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1.
Nanoscale ; 13(1): 388-396, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33351018

RESUMO

Inspired by the self-assembly approach, in this work, the chromogen, 3,3',5,5'-tetramethylbenzidine (TMB), was successfully co-precipitated in aqueous solution to form collective nanoparticles (NPs) of signal molecules (TMB-NPs). Utilizing poly(lactide-co-glycolide) (PLGA) in the molecular delivery approach, the formed emulsion nanovesicle (TMB-NPs@PLGA) exhibits an enrichment of the collective signal molecules in a single antibody-antigen conjugation. A specific antibody-conjugated TMB-NPs@PLGA forms an immunocomplex sandwich structure upon the addition of influenza virus (IV)/A. The addition of dimethyl sulfoxide (DMSO) dissolves the PLGA nanovesicles, releasing the encapsulated TMB-NPs. Sequentially, the TMB-NPs release TMB molecules upon the addition of DMSO. The released TMB is catalytically oxidized by H2O2 with self-assembled protein-inorganic nanoflowers, where copper nanoflowers (CuNFs) acted as the nanozyme. The developed immunoassay demonstrates high sensitivity for IV/A with a limit of detection (LOD) as low as 32.37 fg mL-1 and 54.97 fg mL-1 in buffer and serum, respectively. For practical needs, a clinically isolated IV/A/H3N2 and spike protein of SARS-CoV-2 were detected with the LODs of 17 pfu mL-1 and 143 fg mL-1, respectively. These results show the applicability of the advanced TMB-NPs@PLGA-based colorimetric sensor for the highly sensitive detection of airborne respiratory viruses.


Assuntos
Técnicas Biossensoriais/métodos , Compostos Cromogênicos/química , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Infecções Respiratórias , /isolamento & purificação , Benzidinas/química , /virologia , Humanos , Peróxido de Hidrogênio , Imunoensaio/métodos , Influenza Humana/diagnóstico , Influenza Humana/virologia , Limite de Detecção , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/virologia , Glicoproteína da Espícula de Coronavírus
2.
ACS Appl Mater Interfaces ; 12(52): 57757-57767, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33319976

RESUMO

As a rapid proliferating tissue, tumor cells have to optimize nutrient utilization to withstand harsh conditions. Several approaches have been explored to inhibit the growth and metastasis of tumor by disrupting the reprogrammed tumor metabolism. However, nutrient limitations within solid tumors may induce the metabolic flexibility of malignant cells to sustain growth and survival using one nutrient to fill metabolite pools normally supplied by the other. To overcome this predicament, a promising click-nucleic-acid-containing platform for codelivery of rapamycin, anti-PFKFB4 siRNA, and targeting ligand aptamer AS1411 was applied. PFKFB4 could act as a promising target for tumor therapy for being a molecular fulcrum that could couple glycolysis to autophagy by promoting aggressive metastatic tumors. The downregulation of PFKFB4 can help inhibit the SRC3/Akt/mTOR pathway, leading autophagy to the direction of promoting apoptosis of tumor cells, which is induced by the collapse of tumor cellular homeostasis, while low dosages of rapamycin could decrease surgery-induced immune dysfunction. Enhanced tumor autophagy, favorable in vivo antitumor efficacy, and effective systematic immune activation are observed after treatment, suggesting that autophagy and glycolysis can serve as an integrated target for tumor treatment.


Assuntos
Autofagia , Portadores de Fármacos/química , Glicólise/efeitos dos fármacos , Homeostase , Neoplasias/terapia , Poli T/química , Animais , Aptâmeros de Nucleotídeos/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Sequência de Bases , Células HEK293 , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fosfofrutoquinase-2/deficiência , Fosfofrutoquinase-2/genética , Polietilenoglicóis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Sirolimo/administração & dosagem , Sirolimo/química , Sirolimo/farmacologia
3.
PLoS One ; 15(12): e0243837, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33332399

RESUMO

Renal Cell Carcinoma (RCC) often becomes resistant to targeted therapies, and in addition, dose-dependent toxicities limit the effectiveness of therapeutic agents. Therefore, identifying novel drug delivery approaches to achieve optimal dosing of therapeutic agents can be beneficial in managing toxicities and to attain optimal therapeutic effects. Previously, we have demonstrated that Honokiol, a natural compound with potent anti-tumorigenic and anti-inflammatory effects, can induce cancer cell apoptosis and inhibit the growth of renal tumors in vivo. In cancer treatment, implant-based drug delivery systems can be used for gradual and sustained delivery of therapeutic agents like Honokiol to minimize systemic toxicity. Electrospun polymeric fibrous scaffolds are ideal candidates to be used as drug implants due to their favorable morphological properties such as high surface to volume ratio, flexibility and ease of fabrication. In this study, we fabricated Honokiol-loaded Poly(lactide-co-glycolide) (PLGA) electrospun scaffolds; and evaluated their structural characterization and biological activity. Proton nuclear magnetic resonance data proved the existence of Honokiol in the drug loaded polymeric scaffolds. The release kinetics showed that only 24% of the loaded Honokiol were released in 24hr, suggesting that sustained delivery of Honokiol is feasible. We calculated the cumulative concentration of the Honokiol released from the scaffold in 24hr; and the extent of renal cancer cell apoptosis induced with the released Honokiol is similar to an equivalent concentration of direct application of Honokiol. Also, Honokiol-loaded scaffolds placed directly in renal cell culture inhibited renal cancer cell proliferation and migration. Together, we demonstrate that Honokiol delivered through electrospun PLGA-based scaffolds is effective in inhibiting the growth of renal cancer cells; and our data necessitates further in vivo studies to explore the potential of sustained release of therapeutic agents-loaded electrospun scaffolds in the treatment of RCC and other cancer types.


