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1.
Nat Commun ; 12(1): 5243, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475406

RESUMO

Peroxisome, a special cytoplasmic organelle, possesses one or more kinds of oxidases for hydrogen peroxide (H2O2) production and catalase for H2O2 degradation, which serves as an intracellular H2O2 regulator to degrade toxic peroxides to water. Inspired by this biochemical pathway, we demonstrate the reactive oxygen species (ROS) induced tumor therapy by integrating lactate oxidase (LOx) and catalase (CAT) into Fe3O4 nanoparticle/indocyanine green (ICG) co-loaded hybrid nanogels (designated as FIGs-LC). Based on the O2 redistribution and H2O2 activation by cascading LOx and CAT catalytic metabolic regulation, hydroxyl radical (·OH) and singlet oxygen (1O2) production can be modulated for glutathione (GSH)-activated chemodynamic therapy (CDT) and NIR-triggered photodynamic therapy (PDT), by manipulating the ratio of LOx and CAT to catalyze endogenous lactate to produce H2O2 and further cascade decomposing H2O2 into O2. The regulation reactions of FIGs-LC significantly elevate the intracellular ROS level and cause fatal damage to cancer cells inducing the effective inhibition of tumor growth. Such enzyme complex loaded hybrid nanogel present potential for biomedical ROS regulation, especially for the tumors with different redox state, size, and subcutaneous depth.


Assuntos
Antineoplásicos/farmacologia , Nanogéis/química , Peroxissomos/enzimologia , Fotoquimioterapia/métodos , Animais , Antineoplásicos/química , Catalase/química , Catalase/metabolismo , Catálise , Linhagem Celular Tumoral , Óxido Ferroso-Férrico/química , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Verde de Indocianina/química , Camundongos , Oxigenases de Função Mista/química , Oxigenases de Função Mista/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos
2.
Biomaterials ; 271: 120763, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33780737

RESUMO

Nanomaterials have attracted increased attention because of their excellent drug-carrying capacity. However, these nanomaterials are rarely used in the treatment of metabolic diseases. Liraglutide, a glucagon-like peptide-1 receptor agonist, has been widely used in the treatment of type 2 diabetes mellitus (T2DM). Furthermore, fibroblast growth factor 21 (FGF-21) has been found to improve glucose metabolism and insulin resistance (IR). To investigate whether these two molecules have synergistic effects in vivo, we developed a novel drug delivery system using amino-functionalized and embedded dual-mesoporous silica nanoparticles (N-EDMSNs) to simultaneously carry liraglutide and FGF-21, and observed their biological effects. The resultant N-EDMSNs possessed unique hierarchical porous structures consisting of open large pores (>10 nm) and small mesopores (~2.5 nm) in the silica framework, highly positively charged surfaces and good disperisity in aqueous solution. We found that N-EDMSNs had a high loading capacity for exogenous genes and low toxicity to Hepa1-6 cells. Moreover, N-EDMSNs can simultaneously carry FGF-21 plasmids and liraglutide and successfully transfect them into Hepa1-6 cells. The transfection efficiency of N-EDMSNs was higher than that of Lipofectamine 2000 in vitro. In mice experiments, N-EDMSNs/pFGF21 treatment resulted in higher FGF-21 expression in the liver than pFGF21 treatment with hydrodynamic delivery. Compared with both pFGF21 and liraglutide, N-EDMSNs/pFGF21/Lira treatment significantly reduced the food intake, body weight, and blood glucose; increased the energy expenditure and improved hepatic IR in high-fat diet (HFD)-fed mice. Our results demonstrated that the biological effects of N-EDMSNs/pFGF21/Lira complexes were better than those of pFGF21 combined with liraglutide in vivo.


Assuntos
Diabetes Mellitus Tipo 2 , Nanopartículas , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fatores de Crescimento de Fibroblastos , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Camundongos , Plasmídeos , Dióxido de Silício
3.
Adv Healthc Mater ; 10(9): e2002126, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33644985

RESUMO

Recently, nanoparticle-triggered in situ catalytic Fenton/Fenton-like reaction is widely explored for tumor-specific chemodynamic therapy (CDT). However, despite the great potential of CDT in tumor treatment, insensitive response to the relatively high pH of the tumor sites and the insufficient intratumoral H2 O2 level leads to limited efficiency of most Fenton/Fenton-like reactions, which greatly imped its clinical conversion. This paper reports the fabrication of Fenton-type bimetallic peroxides for ultrasensitive chemodynamic therapy with high pH-activated, synergistic effect/H2 O2 self-supply-mediated cascade Fenton chemistry for the first time. The observations reveal that these bimetallic peroxides exhibit an ultrasensitive acid-activated decomposition-mediated Fenton-like reaction at the relatively high pH of 6.5-7.0, accompanied with highly increased •OH generation efficiency (especially, 40-60-fold increase at pH 7.0) by the metal-mediated synergistic effect-enhanced Fenton chemistry as well as in situ self-generated H2 O2 supplement. Moreover, the bimetallic peroxides exhibit high tumor accumulation which along with a high-efficiency tumor catalytic-therapeutic with negligible side effects in vivo. Developing these novel bimetallic peroxides, together with the already demonstrated capacity of the key metals (Fe, Mn, Cu, etc.) for magnetic resonance imaging or photodynamic/immune-enhanced therapy, will propel interest in development of smart high-efficiency nanoplatform for cancer theranostics.


