models in sealed conditions and even for the N95 pleated particulate model in the unsealed condition. However, in the case of the N95 filtering facepiece model, unsealed respirators showed that the percentage of penetration was very high, decreasing the protection levels to 60% in some cases. Although the number of workplace airborne particle levels varied considerably, the filtration percentages were relatively consistent.


Assuntos
Poluentes Ocupacionais do Ar , Exposição Ocupacional , Dispositivos de Proteção Respiratória , Soldagem , Aerossóis/análise , Poluentes Ocupacionais do Ar/análise , Filtração , Humanos , Hidrocarbonetos , Tamanho da Partícula , Material Particulado/análise , Ventiladores Mecânicos , Local de Trabalho
7.
Artigo em Inglês | MEDLINE | ID: mdl-34201148

RESUMO

Many studies have found that the concentration of fine particulates in the atmosphere has increased. In particular, when using the bus, the situation in which people are exposed to relatively high concentrations of fine particulates is increasing. The purpose of this study is to reduce exposure to these potentially harmful particulates by introducing open shelters at outdoor bus stops. In order to use it as an outdoor fine particulates reduction device, a brush filter using electrostatic force (EF) was used on an experimental scale and the generation of electrostatic force, according to the material, was examined. As electrostatic force was generated, the fine particulates collection performance was about 90% efficiency. In addition, it was confirmed that the efficiency of each particle size was improved by 57% through structural improvement. Finally, through experimentation, it was confirmed that the brush module can be used for about 70 days.


Assuntos
Poluentes Atmosféricos , Poluentes Atmosféricos/análise , Carvão Mineral , Poeira , Humanos , Tamanho da Partícula , Eletricidade Estática
8.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202080

RESUMO

Alveolar macrophages are the first line of defense against intruding pathogens and play a critical role in cancer immunology. The Toll-like receptor (TLR) family mediates an important role in recognizing and mounting an immune response against intruding microbes. TLR-9 is a member of the intracellular TLR family, which recognizes unmethylated CG motifs from the prokaryotic genome. Upon its activation, TLR-9 triggers downstream of the MyD-88-dependent transcriptional activation of NF-κB, and subsequently results in abundant inflammatory cytokines expression that induces a profound inflammatory milieu. The present exploratory investigation aimed at elucidating the potency of schizophyllan for entrapping ODN 1826 (SPG-ODN 1826)-mediated stimulation of TLR-9 in provoking an inflammatory-type response in murine alveolar macrophages. Schizophyllan (SPG), a representative of the ß-glucan family, was used in the present study as a nanovehicle for endosomal trafficking of CpG ODN 1826. TEM analysis of SPG-ODN 1826 nanovehicles revealed that the prepared nanovehicles are spherical and have an average size of about 100 nm. Interestingly, SPG-ODN 1826 nanovehicles were competent in delivering their therapeutic payload within endosomes of murine alveolar macrophage (J774A.1) cells. Exposure of these nanovehicles within LPS stimulated J774A.1, resulted in a significant provocation of reactive oxygen species (ROS) (p < 0.01) in comparison to CpG ODN 1826 alone. Moreover, the formulated nanovehicles succeeded in generating a profound Th1-based cytokine profile constituted by enhanced expression of IFN-γ (p < 0.001) and IL-1ß (p < 0.001) inflammatory cytokines. These findings clearly indicated the immunostimulatory potential of SPG-ODN 1826 nanovehicles for inducing the Th1-type phenotype, which would certainly assist in skewing M2 phenotype into the much-desired M1 type during lung cancer.


Assuntos
Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Nanoestruturas/química , Oligodesoxirribonucleotídeos/química , Sizofirano/química , Receptor Toll-Like 9/agonistas , Animais , Sobrevivência Celular , Citocinas/metabolismo , Endossomos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Ativação de Macrófagos/imunologia , Camundongos , Nanoestruturas/administração & dosagem , Nanoestruturas/ultraestrutura , Tamanho da Partícula
9.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202329

RESUMO

The interactions between pharmaceuticals and nanomaterials and its potentially resulting toxicological effects in living systems are only insufficiently investigated. In this study, two model compounds, acetaminophen, a pharmaceutical, and cerium dioxide, a manufactured nanomaterial, were investigated in combination and individually. Upon inhalation, cerium dioxide nanomaterials were shown to systemically translocate into other organs, such as the liver. Therefore we picked the human liver cell line HuH-7 cells as an in vitro system to investigate liver toxicity. Possible synergistic or antagonistic metabolic changes after co-exposure scenarios were investigated. Toxicological data of the water soluble tetrazolium (WST-1) assay for cell proliferation and genotoxicity assessment using the Comet assay were combined with an untargeted as well as a targeted lipidomics approach. We found an attenuated cytotoxicity and an altered metabolic profile in co-exposure experiments with cerium dioxide, indicating an interaction of both compounds at these endpoints. Single exposure against cerium dioxide showed a genotoxic effect in the Comet assay. Conversely, acetaminophen exhibited no genotoxic effect. Comet assay data do not indicate an enhancement of genotoxicity after co-exposure. The results obtained in this study highlight the advantage of investigating co-exposure scenarios, especially for bioactive substances.


