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1.
Food Chem ; 302: 125328, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404868

RESUMO

To control the oral bioavailability of curcumin, we fabricated solid lipid nanoparticles (SLNs) using tristearin and polyethylene glycol (PEG)ylated emulsifiers. Lipolysis of prepared SLNs via simulated gastrointestinal digestion was modulated by altering the types and concentrations of emulsifiers. After digestion, the size/surface charge of micelles formed from SLN digesta were predictable and >91% of curcumin was bioaccessible in all of the SLNs. The curcumin permeation rate through mucus-covered gut epithelium in vitro was dependent on the size/surface charge of the micelles. Curcumin loaded in long-PEGylated SLNs rapidly permeated the epithelium due to the neutral surface charge of the micelles, resulting in a >12.0-fold increase in bioavailability compared to curcumin solution in a rat model. These results suggest that the bioavailability of curcumin can be controlled by modulating the interfacial properties of SLNs, which will facilitate the development of curcumin formulations for use in functional foods and pharmaceuticals.


Assuntos
Curcumina/administração & dosagem , Curcumina/farmacocinética , Emulsificantes/química , Nanopartículas/química , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Digestão , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Lipídeos/química , Masculino , Nanopartículas/administração & dosagem , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Triglicerídeos/química
2.
Int J Nanomedicine ; 14: 7237-7247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564876

RESUMO

Background: The health hazards of silica nanoparticle (SiNP) are raising worldwide concern as SiNPs has become the second largest manufactured nanomaterial in global markets. However, insufficient data for the adverse health effects and safety evaluation of SiNPs are remaining a big question. Purpose: We evaluated the effects and related mechanism of SiNPs on pulmonary inflammation and collagen production through repeated intravenous administration in mice in a 45-day observation period. Methods: Morphological and ultrastructural change, ultradistribution of SiNPs in lungs were observed in ICR mice through intravenous administration. Oxidative damage, pro-inflammatory cytokines, hydroxyproline content, the marker of fibroblasts and epithelial-mesenchymal transition (EMT), and JAK2/STAT3 and TGF-ß1/Smad3 signaling pathways were detected to explore the lung injuries and related mechanism. Results: The results showed repeated intravenous exposure of SiNPs increased the weight of lung tissues and destroyed pulmonary histomorphological structure. The increased MDA content, depletion of SOD and GSH-Px in lungs were observed in SiNP-treated mice. The protein expressions of JAK2/STAT3 pathway were upregulated in lungs, and the levels of inflammatory cytokines TNF-α, IL-1ß, and IL-6 in serum and lungs were also elevated in SiNPs treated group. The increased hydroxyproline content indicated collagen accumulation in lungs of SiNP-treated mice. Meanwhile, the protein expressions of the marker of myofibroblast (a-SMA), the regulators in connective tissue remodeling (CTGF), TGF-ß, and p-Smad3 were all upregulated in lungs. In addition, we found intravenous administration of SiNPs-induced ultrastructural changes in type II alveolar epithelial cells but without downregulation of the protein expression of the key markers of epithelial cells (E-Cadherin). Conclusion: Our results revealed that oxidative stress and inflammation contributed to the collagen accumulation through activation of JAK2/STAT3 and TGF-ß/Smad3 pathways. It suggests that pulmonary aberrant inflammation and collagen accumulation induced by nanoparticles should be seriously considered for the safety application in diagnostics or therapeutics.


Assuntos
Colágeno/metabolismo , Janus Quinase 2/metabolismo , Nanopartículas/administração & dosagem , Pneumonia/patologia , Transdução de Sinais , Dióxido de Silício/administração & dosagem , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Administração Intravenosa , Animais , Caderinas/metabolismo , Citocinas/metabolismo , Transição Epitelial-Mesenquimal , Fibroblastos/metabolismo , Pulmão/patologia , Pulmão/ultraestrutura , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos ICR , Modelos Biológicos , Miofibroblastos/metabolismo , Nanopartículas/ultraestrutura , Estresse Oxidativo , Fator de Transcrição STAT3/metabolismo
3.
Int J Nanomedicine ; 14: 6407-6424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496694