Assuntos
Compostos de Bifenilo/farmacologia , Neoplasias Renais/patologia , Lignanas/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Tecidos Suporte/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Humanos
4.
Int J Nanomedicine ; 15: 10401-10416, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376328

RESUMO

Objective: Nanotechnology-based photodynamic therapy (PDT) is a relatively new anti-tumor strategy. However, its efficacy is limited by the hypoxic state in the tumor microenvironment. In the present study, a poly(lactic-co-glycolic acid) (PLGA) nanoparticle that encapsulated both IR820 and catalase (CAT) was developed to enhance anti-tumor therapy. Materials and Methods: HA-PLGA-CAT-IR820 nanoparticles (HCINPs) were fabricated via a double emulsion solvent evaporation method. Dynamic light scattering (DLS), transmission electron microscopy (TEM), laser scanning confocal microscopy, and an ultraviolet spectrophotometer were used to identify and characterize the nanoparticles. The stability of the nanoparticle was investigated by DLS via monitoring the sizes and polydispersity indexes (PDIs) in water, PBS, DMEM, and DMEM+10%FBS. Oxygen generation measurement was carried out via visualizing the oxygen bubbles with ultrasound imaging system and an optical microscope. Inverted fluorescence microscopy and flow cytometry were used to measure the uptake and targeting effect of the fluorescent-labeled nanoparticles. The live-dead method and tumor-bearing mouse models were applied to study the HCINP-induced enhanced PDT effect. Results: The results showed that the HCINPs could selectively target melanoma cells with high expression of CD44, and generated oxygen by catalyzing H2O2, which increased the amount of singlet oxygen, ultimately inhibiting tumor growth significantly. Conclusion: The present study presents a novel nanoplatform for melanoma treatment.


Assuntos
Receptores de Hialuronatos/metabolismo , Melanoma/tratamento farmacológico , Nanopartículas/química , Oxigênio/metabolismo , Fotoquimioterapia/métodos , Animais , Catalase/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Receptores de Hialuronatos/genética , Peróxido de Hidrogênio/metabolismo , Verde de Indocianina/análogos & derivados , Verde de Indocianina/química , Melanoma/metabolismo , Melanoma/patologia , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Oxigênio Singlete/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Int J Nanomedicine ; 15: 8507-8517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33154640

RESUMO

Purpose: The vaccine design has shifted from attenuated or inactivated whole pathogen vaccines to more pure and defined subunit vaccines. The purification of antigen proteins, especially the precise display of antigen regions, has become a key step affecting the effectiveness of subunit vaccines. Materials and Methods: This work presents the application of molecular docking for a peptide ligand designed for PCV2 Cap purification and assembly in one step. Based on the PCV2 Cap protein affinity peptide (L11-DYWWQSWE), the amino terminal of PCV2 Cap was covalently coupled with the polylactic acid-glycolic acid copolymer (PLGA) carboxyl terminal through the EDC/NHS method. Results: The PLGA had an average diameter of 106 nm. The average diameter increased to 122 nm after the PCV2 Cap protein conjugation, and the Zeta potential shifted from -13.7 mV to -9.6 mV, indicating that the PCV2 Cap protein stably binds to the PLGA. Compared with the free PCV2 Cap protein group, the neutralizing antibody titer was significantly increased on the 14th day after the PLGA-Cap immunization (P < 0.05). The neutralizing antibody level was extremely significant on the 28th day (P < 0.001). The CCK-8 analysis showed that PLGA-Cap had an obvious cytotoxic effect on RAW264.7 cells at the PLGA nanoparticle concentration up to 200 µg/mL but had no obvious cytotoxic effect on DC2.4 cells. Compared with the Cap protein group, the antigen-presenting cells had a stronger antigen uptake capacity and a higher fluorescence in the PLGA-Cap group. The immune effect showed that the level of the neutralizing antibody produced by this structure is much better than that of purified protein and helps improve the immune system response. Conclusion: This technology provides a potential new perspective for the rapid enrichment of the antigen protein with the affinity peptide ligand.