Assuntos
Acetaminofen/efeitos adversos , Cério/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Nanopartículas , Acetaminofen/administração & dosagem , Transporte Biológico , Linhagem Celular Tumoral , Cério/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Metaboloma , Metabolômica/métodos , Nanopartículas/química , Tamanho da Partícula , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
10.
Int J Nanomedicine ; 16: 4579-4596, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267514

RESUMO

Introduction: The aim of current study was to prepare Linum usitatissimum mucilage (LUM) based nanoparticles, capable of encapsulating hydrophobic drug ezetimibe as nanocarriers. Methods: Solvent evaporation and nanoprecipitation techniques were used to develop nanoparticles by encapsulating ezetimibe in the articulated matrix of polysaccharide fractions. Developed nanoparticles were characterized to determine the particle size, zeta potential, polydispersibility index (PDI), and entrapment efficiency (EE). Morphology and physicochemical characterization were carried out through SEM, FTIR, PXRD and thermal analysis. Saturation solubility and in vitro release studies were also performed. Safety assessment of ezetimibe loaded nanoparticles was evaluated via oral acute toxicity study. Results: The mean particle size, zeta potential, PDI and EE for emulsion solvent evaporation were 683.6 nm, -28.3 mV, 0.39, 63.7% and for nanoprecipitation were 637.7 nm, 0.07, -27.1 mV and 80%, respectively. Thermal analysis confirmed enhanced thermal stability, whereas PXRD confirmed amorphous nature of drug. Saturation solubility (p-value <0.05) demonstrated improved solubility of drug when enclosed in linseed nanoparticles. Nanoprecipitation surpasses emulsion solvent evaporation in dissolution test by possessing smaller size. Acute oral toxicity study indicated no significant changes in behavioral, clinical or histopathological parameters of control and experimental groups. Conclusion: The in vitro release of ezetimibe was augmented by enhancing aqueous solubility through devised nanoparticles. Thus, linseed mucilage could act as biopolymer in the fabrication of nanoparticle formulation. The acute oral toxicological investigations provided evidence that LUMNs were safe after oral administration.


Assuntos
Portadores de Fármacos/química , Ezetimiba/química , Linho/química , Nanopartículas/química , Mucilagem Vegetal/química , Administração Oral , Ezetimiba/administração & dosagem , Tamanho da Partícula , Solubilidade
11.
Int J Nanomedicine ; 16: 4713-4737, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267519

RESUMO

Background: Amiodarone (AMD) is a widely used anti-arrhythmic drug, but its administration could be associated with varying degrees of pulmonary toxicity. In attempting to circumvent this issue, AMD-loaded polymeric nanoparticles (AMD-loaded NPs) had been designed. Materials and Methods: AMD was loaded in NPs by the nanoprecipitation method using two stabilizers: bovine serum albumin and Kolliphor® P 188. The physicochemical properties of the AMD-loaded NPs were determined. Among the prepared NPs, two ones were selected for further investigation of spectral and thermal analysis as well as morphological properties. Additionally, in vitro release patterns were studied and kinetically analyzed at different pH values. In vitro cytotoxicity of an optimized formula (NP4) was quantified using A549 and Hep-2 cell lines. In vivo assessment of the pulmonary toxicity on Sprague Dawley rats via histopathological and immunohistochemical evaluations was applied. Results: The developed NPs achieved a size not more than 190 nm with an encapsulation efficiency of more than 88%. Satisfactory values of loading capacity and yield were also attained. The spectral and thermal analysis demonstrated homogeneous entrapment of AMD inside the polymeric matrix of NPs. Morphology revealed uniform, core-shell structured, and sphere-shaped particles with a smooth surface. Furthermore, the AMD-loaded NPs exhibited a pH-dependent and diffusion-controlled release over a significant period without an initial burst effect. NP4 demonstrated a superior cytoprotective efficiency by diminishing cell death and significantly increasing the IC50 by more than threefold above the pure AMD. Also, NP4 ameliorated AMD-induced pulmonary damage in rats. Significant downregulation of inflammatory mediators and free radicle production were noticed in the NP4-treated rats. Conclusion: The AMD-loaded NPs could ameliorate the pulmonary injury induced by the pure drug moieties. Cytoprotective, anti-fibrotic, anti-inflammatory, and antioxidant properties were presented by the optimized NPs (NP4). Future studies may be built on these findings for diminishing AMD-induced off-target toxicities.