RESUMO

Chagas disease is one of the most important public health problems in Latin America due to its high mortality and morbidity levels. There is no effective treatment for this disease since drugs are usually toxic with low bioavailability. Serious efforts to achieve disease control and eventual eradication have been unsuccessful to date, emphasizing the need for rapid diagnosis, drug development, and a reliable vaccine. Novel systems for drug and vaccine administration based on nanocarriers represent a promising avenue for Chagas disease treatment. Nanoparticulate systems can reduce toxicity, and increase the efficacy and bioavailability of active compounds by prolonging release, and therefore improve the therapeutic index. Moreover, nanoparticles are able to interact with the host's immune system, modulating the immune response to favour the elimination of pathogenic microorganisms. In addition, new advances in diagnostic assays, such as nanobiosensors, are beneficial in that they enable precise identification of the pathogen. In this review, we provide an overview of the strategies and nanocarrier-based delivery systems for antichagasic agents, such as liposomes, micelles, nanoemulsions, polymeric and non-polymeric nanoparticles. We address recent progress, with a particular focus on the advances of nanovaccines and nanodiagnostics, exploring new perspectives on Chagas disease treatment.


Assuntos
Doença de Chagas/tratamento farmacológico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Portadores de Fármacos/administração & dosagem , Humanos , Micelas , Nanopartículas/administração & dosagem , Polímeros/química
4.
Int J Nanomedicine ; 14: 6589-6600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496700

RESUMO

Background: The RAS family of oncogenes (KRAS, HRAS, NRAS) are the most frequent mutations in cancers and regulate key signaling pathways that drive tumor progression. As a result, drug delivery targeting RAS-driven tumors has been a long-standing challenge in cancer therapy. Mutant RAS activates cancer cells to actively take up nutrients, including glucose, lipids, and albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate. Purpose: We exploit macropinocytosis pathway to deliver nanoparticles (NPs) in cancer cells harboring activating KRAS mutations. Methods: NPs were synthesized by the desolvation method. The physicochemical properties and stability of NPs were characterized by dynamic light scattering and transmission electron microscopy. Uptake of fluorescently labelled NPs in wild-type and mutant KRAS cells were quantitively determined by flow cytometry and qualitatively by fluorescent microscopy. NP uptake by KRAS-driven macropinocytosis was confirmed by pharmacological inhibition and genetic knockdown. Results: We have synthesized stable albumin NPs that demonstrate significantly greater uptake in cancer cells with activating mutations of KRA S than monomeric albumin (ie, dissociated form of clinically used nab-paclitaxel). From pharmacological inhibition and semi-quantitative fluorescent microscopy studies, these NPs exhibit significantly increased uptake in mutant KRAS cancer cells than wild-type KRAS cells by macropinocytosis. Conclusions: The uptake of albumin nanoparticles is driven by KRAS. This NP-based strategy targeting RAS-driven macropinocytosis is a facile approach toward improved delivery into KRAS-driven cancers.


Assuntos
Espaço Intracelular/metabolismo , Nanopartículas/administração & dosagem , Oncogenes , Pinocitose , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Linhagem Celular Tumoral , Fenômenos Químicos , Humanos , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Soroalbumina Bovina/metabolismo
5.
Medicine (Baltimore) ; 98(36): e16935, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490376

RESUMO

BACKGROUND: Although several previous studies demonstrated the feasibility and efficacy of indocyanine green (ICG) for thyroid cancer surgery, ICG was administered through venous injection and focused on parathyroid gland protection. We thus aimed to study the feasibility of imaging using ICG combined with carbon nanoparticles (CNs) in the identification of sentinel lymph nodes (SLNs) in patients diagnosed with papillary thyroid microcarcinoma (PTMC). METHODS: Two approaches were applied to detect lymph nodes in PTMC surgery. Patients were randomized into 2 groups. ICG and CNs were injected into the thyroid in Group A. In Group B, only CNs was injected. Black-stained or fluorescent nodes observed using near-infrared fluorescence imaging systems were defined as SLNs. SLN and central lymph node (CLN) dissection was completed in both groups. The pathological and postoperative outcomes were compared between 2 groups. RESULTS: There were 40 patients in Group A and 60 in Group B. A total of 138 SLNs were identified; 72 and 66 SLNs were detected and dissected in Groups A and B, respectively. The number of SLNs identified (per patient) in Group A was higher than that in Group B (P = .027). The number of harvested CLNs was 161 and 192 in Groups A and B, respectively, out of which 45 and 48 lymph nodes with metastasis were confirmed by permanent pathology. The CLN metastatic rate in Group A was higher than that in Group B (P = .048). CONCLUSION: Imaging using ICG combined CNs is feasible and safe for SLN identification in PTMC patients. Compared with using only CNs, more SLNs can be removed and more metastatic lymph nodes can be confirmed when using the combined method. Although the combined method appears to accurately stage tumors, further research is needed.