Assuntos
Proteínas do Capsídeo/imunologia , Circovirus/imunologia , Nanopartículas/química , Peptídeos/imunologia , Vacinas Virais/imunologia , Vacinas Virais/isolamento & purificação , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Células Apresentadoras de Antígenos/metabolismo , Sítios de Ligação , Linhagem Celular , Infecções por Circoviridae/imunologia , Citocinas/biossíntese , Inflamação/patologia , Ligantes , Camundongos , Simulação de Acoplamento Molecular , Nanopartículas/ultraestrutura , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
6.
Int J Nanomedicine ; 15: 8059-8074, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116518

RESUMO

Introduction: Thymoquinone (TQ) is the main active compound extracted from Nigella sativa a traditional herb with wide therapeutic applications and recognizable anticancer properties. This study aimed to formulate and characterize TQ-nanoparticles using PLGA as a biocompatible coating material (TQ-PLGA NPs) with the evaluation of its therapeutic properties in human melanoma cancer cells. Methods: The TQ-PLGA NPs were prepared and characterized for size, zeta potential, encapsulation efficiency, and release profile. Results: The particle size was 147.2 nm, with 22.1 positive zeta potential and 96.8% encapsulation efficiency. The NPs released 45.6% of the encapsulated TQ within 3 h followed by characteristic sustained release over 7 days with a total of 69.7% cumulative release. TQ-PLGA NPs were taken up effectively by the cells in a time-dependent manner up to 24 h. Higher cell toxicity was determined within the first 24 h in melanoma cells due to the rapid release of TQ from the NPs and its low stability in the cell culture media. Conclusion: TQ-PLGA NPs is a potential anticancer agent taking advantage of the sustained release and tailored size that allows accumulation in the cancer tissue by the enhanced permeability and retention effect. However, stability problems of the active ingredient were address in this study and requires further investigation.


Assuntos
Benzoquinonas/farmacologia , Composição de Medicamentos , Endocitose , Melanoma/patologia , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Varredura Diferencial de Calorimetria , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Meios de Cultura , Liberação Controlada de Fármacos , Fluorescência , Humanos , Melanoma/tratamento farmacológico , Nanopartículas/ultraestrutura , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Int J Nanomedicine ; 15: 6761-6777, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982232

RESUMO

Purpose: Guided bone regeneration (GBR) therapy, which is a widely used technique in clinical practice and is effective in improving the repair of alveolar bone defects or bone mass deficiency regeneration, requires the use of membrane materials with good biocompatibility, barrier function, rigidity matching the space maintenance ability, economic benefits and excellent clinical applicability. The aim of this study was to develop an electrospun attapulgite (ATT)-doped poly (lactic-co-glycolic acid) (PLGA) scaffold (PLGA/ATT scaffold) as a novel material for GBR applications. Methods and Results: Scanning electron microscopy (SEM) and X-ray diffraction (XRD) were used to determine the morphology and the crystalline structure of the PLGA/ATT scaffolds, respectively. Porosity and contact-angle measurements were also carried out to further characterize the physical properties of the PLGA/ATT scaffolds. The results of in vitro studies showed that bone marrow mesenchymal stem cells (BMSCs) attached more readily to and spread better over the PLGA/ATT scaffolds than the Bio-Gide membrane. Furthermore, in the in vitro osteoinductive experiments with BMSCs, the PLGA/ATT scaffolds were found to enhance the activity of alkaline phosphatase (ALP), promote the formation of mineralized bone nodules, and up-regulate the expression of several osteogenic markers-namely, runt-related transcription factor 2, alkaline phosphatase, osteopontin, and osteocalcin-which are similar to the effects of the Bio-Gide membrane. Further, in in vivo studies, the results of sequential fluorescent labeling, micro-computed tomography, and histological analysis suggest that using the PLGA/ATT scaffolds for repairing V-shaped buccal dehiscence on a dog's tooth root improved bone regeneration, which is not only similar to the result obtained using the Bio-Gide membrane but also much better than that obtained using PLGA scaffolds and the negative control. Conclusion: To achieve satisfactory therapeutic results and to lower the cost of GBR treatment, this study provided a promising alternative material of bio-degradable membrane in clinical treatment.


Assuntos
Perda do Osso Alveolar/terapia , Regeneração Óssea/fisiologia , Compostos de Magnésio/farmacologia , Compostos de Silício/farmacologia , Tecidos Suporte/química , Animais , Regeneração Óssea/efeitos dos fármacos , Calcificação Fisiológica , Colágeno , Cães , Expressão Gênica , Gengiva/citologia , Humanos , Compostos de Magnésio/química , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteogênese/fisiologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Porosidade , Ratos Sprague-Dawley , Compostos de Silício/química , Raiz Dentária/diagnóstico por imagem , Microtomografia por Raio-X
8.
PLoS One ; 15(9): e0239366, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32991599