Assuntos
Amiodarona/química , Amiodarona/toxicidade , Portadores de Fármacos/química , Pulmão/efeitos dos fármacos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Células A549 , Animais , Morte Celular/efeitos dos fármacos , Difusão , Células Hep G2 , Humanos , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley
12.
Ceska Slov Farm ; 70(1): 32-40, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237951

RESUMO

Microparticles based on biodegradable synthetic lactic acid and glycolic acid copolymer (PLGA) were successfully prepared by the solvent evaporation method. Ibuprofen was chosen as the model drug. Various formulation and process parameters have been used to prepare each sample with emphasis on size reduction. The effect of the emulsification method (direct emulsification or emulsification using an ULTRA-TURRAX or a NE-1000 dispenser), the volume of the aqueous phase (200, 800 ml) and the stirring speed of the emulsion system (600, 1000 rpm) on the characteristic properties of microparticles, such as encapsulation efficiency, drug loading and particle morphology, was observed. The resulting microparticles were evaluated by optical microscopy or laser diffraction and the dissolution test was performed. It was found that the sample prepared by direct emulsification with 800 ml of an aqueous phase at 600 rpm provided the most favorable results, meanwhile the emulsification pre-step using a homogenizer caused promising particle size reduction. Gradual emulsification was evaluated as inapplicable due to great losses. Key words: microparticles solvent evaporation PLGA ibuprofen size reduction.


Assuntos
Ibuprofeno , Ácido Poliglicólico , Microesferas , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
13.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198694

RESUMO

Plasmonic nanoparticles are increasingly employed in several fields, thanks to their unique, promising properties. In particular, these particles exhibit a surface plasmon resonance combined with outstanding absorption and scattering properties. They are also easy to synthesize and functionalize, making them ideal for nanotechnology applications. However, the physicochemical properties of these nanoparticles can make them potentially toxic, even if their bulk metallic forms are almost inert. In this review, we aim to provide a more comprehensive understanding of the potential adverse effects of plasmonic nanoparticles in zebrafish (Danio rerio) during both development and adulthood, focusing our attention on the most common materials used, i.e., gold and silver.


Assuntos
Modelos Animais , Nanopartículas/toxicidade , Testes de Toxicidade , Animais , Tamanho da Partícula , Peixe-Zebra
14.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199292

RESUMO

Giant unilamellar vesicles (GUV) are powerful tools to explore physics and biochemistry of the cell membrane in controlled conditions. For example, GUVs were extensively used to probe cell adhesion, but often using non-physiological linkers, due to the difficulty of incorporating transmembrane adhesion proteins into model membranes. Here we describe a new protocol for making GUVs incorporating the transmembrane protein integrin using gel-assisted swelling. We report an optimised protocol, enumerating the pitfalls encountered and precautions to be taken to maintain the robustness of the protocol. We characterise intermediate steps of small proteoliposome formation and the final formed GUVs. We show that the integrin molecules are successfully incorporated and are functional.


Assuntos
Géis/química , Integrinas/metabolismo , Lipossomas Unilamelares/química , Adesão Celular , Fluorescência , Humanos , Bicamadas Lipídicas/metabolismo , Lipídeos/química , Tamanho da Partícula
15.
Int J Nanomedicine ; 16: 4451-4470, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234436