Assuntos
Carbono/administração & dosagem , Carcinoma Papilar/patologia , Verde de Indocianina/administração & dosagem , Excisão de Linfonodo/métodos , Nanopartículas/administração & dosagem , Linfonodo Sentinela/cirurgia , Neoplasias da Glândula Tireoide/patologia , Adulto , Carbono/química , Carcinoma Papilar/cirurgia , Corantes/administração & dosagem , Estudos de Viabilidade , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Nanopartículas/química , Imagem Óptica/métodos , Linfonodo Sentinela/patologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/métodos
6.
Int J Nanomedicine ; 14: 5229-5242, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371958

RESUMO

Purpose: Dexamethasone (Dex) has long been used as a potent immunosuppressive agent in the treatment of inflammatory and autoimmune diseases, despite serious side effects. In the present study, Dex and model antigen ovalbumin (OVA) were encapsulated with poly(lactic-co-glycolic acid) to deliver Dex and OVA preferentially to phagocytic cells, reducing systemic side effects of Dex. The OVA-specific immune tolerance-inducing activity of the nanoparticles (NPs) was examined. Methods: Polymeric NPs containing OVA and Dex (NP[OVA+Dex]) were prepared by the water-in-oil-in-water double emulsion solvent evaporation method. The effects of NP[OVA+Dex] on the maturation and function of immature dendritic cells (DCs) were examined in vitro. Furthermore, the OVA-specific immune tolerizing effects of NP[OVA+Dex] were confirmed in mice that were intravenously injected or orally fed with the NPs. Results: Immature DCs treated in vitro with NP[OVA+Dex] did not mature into immunogenic DCs but instead were converted into tolerogenic DCs. Furthermore, profoundly suppressed generation of OVA-specific cytotoxic T cells and production of OVA-specific IgG were observed in mice injected with NP[OVA+Dex], whereas regulatory T cells were concomitantly increased. Feeding of mice with NP[OVA+Dex] also induced OVA-specific immune tolerance. Conclusion: The present study demonstrates that oral feeding as well as intravenous injection of poly(lactic-co-glycolic acid) NPs encapsulating both antigen and Dex is a useful means of inducing antigen-specific immune tolerance, which is crucial for the treatment of autoimmune diseases.


Assuntos
Antígenos/imunologia , Materiais Biocompatíveis/química , Dexametasona/farmacologia , Epitopos/imunologia , Tolerância Imunológica , Nanopartículas/química , Administração Oral , Animais , Apresentação do Antígeno/efeitos dos fármacos , Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Imunidade/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Ovalbumina/imunologia , Fagocitose/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
7.
AAPS PharmSciTech ; 20(7): 270, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363872

RESUMO

Currently, there is no specific treatment for acute lung injury (ALI). E-selectin-binding peptide (Esbp), a high-affinity peptide that delivers drugs targeting inflammatory vascular endothelial cells, can bind to E-selectin and act as a targeting ligand for selective drug delivery. In this study, we coupled the thiol groups of Esbp to the amino groups on the surface of bovine serum albumin (BSA) using succinimidyl iodoacetic acid to make Esbp-modified BSA nanoparticles (BSANPs) at the average ratio of 19.3 µg Esbp to 1 mg BSA. The Esbp-modified BSANPs were spherical in shape and had a particle size of 266.7 ± 2.7 nm, polydispersity index of 0.165 ± 0.02, zeta potential of - 33.64 ± 1.23 mV, encapsulation efficiency of 84.3 ± 2.3%, and drug loading of 6.7 ± 0.32%. The cumulative release rate of dexamethasone-loaded Esbp-modified BSANPs was 51.2% within 12 h, significantly lower than that of 88.2% of free drugs. Moreover, Esbp-modified BSANPs could be uptaken in vitro by activated human umbilical vein endothelial cells and in vivo by the lungs of the established ALI mouse model. These results indicated that our Esbp-modified BSANPs delivery system has characteristics of good targeting ability and biocompatibility and is able to inhibit inflammation. Overall, our Esbp-modified BSANPs delivery system has therapeutic potentials as a new targeting drug system for the treatment of ALI in the future.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Dexametasona/administração & dosagem , Selectina E/administração & dosagem , Antígenos HLA-D/administração & dosagem , Nanopartículas/administração & dosagem , Soroalbumina Bovina/administração & dosagem , Lesão Pulmonar Aguda/metabolismo , Animais , Bovinos , Linhagem Celular Tumoral , Dexametasona/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Selectina E/metabolismo , Antígenos HLA-D/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Nanopartículas/metabolismo , Tamanho da Partícula , Soroalbumina Bovina/metabolismo , Resultado do Tratamento
8.
Int J Nanomedicine ; 14: 5287-5301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31406460