RESUMO

Platelet-derived growth factor-bb (PDGF-BB) is a potent chemokine and mitogen for fibroblasts, keratinocytes, and vascular endothelium in the injured area, believed to be effective in wound healing. However, the short half-life of PDGF-BB and its rapid release from the wound surface limited its efficacy in vivo and vitro. To evaluate the wound healing effects of dorsal skin in SD rats with polydopamine-assisted immobilized PDGF-BB on PLGA nanofibrous substrate. First, the effects of pDA-coating and PDGF-BB immobilization on the morphology, compositions, and hydrophilicity of substrates were evaluated in details. Second, the wound healing effect of pDA/PLGA/PDGF-BB substrate was assessed in the dorsal skin of SD rats. Last, the cytokine analysis by ELISA method was employed to evaluate the advantages of pDA/PLGA/PDGF-BB substrate on anti-inflammatory, angiogenesis, and cellular proliferation. This method significantly improved the immobilization amount and stability of PDGF-BB on the substrate (p<0.01), further improved the hydrophilicity of substrates (p<0.05). Furthermore, the wound closure process was much more accelerated in the pDA/PLGA/PDGF-BB group (p<0.05). H&E and CD31 staining informed that the wound treated by pDA/PLGA/PDGF-BB substrate showed a high degree of regeneration and angiogenesis. The cytokine analysis showed that pDA significantly reduced the high level of inflammatory cytokines such as TNF-α (p<0.05). And the immobilized PDGF-BB significantly elevated the level of TGF-ß and VEGF (p<0.05). The pDA/PLGA/PDGF-BB substrate showed great therapeutic effect on wound healing compared with other control groups via regulating anti-inflammatory, angiogenesis, and cellular proliferation. Absolutely, this report offered an available novel method for skin regeneration.


Assuntos
Becaplermina/química , Becaplermina/farmacologia , Citocinas/metabolismo , Indóis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Cicatrização/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Proteínas Imobilizadas/química , Proteínas Imobilizadas/farmacologia , Cinética , Masculino , Ratos , Ratos Sprague-Dawley
9.
Int J Nanomedicine ; 15: 5527-5543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848386

RESUMO

Background: Poly(lactic-co-glycolic acid) (PLGA) has been extensively applied for sustained drug delivery and vaccine delivery system. However, vaccines delivered by PLGA nanoparticles alone could not effectively activate antigen-presenting cells (APCs) to induce strong immune responses. Purpose: The aim of the present study was to design polyethylenimine (PEI)-modified Chinese yam polysaccharide (CYP)-encapsulated PLGA nanoparticles (CYPP-PEI) as a vaccine delivery system and evaluate the adjuvant activities in vitro and in vivo. Materials and Methods: Cationic-modified nanoparticles exhibited high antigen absorption and could be efficiently taken by APCs to enhance the immune responses. Therefore, PEI-modified CYP-encapsulated PLGA nanoparticles (CYPP-PEI) were prepared. The storage stability and effective adsorption capacity for porcine circovirus-2 (PCV-2) antigen of these antigen-absorbed nanoparticles were measured for one month. Furthermore, the adjuvant activity of CYPP-PEI nanoparticles was evaluated on macrophages in vitro and through immune responses triggered by PCV-2 antigen in vivo. Results: The PCV-2 absorbed CYPP-PEI nanoparticles showed excellent storage stability and high absorption efficiency of PCV-2 antigen. In vitro, CYPP-PEI nanoparticles promoted antigen uptake, enhanced surface molecular expressions of CD80 and CD86, and improved cytokine secretion of TNF-α, IFN-γ, and IL-12p70 in macrophages. After immunization with CYPP-PEI/PCV-2 formulation in mice, the expressions of surface activation markers on dendritic cells which located in draining lymph nodes were increased, such as MHCI, MHCII, and CD80. In addition, CYPP-PEI nanoparticles induced dramatically high PCV-2-specific IgG levels which could last for a long time and stimulated the secretion of subtype antibodies and cytokines. The results showed that CYPP-PEI could induce Th1/Th2 mixed but Th1-biased type immune responses. Conclusion: Polyethylenimine-modified Chinese yam polysaccharide-encapsulated PLGA nanoparticle was a potential vaccine delivery system to trigger strong and persistent immune responses.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Dioscorea/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Polissacarídeos/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Antígenos/farmacologia , Circovirus/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Estabilidade de Medicamentos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos ICR , Nanopartículas/administração & dosagem , Polietilenoimina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Vacinas/administração & dosagem , Vacinas/imunologia
10.
Int J Nanomedicine ; 15: 5927-5949, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848397