RESUMO

Background: Liver fibrosis is a chronic liver disease with excessive production of extracellular matrix proteins, leading to cirrhosis, hepatocellular carcinoma, and death. Purpose: This study aimed at the development of a novel derivative of polyethyleneimine (PEI) that can effectively deliver transforming growth factor ß (TGFß) siRNA and inhibit chemokine receptor 4 (CXCR4) for TGFß silencing and CXCR4 Inhibition, respectively, to treat CCl4-induced liver fibrosis in a mouse model. Methods: Cyclam-modified PEI (PEI-Cyclam) was synthesized by incorporating cyclam moiety into PEI by nucleophilic substitution reaction. Gel electrophoresis confirmed the PEI-Cyclam polyplex formation and stability against RNAase and serum degradation. Transmission electron microscopy and zeta sizer were employed for the morphology, particle size, and zeta potential, respectively. The gene silencing and CXCR4 targeting abilities of PEI-Cyclam polyplex were evaluated by luciferase and CXCR4 redistribution assays, respectively. The histological and immunohistochemical staining determined the anti-fibrotic activity of PEI-Cyclam polyplex. The TGFß silencing of PEI-Cyclam polyplex was authenticated by Western blotting. Results: The 1H NMR of PEI-Cyclam exhibited successful incorporation of cyclam content onto PEI. The PEI-Cyclam polyplex displayed spherical morphology, positive surface charge, and stability against RNAse and serum degradation. Cyclam modification decreased the cytotoxicity and demonstrated CXCR4 antagonistic and luciferase gene silencing efficiency. PEI-Cyclam/siTGFß polyplexes decreased inflammation, collagen deposition, apoptosis, and cell proliferation, thus ameliorating liver fibrosis. Also, PEI-Cyclam/siTGFß polyplex significantly downregulated α-smooth muscle actin, TGFß, and collagen type III. Conclusion: Our findings validate the feasibility of using PEI-Cyclam as a siRNA delivery vector for simultaneous TGFß siRNA delivery and CXCR4 inhibition for the combined anti-fibrotic effects in a setting of CCl4-induced liver fibrosis.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Compostos Heterocíclicos/química , Cirrose Hepática/genética , Polietilenoimina/química , RNA Interferente Pequeno/genética , Fator de Crescimento Transformador beta/genética , Animais , Apoptose/efeitos dos fármacos , Portadores de Fármacos/química , Inativação Gênica , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Camundongos , Tamanho da Partícula , RNA Interferente Pequeno/química , Receptores CXCR4/genética , Fator de Crescimento Transformador beta/deficiência
16.
Int J Nanomedicine ; 16: 4481-4494, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239300

RESUMO

Purpose: Apatinib (Apa) is a novel anti-vascular endothelial growth factor with the potential to treat diabetic retinopathy (DR); a serious condition leading to visual impairment and blindness. DR treatment relies on invasive techniques associated with various complications. Investigating topical routes for Apa delivery to the posterior eye segment is thus promising but also challenging due to ocular barriers. Hence, the study objective was to develop Apa-loaded bovine serum albumin nanoparticles (Apa-BSA-NPs) coated with hyaluronic acid (HA); a natural polymer possessing unique mucoadhesive and viscoelastic features with the capacity to actively target CD44 positive retinal cells, for topical administration in DR. Methods: Apa-BSA-NPs were prepared by desolvation using glutaraldehyde for cross-linking. HA-coated BSA-NPs were also prepared and HA: NPs ratio optimized. Nanoparticles were characterized for colloidal properties, entrapment efficiency (EE%), in vitro drug release and mucoadhesive potential. In vitro cytotoxicity on rabbit corneal epithelial cells (RCE) was assessed using MTT assay, while efficacy was evaluated in vivo in a diabetic rat model by histopathological examination of the retina by light and transmission electron microscopy. Retinal accumulation of fluorescently labeled BSA-NP and HA-BSA-NP was assessed using confocal microscope scanning. Results: Apa-HA-BSA-NPs prepared under optimal conditions showed size, PdI and zeta potential: 222.2±3.56 nm, 0.221±0.02 and -37.3±1.8 mV, respectively. High EE% (69±1%), biphasic sustained release profile with an initial burst effect and mucoadhesion was attained. No evidence of cytotoxicity was observed on RCE cells. In vivo histopathological studies on DR rat model revealed alleviated retinal micro- and ultrastructural changes in the topical HA-Apa-BSA-NP treated eyes with normal basement membrane and retinal thickness comparable to normal control and intravitreally injected nanoparticles. Improved retinal accumulation for HA-BSA-NP was also observed by confocal microscopy. Conclusion: Findings present HA-Apa-BSA-NPs as a platform for enhanced topical therapy of DR overcoming the devastating ocular complications of the intravitreal route.


Assuntos
Retinopatia Diabética/metabolismo , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Piridinas/administração & dosagem , Piridinas/química , Soroalbumina Bovina/química , Animais , Retinopatia Diabética/tratamento farmacológico , Liberação Controlada de Fármacos , Tamanho da Partícula , Piridinas/metabolismo , Piridinas/uso terapêutico , Coelhos , Ratos , Retina/metabolismo
17.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200376

RESUMO

The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B.