RESUMO

Purpose: Nanoparticle (NP)-mediated targeted delivery of therapeutic genes or siRNAs to tumors has potential advantages. In this study, hyaluronic acid (HA)-modified chitosan nanoparticles (CS NPs-HA) loaded with cyanine 3 (Cy3)-labeled siRNA (sCS NPs-HA) were prepared and characterized. Methods: Human non-small cell lung cancer (NSCLC) A549 cells expressing receptor CD44 and tumor-bearing mice were used to evaluate the cytotoxic and antitumor effects of sCS NPs-HA in vitro and in vivo. Results: The results showed that noncytotoxic CS NPs-HA of small size (100-200 nm) effectively delivered the Cy3-labeled siRNA to A549 cells via receptor CD44 and inhibited cell proliferation by downregulating the target gene BCL2. In vivo experiment results revealed that sCS NPs-HA directly delivered greater amounts of Cy3-labeled siRNA to the tumor sites, resulting in the inhibition of tumor growth by downregulating BCL2, as compared to unmodified NPs loaded with siRNA (sCS NPs) and to naked Cy3-labeled siRNA. Conclusion: The HA-modified NPs based on chitosan could serve as a promising carrier for siRNA delivery and targeted therapy for NSCLC expressing CD44.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Quitosana/química , Ácido Hialurônico/química , Neoplasias Pulmonares/terapia , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Células A549 , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Fluorescência , Inativação Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem
9.
Int J Nanomedicine ; 14: 5175-5186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409986

RESUMO

Background: As a promising nanomaterial for biomedical applications, zirconia nanoparticles (ZrO2) have aroused concern recently, but the toxicity of ZrO2 in vivo has received little attention. Purpose: The aim of this study is to demonstrate the systematic single dose toxicity, biodistribution and oxidative damage of ZrO2 in vivo after intravenous injection in mice. Materials and methods: Ten ICR mice were used at the high dose of ZrO2 including 600, 500, 400 and 300mg/kg. Maximum tolerated dose (MTD) of 150 nm ZrO2 was determined as 500mg/kg. Hematology analysis and blood biochemical assay were determined for the evaluation of oxidative damage caused by ZrO2. Biodistribution of ZrO2 was investigated by ICP-OES and TEM. Results: Mice treated with higher dose (500mg/kg) showed significant spread in white blood cell counts (p<0.05). Especially, the serum ALT levels of 500mg/kg groups increased significantly (p<0.05) compared with the control group. ZrO2 particles would not induce any changes in appearance and micromorphology of liver at 100 and 350mg/kg. Spleen samples showed no significant changes in micromorphology of the lymphoid follicles and in the size of the red pulp after injection of ZrO2 at all doses. The serum of ZrO2-treated animals (350 and 500mg/kg) has reduced levels of SOD compared to the control group (p<0.05). ZrO2 persists in membrane-enclosed vesicles called lysosomes in the liver and spleen macrophages without abnormal changes of ultrastructure. Conclusion: These findings would contribute to the future development of ZrO2-based drug delivery system and other biomedical applications.