RESUMO

Purpose: A multi-functional nanoplatform with diagnostic imaging and targeted treatment functions has aroused much interest in the nanomedical research field and has been paid more attention in the field of tumor diagnosis and treatment. However, some existing nano-contrast agents have encountered difficulties in different aspects during clinical promotion, such as complicated preparation process and low specificity. Therefore, it is urgent to find a nanocomplex with good targeting effect, high biocompatibility and significant therapeutic effect for the integration of diagnosis and treatment and clinical transformation. Materials and Methods: Nanoparticles (NPs) targeting breast cancer were synthesized by phacoemulsification which had liquid fluorocarbon perfluoropentane(PFP) in the core and were loaded with Iron(II) phthalocyanine (FePc) on the shell. The aptamer (APT) AS1411 was outside the shell used as a molecular probe. Basic characterization and targeting abilities of the NPs were tested, and their cytotoxicity and biological safety in vivo were evaluated through CCK-8 assay and blood bio-chemical analysis. The photoacoustic (PA) and ultrasound (US) imaging system were used to assess the effects of AS1411-PLGA@FePc@PFP (A-FP NPs) as dual modal contrast agent in vitro and in vivo. The effects of photothermal therapy (PTT) in vitro and in vivo were evaluated through MCF-7 cells and tumor-bearing nude mouse models. Results: A-FP NPs, with good stability, great biocompatibility and low toxicity, were of 201.87 ± 1.60 nm in diameter, and have an active targeting effect on breast cancer cells and tissues. With the help of PA/US imaging, it was proved to be an excellent dual modal contrast agent for diagnosis and guidance of targeted therapy. Meanwhile, it can heat up under near-infrared (NIR) laser irradiation and has achieved obvious antitumor effect both in vitro and in vivo experiments. Conclusion: As a kind of nanomedicine, A-FP NPs can be used in the integration of diagnosis and treatment. The treatment effects and biocompatibility in vivo may provide new thoughts in the clinical transformation of nanomedicine and early diagnosis and treatment of breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Indóis/química , Nanopartículas Multifuncionais/química , Oligodesoxirribonucleotídeos/farmacologia , Animais , Aptâmeros de Nucleotídeos/administração & dosagem , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Neoplasias da Mama/patologia , Meios de Contraste/química , Feminino , Fluorcarbonetos/química , Humanos , Ferro/química , Células MCF-7 , Camundongos Endogâmicos BALB C , Nanopartículas Multifuncionais/administração & dosagem , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/química , Fototerapia/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ultrassonografia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Life Sci ; 261: 118361, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861796

RESUMO

AIM: Antibody-conjugated nanoparticles have attracted much attention in the field of cancer treatment due to the enhancement of the tumor cell response to anticancer drugs as well as reducing the side effects of chemotherapeutic agents on healthy tissues. However, most studies in this field generally mentioned the specific cellular uptake of conjugated nanoparticles. In this study, we loaded doxorubicin (DXR: as an effective antineoplastic agent) in PLGA-PEG (D,L-lactic-co-glycolic acid)-(polyethylene glycol) biocompatible polymeric nanoparticles (NPs) and then conjugated with anti-EGFRvIII antibody. The resulting nanoparticles had remarkable sensitivity to pH decrease and were capable of targeting specific cells. MATERIALS AND METHODS: To this aim, PLGA-PEG-COOH was used for the synthesis of nanoparticles and stabilized by polyvinyl alcohol (PVA) according to the nanoprecipitation method. The carboxylic groups on the surface of PLGA-PEG NPs were activated by EDC/NHS and covalently conjugated to amino groups of the monoclonal antibody. The prepared NPs were characterized by Zetasizer and transmission electron microscopy (TEM). The resulting NPs were evaluated in terms of entrapment efficiency (EE), drug loading efficiency (DLE), drug-release profile, and cell internalization. Intrinsic cytotoxicity was assessed by the MTT, apoptosis (Annexin V-PI) and cell cycle assays. KEY FINDINGS: The in vitro drug release assessment of conjugated particles (MAb-DXR-PLGA NPs) showed a slow sustained DXR release in physiological pH (7.4) values, while the initial drug release was markedly higher (the 1.9 fold) in acidic pH (6.5) ranges. The selectivity for cellular internalization of MAb-DXR-PLGA NPs into U87MG vIII cells (overexpressing EGFRvIII) in comparison with U87MG cells (lacking EGFRvIII expression) was also confirmed. The MTT assay demonstrated that the cytotoxicity of MAb-DXR-PLGA NPs against U87MG vIII cells was more pronounced when compared with BSA-DXR-PLGA NPs. The results of the MTT assay were also confirmed by apoptosis and cell cycle assays. SIGNIFICANCE: Our findings suggest that the designed anti-EGFRvIII MAb-DXR-PLGA NPs could be considered as a proper option for targeted drug delivery systems due to pH sensitivity and specific cellular internalization.