Assuntos
Solubilidade/efeitos dos fármacos , Sorafenibe/química , Acetona/química , Biofarmácia/métodos , Química Farmacêutica/métodos , Cristalização/métodos , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Pós/química , Difração de Raios X/métodos
18.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198955

RESUMO

Hyaluronic acid (HA) is one of the most used biopolymers in the development of drug delivery systems, due to its biocompatibility, biodegradability, non-immunogenicity and intrinsic-targeting properties. HA specifically binds to CD44; this property combined to the EPR effect could provide an option for reinforced active tumor targeting by nanocarriers, improving drug uptake by the cancer cells via the HA-CD44 receptor-mediated endocytosis pathway. Moreover, HA can be easily chemically modified to tailor its physico-chemical properties in view of specific applications. The derivatization with cholesterol confers to HA an amphiphilic character, and then the ability of anchoring to niosomes. HA-Chol was then used to coat Span® or Tween® niosomes providing them with an intrinsic targeting shell. The nanocarrier physico-chemical properties were analyzed in terms of hydrodynamic diameter, ζ-potential, and bilayer structural features to evaluate the difference between naked and HA-coated niosomes. Niosomes stability was evaluated over time and in bovine serum. Moreover, interaction properties of HA-coated nanovesicles with model membranes, namely liposomes, were studied, to obtain insights on their interaction behavior with biological membranes in future experiments. The obtained coated systems showed good chemical physical features and represent a good opportunity to carry out active targeting strategies.


Assuntos
Materiais Biomiméticos/química , Colesterol/química , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/farmacologia , Animais , Bovinos , Membrana Celular , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Ácido Hialurônico/síntese química , Ácido Hialurônico/química , Lipossomos , Nanoestruturas , Tamanho da Partícula , Soro/química
19.
Nutrients ; 13(6)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205279

RESUMO

Lipoprotein subclasses possess crucial cardiometabolic information. Due to strong multicollinearity among variables, little is known about the strength of influence of physical activity (PA) and adiposity upon this cardiometabolic pattern. Using a novel approach to adjust for covariates, we aimed at determining the "net" patterns and strength for PA and adiposity to the lipoprotein profile. Principal component and multivariate pattern analysis were used for the analysis of 841 prepubertal children characterized by 26 lipoprotein features determined by proton nuclear magnetic resonance spectroscopy, a high-resolution PA descriptor derived from accelerometry, and three adiposity measures: body mass index, waist circumference to height, and skinfold thickness. Our approach focuses on revealing and validating the underlying predictive association patterns in the metabolic, anthropologic, and PA data to acknowledge the inherent multicollinear nature of such data. PA associates to a favorable cardiometabolic pattern of increased high-density lipoproteins (HDL), very large and large HDL particles, and large size of HDL particles, and decreasedtriglyceride, chylomicrons, very low-density lipoproteins (VLDL), and their subclasses, and to low size of VLDL particles. Although weakened in strength, this pattern resists adjustment for adiposity. Adiposity is inversely associated to this pattern and exhibits unfavorable associations to low-density lipoprotein (LDL) features, including atherogenic small and very small LDL particles. The observed associations are still strong after adjustment for PA. Thus, lipoproteins explain 26.0% in adiposity after adjustment for PA compared to 2.3% in PA after adjustment for adiposity.


Assuntos
Adiposidade , Fatores de Risco Cardiometabólico , Exercício Físico , Lipoproteínas/sangue , Índice de Massa Corporal , Criança , Feminino , Humanos , Lipoproteínas LDL/sangue , Masculino , Noruega , Tamanho da Partícula , Pregas Cutâneas
20.
Artigo em Inglês | MEDLINE | ID: mdl-34207363

RESUMO

Titanium is the ninth most abundant element, approximately 0.7% of the Earth crust. It is used worldwide in large quantities for various applications. The IARC includes TiO2 in Group 2B as possibly carcinogenic to humans suggesting that pathological effects correlate to particle size and shape. This study case quantifies the release of natural TiO2 particles during mining activity, involving meta-basalt and shale lithologies in the Ligurian Alps, during excavation of the Terzo Valico as part of the Trans-European Transport Network. Type, width, length, aspect ratio, and concentration of TiO2 particles in needle habit were determined. The different samplings have reported that airborne concentrations in meta-basalt were 4.21 ff/L and 23.94 ff/L in shale. In both cases, the concentration never exceeds the limits established by various organizations for workers health protection. Nevertheless, TiO2 elongated particles, recognized as rutile, showed the dimensional characteristic of fibres, as reported by WHO. These fibres deserve particular attention because they can reach the alveolar space and trigger inflammation and chronic diseases. The results indicate that monitoring the TiO2 in both working environments and Ti-rich geological formations, associated with epidemiological studies, may represent a useful tool to determine the exposure risk of workers and the general population.


Assuntos
Titânio , Humanos , Tamanho da Partícula
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