Assuntos
Nanopartículas/administração & dosagem , Nanopartículas/toxicidade , Estresse Oxidativo , Zircônio/administração & dosagem , Zircônio/toxicidade , Animais , Sistemas de Liberação de Medicamentos , Feminino , Injeções Intravenosas , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Baço/metabolismo , Distribuição Tecidual/efeitos dos fármacos
10.
Zhongguo Yi Liao Qi Xie Za Zhi ; 43(4): 275-278, 2019 Jul 30.
Artigo em Chinês | MEDLINE | ID: mdl-31460720

RESUMO

Using three-dimensional printing to produce antibacterial wound dressing is a new topic that will change the production style of wound dressing industry. Combining with post-3D-printed process, a desktop fused deposition molding equipment can be used to produce wound dressing containing polyvinyl alcohol, alginate and chitosan. The wound dressing produced by FDM has good aspects of absorbency, moisture vapour transmission rate and mechanical property. After loaded with antibacterial agent iodine and silver nano particle, the antibacterial activity rate increases to 99% and it is suitable to use as antibacterial wound dressing. This method affects the production of wound dressing to a more cost-effective way, and provides a possible individualized treatment for patient in the future.


Assuntos
Antibacterianos , Bandagens , Impressão Tridimensional , Cicatrização , Alginatos/química , Antibacterianos/administração & dosagem , Bactérias/efeitos dos fármacos , Bandagens/economia , Bandagens/normas , Quitosana/química , Humanos , Iodo/administração & dosagem , Iodo/farmacologia , Nanopartículas/administração & dosagem , Álcool de Polivinil/química , Prata/administração & dosagem , Prata/farmacologia
11.
Int J Nanomedicine ; 14: 5785-5797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440047

RESUMO

Introduction: The targeted delivery of anti-cancer drugs to tumor tissue has been recognized as a promising strategy to increase their therapeutic efficacy and reduce side effects. Mesoporous silica-coated superparamagnetic Fe3O4 nanoparticles (NH2-MSNs), a kind of nanocarrier, can passively enter tumor tissues to enhance the permeability and retention of drugs. However, NH2-MSNs do not specifically bind to cancer cells. This drawback encouraged us to develop a more efficient nanocarrier for cancer therapy. Methods: Herein, we describe the development of an effective nanocarrier based on NH2-MSNs, which were modified with hyaluronic acid on their surface (HA-MSNs) and loaded with doxorubicin (DOX). We have successfully fabricated uniform spherical HA-MSNs nanocarriers. The targeting ability of this delivery system was evaluated through specific uptake by cells and IVIS imaging. Results: DOX-HA-MSNs nanocarriers displayed more dramatic cytotoxic activity against 4T1 breast cancer cells compared to GES-1 gastric mucosa cells. In vivo results revealed that once DOX-HA-MSNs nanocarriers are exposed to an external magnetic field, they could be rapidly attracted to the magnet and effectively cross the cytoplasmic membrane via CD44 receptor-mediated transcytosis. This allows them to access the cancer cell cytoplasm and release DOX based on changes in the physiological environment. Both in vitro and in vivo results demonstrated that the HA-MSNs nanocarriers provided better therapeutic efficacy. Conclusion: The HA-MSNs nanocarriers represent an effective new paradigm to treat cancers due to active targeting to the tumor cells. Moreover, the specific uptake by the tumor effectively protects normal tissues to reduce off-target side effects. The reported findings support further investigation of HA-MSNs for cancer therapy.


Assuntos
Dextranos/química , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Nanopartículas de Magnetita/química , Dióxido de Silício/química , Animais , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Humanos , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Espectroscopia Fotoeletrônica , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Ensaios Antitumorais Modelo de Xenoenxerto
12.
AAPS PharmSciTech ; 20(7): 258, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332638

RESUMO

Febuxostat suffers from relatively low bioavailability owing to the poor drug solubility and hepatic first-pass effect. This study aimed to prepare highly drug-loaded self-nanoemulsifying self-nanosuspension systems (SNESNS). SNESNS were designed to improve febuxostat's oral bioavailability by enhancing its solubility. Different oil and surfactant/co-surfactant mixtures were used for the preparation of SNESNS. The prepared SNESNS were estimated for their particle size, in vitro drug release and transmission electron microscopy (TEM). Results revealed that the oil mixture of Capryol™ 90:Miglyol® 812 (1:1 w/w) with surfactant/co-surfactant mixture of Cremophor® RH 40/Transcutol® HP loaded with drug in 4-fold greater concentration than its saturated solubility resulted in the formation of SNESNS by dilution under the effect of magnetic stirring. SNESNS were freeze-dried using trehalose as a cryoprotectant. TEM images and the bimodal particle size curve confirmed the formation of the biphasic nanosystems after dilution (nanoemulsion and nanosuspension). Higher Cmax and AUC0-48 values compared to those of the market product Feburic® tablets confirmed the success of the SNESNS as a promising carrier for drugs suffering from poor water solubility like febuxostat.