Assuntos
Anticorpos Monoclonais/farmacologia , Doxorrubicina/farmacologia , Endocitose , Receptores ErbB/imunologia , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas/ultraestrutura
12.
J Oleo Sci ; 69(9): 1125-1132, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32788521

RESUMO

Controlling the size of nanoparticles is important for drug delivery methods such as pulmonary administration, transdermal administration, and intravenous administration. In this study, we have investigated the effect of polymer conformation in organic solvents on the size of the nanoparticles. Poly(L-lactide-co-glycolide) (PLLGA), a promising nanoparticle carrier, was used as the polymer. A mixed solution of dichloromethane, which is a good solvent, and a lower alcohol (methanol, ethanol, and 1-propanol), which is a poor solvent, was used as the solvent for dissolving PLLGA. An oil-in-water emulsion was prepared by sonication using the mixed solution of organic solvents in which PLLGA was dissolved as a dispersed phase and an amino acid aqueous solution as a continuous phase. Nanocomposite particles were prepared from the emulsion using a spray dryer and redispersed in purified water to obtain the PLLGA nanoparticles. The conformation of PLLGA molecules in the organic solvents was evaluated by analyzing the results of the viscosity measurements. The polymer coil radius and the volume per polymer coil were observed to decrease with the increase in the ratio of the lower alcohol in the solvent, whereas these values tended to decrease with the use of more hydrophilic lower alcohols. In addition, based on the results of the calculated entanglement index, it was found that when the hydrophobicity of the dispersed phase is reduced, the polymers were hardly entangled with each other. These results were significant, specifically when the ratio of the lower alcohol in the solvent was low. Estimation of the Pearson's correlation coefficients indicated that there were positive correlations between these indices and the mean volume diameter of PLLGA nanoparticles. This study shows that changing the composition of the dispersed phase, in which the PLLGA is dissolved, can change the conformation of the PLLGA molecules and control the size of the PLLGA nanoparticles.


Assuntos
Cloreto de Metileno/química , Nanopartículas/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Solventes/química , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Emulsões , Interações Hidrofóbicas e Hidrofílicas , Conformação Molecular , Psicoterapia Breve , Sonicação
13.
Int J Nanomedicine ; 15: 5389-5403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801695

RESUMO

Hypothesis: Developing oral formulations to enable effective release of poorly water-soluble drugs like progesterone is a major challenge in pharmaceutics. Coaxial electrospray can generate drug-loaded nanoparticles of strategic compositions and configurations to enhance physiological dissolution and bioavailability of poorly water-soluble drug progesterone. Experiments: Six formulations comprising nanoparticles encapsulating progesterone in different poly(lactide-co-glycolide) (PLGA) matrix configurations and compositions were fabricated and characterized in terms of morphology, molecular crystallinity, drug encapsulation efficiency and release behavior. Findings: A protocol of fabrication conditions to achieve 100% drug encapsulation efficiency in nanoparticles was developed. Scanning electron microscopy shows smooth and spherical morphology of 472.1±54.8 to 588.0±92.1 nm in diameter. Multiphoton Airyscan super-resolution confocal microscopy revealed core-shell nanoparticle configuration. Fourier transform infrared spectroscopy confirmed presence of PLGA and progesterone in all formulations. Diffractometry indicated amorphous state of the encapsulated drug. UV-vis spectroscopy showed drug release increased with hydrophilic copolymer glycolide ratio while core-shell formulations with progesterone co-dissolved in PLGA core exhibited enhanced release over five hours at 79.9±1.4% and 70.7±3.5% for LA:GA 50:50 and 75:25 in comparison with pure progesterone without polymer matrix in the core at 67.0±1.7% and 57.5±2.8%, respectively. Computational modeling showed good agreement with the experimental drug release behavior in vitro.


Assuntos
Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Progesterona/administração & dosagem , Progesterona/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Microscopia Eletrônica de Varredura , Nanopartículas/administração & dosagem , Tamanho da Partícula , Solubilidade , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química , Difração de Raios X
14.
Arch Biochem Biophys ; 691: 108485, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32712288

RESUMO

Most problems associated with chemotherapeutic agents involve non-specific cytotoxicity, low intratumoral accumulation and drug resistance. Targeted drug delivery systems (TDDS) based on nanoparticles (NPs) are a new strategy for better therapeutic efficiency, along with reduction of side effects commonly seen with cancer drugs. Poly (lactic-co-glycolic acid) (PLGA), as one of the furthest developed synthetic polymer, has gained significant attention because of excellent properties-including biodegradability and biocompatibility, controlled release of drug, protection of drug or gene from decomposition and ability to modify surface with targeting agents for both cancer diagnosis and therapy. Aptamers are single-stranded RNA or DNA that can fold through intramolecular interactions into specific three-dimensional structures to selectively and exclusively bind with interested biomarkers. In this review, we explain the latest developments regarding the application of aptamer-decorated PLGA NPs in delivery of therapeutic agents or cancer-related genes into cancer cells. Additionally, we discuss the most recent efforts in the field of aptamer-grafted PLGA-based NPs as theranostics and stimuli-responsive agents.


Assuntos
Antineoplásicos/uso terapêutico , Aptâmeros de Nucleotídeos/química , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Sequência de Bases , Linhagem Celular Tumoral , Humanos , Neoplasias/diagnóstico por imagem , Nanomedicina Teranóstica/métodos
15.
AAPS PharmSciTech ; 21(5): 194, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32666160

RESUMO

For polymer-based controlled release drug products (e.g. microspheres and implants), active pharmaceutical ingredient distribution and microporosity inside the polymer matrix are critical for product performance, particularly drug release kinetics. Due to the decreasing domain size and increasing complexity of such products, conventional characterization and release test techniques are limited by their resolution and speed. In this study, samples of controlled release poly(lactic-co-glycolic acid) microspheres in the diameter range of 30-80 µm are investigated with focused ion beam scanning electron microscope imaging at 20 nm or higher resolution. Image data is quantified with artificial intelligence-based image analytics to provide size distributions of drug particles and pores within the microsphere sample. With an innovative image-based numerical simulation method, release profiles are predicted in a matter of days regardless of the designed release time. A mechanistic understanding on the impact of porosity to the interplays of drug, formulation, process, and dissolution was gained.


Assuntos
Preparações de Ação Retardada , Microscopia Eletrônica de Varredura/métodos , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Inteligência Artificial , Composição de Medicamentos , Cinética , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Porosidade , Solubilidade
16.
Int J Nanomedicine ; 15: 3965-3980, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606658

RESUMO

Aim: Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. Materials and Methods: PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P2h), 4h (P4h) and 12h (P12h). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit®-S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. Results: M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P2h, P4h and P12h were 10.1%, 28.60% and 65.45%. Significant (p < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in Tmax (from 2.5h to 6h), a prolongation in MRT0-∞ (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). Conclusion: E-M14C is a potential system for possible colon targeting of etoricoxib.


Assuntos
Colo/efeitos dos fármacos , Etoricoxib/farmacologia , Etoricoxib/farmacocinética , Voluntários Saudáveis , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ácidos Polimetacrílicos/química , Administração Oral , Adulto , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Colo/metabolismo , Liberação Controlada de Fármacos , Humanos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Adulto Jovem
17.
Int J Nanomedicine ; 15: 4417-4429, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606686

RESUMO

Purpose: Currently, the clinical benefits of tea polyphenols have contributed to the development of efficient systemic delivery systems with adequate bioavailability and stability. In this study, we aimed to establish a nanoparticle model to overcome the shortcomings of epigallocatechin gallate (EGCG) in the treatment of lung cancer. Materials and Methods: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with EGCG were prepared by the oil-in-water emulsion solvent evaporation technique. The characteristics of NPs, entrapment efficiency, and in vitro release were systematically evaluated. The cellular uptake, cytotoxic activity, and the effect of the formulation on cellular apoptosis of free-from EGCG and the NPs were compared. The interaction between protein-NF-κB and EGCG was detected by bio-layer interferometry (BLI). NF-κB signaling was evaluated by Western blotting and q-RT-PCR. The efficacy of the optimized nanoformulation was evaluated using a patient-derived tumor xenograft (PDX) model. Results: EGCG-loaded NPs (175.8±3.8 nm in size) demonstrated its optimal efficacy, with approximately 86.0% of encapsulation efficiency and 14.2% of loading efficiency. Additionally, EGCG-encapsulated PLGA-NPs offered a 3-4-fold dose advantage compared to free EGCG in terms of exerting antiproliferative effects and inducing apoptosis at lower doses (12.5, 25 µM). Molecular interaction assays demonstrated that EGCG binds to NF-κB with high affnity (KD=4.8×10-5 M). EGCG-NPs were more effective at inhibiting NF-κB activation and suppressing the expression of NF-κB-regulated genes than free EGCG. Furthermore, EGCG-NPs showed superior anticancer activity in the PDX model than free EGCG. Conclusion: These findings indicated that the prepared EGCG-NPs were more effective than free EGCG in inhibiting lung cancer tumors in the PDX model.


Assuntos
Antineoplásicos/uso terapêutico , Catequina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Catequina/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Nanopartículas/química
18.
Int J Nanomedicine ; 15: 4483-4500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606690