Assuntos
Formas de Dosagem , Sistemas de Liberação de Medicamentos/métodos , Emulsões , Liofilização , Nanopartículas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos , Feminino , Camundongos , Tamanho da Partícula , Solubilidade , Tensoativos/administração & dosagem
13.
Bioelectrochemistry ; 130: 107328, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31306879

RESUMO

Blood vessels, the extracellular space, and the cell membrane represent physiologic barriers to nanoparticle-based drug delivery for cancer therapy. We demonstrate that electroporation (EP) can assist in the delivery of dye stabilized sorafenib nanoparticles (SFB-IR783) by increasing the permeability of endothelial monolayers, improving diffusion through the extracellular space in tumorspheres, and by disrupting plasma membrane function in cancer cells. These changes occur in a dose-dependent fashion, increasing proportionally with electric field strength. Cell death from irreversible electroporation (IRE) was observed to contribute to the persistent transport of SFB-IR783 through these physiologic barriers. In a model of mice bearing bilateral xenograft HCT116 colorectal tumors, treatment with EP resulted in the immediate and increased uptake of SFB-IR783 when compared with the untreated contralateral tumor. The uptake of SFB-IR783 was independent of direct transfection of cells through EP and was mediated by changes in vascular permeability and extracellular diffusion. The combination of EP and SFB-IR783 was observed to result in 40% reduction in mean tumor diameter when compared with sham treatment (p < .05) at the time of sacrifice, which was not observed in cohorts treated with EP alone or SFB-IR783 alone. Treatment of tumor with EP can augment the uptake and increase the efficacy of nanoparticle therapy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/tratamento farmacológico , Sorafenibe/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Eletroporação/métodos , Feminino , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Sorafenibe/farmacocinética , Sorafenibe/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos
15.
Eur J Pharm Biopharm ; 142: 258-264, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276759

RESUMO

The effect of drug load and digestion on the solubilization and absorption of fenofibrate in self-nanoemulsifying drug delivery system (SNEDDS) was assessed in a pharmacokinetic study in rats and in an in vitro lipolysis model. SNEDDS containing fenofibrate at 75% of equilibrium solubility (Seq), a super-saturated SNEDDS (super-SNEDDS) containing fenofibrate at 150% of Seq and a super-SNEDDS suspension containing fenofibrate at 100% of Seq and an additional 50% Seq fenofibrate suspended (150% of Seq in total) were used. To assess the effect of lipid digestion on fenofibrate absorption in rats and fenofibrate solubilization during in vitro lipolysis, the lipase inhibitor orlistat was added at 1% (w/w) to the SNEDDS, resulting in six different SNEDDS: SNEDDS, super-SNEDDS and super-SNEDDS suspension with and without orlistat 1% (w/w). In vivo, super-SNEDDS had a higher Cmax and AUC0-30h compared to SNEDDS and super-SNEDDS suspension, both with and without orlistat. While orlistat did not affect fenofibrate absorption in SNEDDS and super-SNEDDS, an increase of Tmax and AUC0-30h for super-SNEDDS suspension was found when orlistat was present. During in vitro lipolysis, the addition of orlistat decreased digestion and lowered drug precipitation. Super-SNEDDS showed significantly increased absorption in rats compared to SNEDDS and super-SNEDDS suspension and the inhibition of digestion resulted in prolonged and increased absorption for the super-SNEDDS suspension.