RESUMO

Purpose: Tumor metastasis and drug resistance have always been vital aspects to cancer mortality and prognosis. To compromise metastasis and drug resistance, a nanoparticle IPPD-PHF2 (IR780/PLGA-PEI(Dox)-PHF2) has been engineered to accomplish efficient targeted epigenotherapy forced by PHF2-induced MET (mesenchymal to epithelial transition). Materials and Methods: IPPD-PHF2 nanoparticle was synthesized and characterized by several analytical techniques. The transfection efficiency of IPP-PHF2 (IR780/PLGA-PEI-PHF2) was compared with PP-PHF2 (PLGA-PEI-PHF2) in vitro by WB and in vivo by IHC, and the cytotoxicity of IPP was compared with Lipo2000 in vitro by CCK8 assay. The inhibition of cancer cell migration caused by PHF2-upregulation was tested by wound healing assay, and the enhanced chemotherapeutic sensitivity was detected by flow cytometry. Tumor-targeting property of IPPD-PHF2 was proved by fluorescent imaging in vivo with MDA-MB-231 tumor-bearing nude mice. Except for fluorescent imaging ability, considerable photoacoustic signals of IPPD-PHF2 at tumor sites were verified. The anti-tumor activity of IPPD-PHF2 was investigated using in vivo human breast cancer MDA-MB-231 cell models. Results: Tumor-targeting nanoparticle IPPD-PHF2 had an average size of about 319.2 nm, a stable zeta potential at about 38 mV. The encapsulation efficiency of doxorubicin was around 39.28%, and the adsorption capacity of plasmids was about 64.804 µg/mg. Significant up-regulation of PHF2 induced MET and caused reduced migration as well as enhanced chemotherapeutic sensitivity. Either IPPD (IR780/PLGA-PEI(Dox)) or IPP-PHF2 (IR780/PLGA-PEI-PHF2) presented minor therapeutic effects, whereas IPPD-PHF2 specifically accumulated within tumors, showed extraordinary transfection efficiency specifically in tumor sites, acted as inhibitors of metastasis and proliferation, and presented good multimodality imaging potentials in vivo. Conclusion: IPPD-PHF2 NPs is a promising tool to bring epigenotherapy into a more practical era, and the potential application of harm-free multimodality imaging guidance is of great value.


Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transfecção , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Indóis/química , Camundongos Nus , Nanopartículas/ultraestrutura , Metástase Neoplásica , Técnicas Fotoacústicas , Polietilenoimina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
19.
Macromol Rapid Commun ; 41(15): e2000314, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32608550

RESUMO

Light induced degradation of polymers has drawn increasing interest due to the need for externally controllable modulation of materials properties. However, the portfolio of polymers, that undergo precisely controllable degradation, is limited and typically requires UV light. A novel class of backbone-degradable polymers that undergo aerobic degradation in the presence of visible light, yet remain stable against broad-spectrum light under anaerobic conditions is reported. In this design, the polymer backbone is comprised of 9,10-dialkoxyanthracene units that are selectively cleaved by singlet oxygen in the presence of green light as confirmed by NMR and UV/vis spectroscopy. The resulting polymers have been processed by electrohydrodynamic (EHD) co-jetting into bicompartmental microfibers, where one hemisphere is selectively degraded on demand.


Assuntos
Antracenos/química , Polímeros/química , Polímeros/efeitos da radiação , Luz , Espectroscopia de Ressonância Magnética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Oxigênio Singlete/química , Análise Espectral , Raios Ultravioleta
20.
Int J Nanomedicine ; 15: 3303-3318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494131

RESUMO

Background: Poultry vaccine has limited choices of adjuvants and is facing severe threat of infectious diseases due to ineffective of widely used commercial vaccines. Thus, development of novel adjuvant that offers safe and effective immunity is of urgent need. Materials and Methods: The present research engineers a novel chicken adjuvant with potent immune-potentiating capability by incorporating avian toll-like receptor 21 (TLR21) agonist CpG ODN 2007 with a poly(lactic-co-glycolic acid) (PLGA)-based hollow nanoparticle platform (CpG-NP), which subsequently assessed ex vivo and in vivo. Results: CpG-NPs with an average diameter of 164 nm capable of sustained release of CpG for up to 96 hours were successfully prepared. With the ex vivo model of chicken bone marrow-derived dendritic cells (chBMDCs), CpG-NP was engulfed effectively and found to induce DC maturation, promoting dendrite formation and upregulation of CD40, CD80 and CCR7. In addition to enhanced expression of IL-1ß, IL-6, IL-12 and IFN-γ, 53/84 immune-related genes were found to be stimulated in CpG-NP-treated chBMDCs, whereas only 39 of such genes were stimulated in free CpG-treated cells. These upregulated genes suggest immune skewing toward T helper cell 1 bias and evidence of improved mucosal immunity upon vaccination with the CpG-NP. The CpG-NP-treated chBMDCs showed protective effects to DF-1 cells against avian influenza virus H6N1 infection. Upon subsequent coupling with infectious bronchitis virus subunit antigen administration, chickens were immunostimulated to acquire higher humoral immune response and protective response against viral challenge. Conclustion: This work presents a novel hollow CpG-NP formulation, demonstrating effective and long-lasting immunostimulatory ability ex vivo and in vivo for chickens, as systemically compared to free CpG. This enhanced immune stimulation benefits from high stability and controlled release of internal component of nanoparticles that improve cellular delivery, lymphoid organ targeting and sustainable DC activation. CpG-NP has broad application potential in antiviral and vaccine development.


Assuntos
Antivirais/farmacologia , Galinhas/imunologia , Imunidade/efeitos dos fármacos , Nanopartículas/química , Oligodesoxirribonucleotídeos/farmacologia , Polímeros/química , Vacinas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Cães , Imunidade Humoral/efeitos dos fármacos , Imunização , Vírus da Bronquite Infecciosa/efeitos dos fármacos , Células Madin Darby de Rim Canino , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
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