Assuntos
Fenofibrato/administração & dosagem , Fenofibrato/metabolismo , Administração Oral , Animais , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade/efeitos dos fármacos , Suspensões/administração & dosagem , Suspensões/farmacocinética
16.
Eur J Pharm Biopharm ; 142: 281-290, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279918

RESUMO

Poly(acrylamide-co-acrylonitrile) (P(AAm-co-AN)), an upper critical solution temperature (UCST)-type copolymer in water, was synthesized by reversible addition fragmentation chain transfer (RAFT) copolymerization and used as a macro-RAFT agent for the polymerization of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) to yield amphiphilic diblock P(AAm-co-AN)-b-POEGMA copolymer. A series of copolymers with different AN content was obtained allowing to finely tune the UCST behavior (cloud point (Tt-UCST) from 35 to 78 °C). Addition of the POEGMA block did not modify the Tt-UCST regardless its Mn but provided a lower critical solution temperature behavior at high temperature. Nanoparticles were then formulated by the nanoprecipitation technique revealing that copolymers with higher Tt-UCST yield smaller, better-defined nanoparticles. Eventually, doxorubicin (Dox) was encapsulated into nanoparticles made from the copolymer having a Tt-UCST close to mild hyperthermia (~43 °C). Surprisingly, Dox encapsulation increased Tt-UCST and gave smaller nanoparticles as opposed to their unloaded counterparts. The dilution of the suspension also led to a decrease of Tt-UCST. No obvious hyperthermia effect was observed on the cytotoxicity of Dox-loaded nanoparticles. Our study highlighted the influence of macromolecular engineering, drug encapsulation and nanoparticle dilution on UCST behavior, important features often overlooked despite their crucial impact in the development of thermosensitive nanoscale drug delivery systems.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Febre/tratamento farmacológico , Nanopartículas/administração & dosagem , Nanopartículas/química , Polímeros/química , Tecnologia Farmacêutica/métodos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Metacrilatos/administração & dosagem , Metacrilatos/química , Polimerização/efeitos dos fármacos , Temperatura Ambiente , Água/química
17.
AAPS PharmSciTech ; 20(6): 250, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31297635

RESUMO

Melanoma is regarded as the fifth and sixth most common cancer in men and women, respectively, and it is estimated that one person dies from melanoma every hour in the USA. Unfortunately, the treatment of melanoma is difficult because of its aggressive metastasis and resistance to treatment. The treatment of melanoma continues to be a challenging issue due to the limitations of available treatments such as a low response rate, severe adverse reactions, and significant toxicity. Natural polyphenols have attracted considerable attention from the scientific community due to their chemopreventive and chemotherapeutic efficacy. It has been suggested that poorly soluble polyphenols such as curcumin, resveratrol, quercetin, coumarin, and epigallocatechin-3-gallate may have significant benefits in the treatment of melanoma due to their antioxidant, anti-inflammatory, antiproliferative, and chemoprotective efficacies. The major obstacles for the use of polyphenolic compounds are low stability and poor bioavailability. Numerous nanoformulations, including solid lipid nanoparticles, polymeric nanoparticles, micelles, and liposomes, have been formulated to enhance the bioavailability and stability, as well as the therapeutic efficacy of polyphenols. This review will provide an overview of poorly soluble polyphenols that have been reported to have antimetastatic efficacy in melanomas.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Melanoma/tratamento farmacológico , Polifenóis/administração & dosagem , Polifenóis/química , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/metabolismo , Disponibilidade Biológica , Catequina/administração & dosagem , Catequina/análogos & derivados , Catequina/química , Catequina/metabolismo , Curcumina/administração & dosagem , Curcumina/química , Curcumina/metabolismo , Humanos , Melanoma/metabolismo , Melanoma/prevenção & controle , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/metabolismo , Polifenóis/metabolismo , Quercetina/administração & dosagem , Quercetina/química , Quercetina/metabolismo , Resveratrol/administração & dosagem , Resveratrol/química , Resveratrol/metabolismo , Neoplasias Cutâneas/metabolismo , Solubilidade
18.
Nat Commun ; 10(1): 2993, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278269

RESUMO

Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.


Assuntos
Terapia Genética/métodos , Cirrose Hepática Experimental/terapia , Neoplasias Hepáticas/terapia , Hepatopatia Gordurosa não Alcoólica/terapia , Relaxina/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Linhagem Celular Tumoral/transplante , Progressão da Doença , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Plasmídeos/genética , Receptores Acoplados a Proteínas-G/metabolismo , Relaxina/metabolismo , Resultado do Tratamento , Microambiente Tumoral/genética , Regulação para Cima
19.
Parasitol Res ; 118(9): 2669-2678, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278518

RESUMO

The aims of this study were to produce biogenic antimony sulfide nanoparticles (NPs) using Serratia marcescens (S. marcescens) and investigate the potential anti-leishmanial effects of these NPs on Leishmania major (L. major) (MRHO/IR/75/ER) in both in vitro and in vivo experiments. Biogenic antimony sulfide NPs were synthesized through intracellular biological methods using S. marcescens. The efficiency of various concentrations of antimony sulfide NPs was assessed using in vitro experiments on amastigotes of L. major at various times post-infection. In vivo experiments were carried out in BALB/c mice inoculated subcutaneously with 2 × 106L. major promastigotes (MHROM/IR/75/ER) and treated with antimony sulfide NPs (70 µg/mL, tropically), meglumine antimoniate (glucantime) as positive control and sterile phosphate-buffered saline (PBS, pH 7.4) as vehicle control. Results of in vitro experiments revealed that the anti-leishmanial activity increased when the antimony sulfide NPs concentration increased. The IC50 (50% inhibitory concentration) of antimony sulfide NPs against amastigotes was calculated as 62.5 µg/mL. In in vivo experiments, the average size of lesions significantly decreased to 8.6 ± 2.7 mm2 in mice inoculated with L. major promastigotes and treated with antimony sulfide NPs, compared with that in the negative control group (P = 0.015). Furthermore, results showed that antimony sulfide NPs significantly decreased the parasite load in the test group, compared with the negative control group (P = 0.001). Various concentrations of antimony sulfide NPs showed a great anti-leishmanial efficiency against L. major (MRHO/IR/75/ER), with the greatest efficiency shown by a concentration of 62.5 µg/mL in in vitro and in vivo experiments.


Assuntos
Antimônio/administração & dosagem , Antiprotozoários/administração & dosagem , Antipruriginosos/administração & dosagem , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Nanopartículas/administração & dosagem , Sulfetos/administração & dosagem , Animais , Humanos , Concentração Inibidora 50 , Leishmania major/fisiologia , Leishmaniose Cutânea/parasitologia , Camundongos , Camundongos Endogâmicos BALB C
20.
Int J Nanomedicine ; 14: 3799-3817, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213802

RESUMO

Background and aim: We have synthesized a novel lactone-stabilized camptothecin (CPT) analog named CZ48 and demonstrated its potent anticancer effects via bioconversion to the active CPT in earlier studies. Herein, we aimed to develop, optimize and characterize CZ48 nanosuspensions, for a sustained delivery of this drug in humans with an intravenous (i.v.) administration. Methods and materials: A three-factor, five-level central composite design (CCD) was employed to establish the impacts of the critical influencing factors (concentrations (wt%) of CZ48, polysorbate 80 (Tween-80), and Pluronic® F-108 (F-108)) on the responses (particle size and zeta potential). Based on the quantitative influencing factor-response relationships, two optimized CZ48 nanosuspensions of 197.22 ± 7.12 nm (NS-S) and 589.35 ± 23.27 nm (NS-L) were developed with the zeta potential values of -26.5 mV and -27.9 mV, respectively. Results: CZ48 released from the nanosuspensions in a sustained manner in contrast to the rapid release from cosolvent in both PBS and human plasma. Moreover, NS-S exhibited more favored pharmacokinetic properties than NS-L, with a 31-fold prolonged elimination half-life of CPT, and a 2.4-fold enhanced CPT exposure over cosolvent. In efficacy study, NS-S exhibited significant tumor suppression and an improved survival rate with a higher tolerable dose, compared to CZ48 cosolvent. Conclusion: We have successfully developed CZ48 nanosuspensions with significantly favorable pharmacokinetics and improved efficacy using CCD approach. The formulation offers potential merits as a preferred candidate for clinical trials with the prolonged CPT exposure, which is known to correlate with the clinical efficacy.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Nanopartículas/química , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/sangue , Camptotecina/química , Camptotecina/farmacocinética , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Nus , Nanopartículas/administração & dosagem , Tamanho da Partícula , Suspensões , Distribuição Tecidual/efeitos dos fármacos , Inibidores da Topoisomerase I
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