Assuntos
Nanopartículas , Peróxidos , Catálise , Linhagem Celular Tumoral , Peróxido de Hidrogênio , Concentração de Íons de Hidrogênio
4.
Angew Chem Int Ed Engl ; 59(47): 21143-21150, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-32729980

RESUMO

Unpredictable in vivo therapeutic feedback of hydroxyl radical (. OH) efficiency is the major bottleneck of chemodynamic therapy. Herein, we describe novel Fenton-based nanotheranostics NQ-Cy@Fe&GOD for spatio-temporally reporting intratumor . OH-mediated treatment, which innovatively unites dual-channel near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI) signals. Specifically, MRI signal traces the dose distribution of Fenton-based iron oxide nanoparticles (IONPs) with high-spatial resolution, meanwhile timely fluorescence signal quantifies . OH-mediated therapeutic response with high spatio-temporal resolution. NQ-Cy@Fe&GOD can successfully monitor the intracellular release of IONPs and . OH-induced NQO1 enzyme in living cells and tumor-bearing mice, which makes a breakthrough in conquering the inherent unpredictable obstacles on spatio-temporally reporting chemodynamic therapy, so as to manipulate dose-dependent therapeutic process.


Assuntos
Antineoplásicos/farmacologia , Peróxido de Hidrogênio/farmacologia , Radical Hidroxila/farmacologia , Ferro/farmacologia , Nanopartículas Magnéticas de Óxido de Ferro/química , Imageamento por Ressonância Magnética , Imagem Óptica , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dicumarol/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Peróxido de Hidrogênio/síntese química , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Raios Infravermelhos , Ferro/química , Camundongos , Camundongos Nus , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo
5.
ACS Appl Mater Interfaces ; 12(22): 24644-24654, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32407072

RESUMO

Recently, Mn(II)-based T1-weighted magnetic resonance imaging (MRI) contrast agents (CAs) have been explored widely for cancer diagnosis. However, the "always-on" properties and poor excretability of the conventional Mn(II)-based CAs leads to high background signals and unsatisfactory clearance from the body. Here, we report an "in situ three-dimensional to two-dimensional (3D-to-2D) transformation" method to prepare novel excretable 2D manganese-based layered silicates (Mn-LSNs) with extremely high signal-to-noise for tumor-specific MR imaging for the first time. Our observations combined with density functional theory (DFT) calculations reveal that 3D metal (Mn, Fe, Co) oxide nanoparticles are initially formed from the molecular precursor solution and then in situ transform into 2D metal (Mn, Fe, Co)-based layered silicates triggered by the addition of tetraethyl orthosilicate, which provides a time-saving and versatile way to prepare novel 2D silicate nanomaterials. The unique ion-exchangeable capacity and high host layer charge density endow Mn-LSNs with an "ON/OFF" pH/GSH stimuli-activatable T1 relaxivity with superb high signal-to-noise (640-, 1200-fold for slightly acidic and reductive changes, respectively). Further in vivo MR imaging reveals that Mn-LSNs exhibit a continuously rapid T1-MRI signal enhancement in tumor tissue and no visible signal enhancement in normal tissue, indicating an excellent tumor-specific imaging. In addition, Mn-LSNs exhibit a rapid excretion from the mouse body in 24 h and invisible organ toxicity, which could help to solve the critical intractable degradation issue of conventional inorganic CAs. Moreover, the tumor microenvironment (pH/GSH/H2O2) specific degradability of Mn-LSNs could help to improve the penetration depth of particles into the tumor parenchyma. Developing this novel Mn-LSNs contrast agent, together with the already demonstrated capacity of layered silicates for drug and gene delivery, provides opportunities for future cancer theranostics.


Assuntos
Meios de Contraste/farmacologia , Nanopartículas Metálicas/química , Neoplasias/diagnóstico por imagem , Silicatos/farmacologia , Animais , Linhagem Celular Tumoral , Meios de Contraste/farmacocinética , Meios de Contraste/toxicidade , Teoria da Densidade Funcional , Humanos , Imageamento por Ressonância Magnética , Manganês/química , Nanopartículas Metálicas/toxicidade , Camundongos Endogâmicos BALB C , Modelos Químicos , Silicatos/farmacocinética , Silicatos/toxicidade
6.
Adv Mater ; 32(23): e2000791, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32337783

RESUMO

Exploring innovative technologies to precisely quantify biomolecules is crucial but remains a great challenge for disease diagnosis. Unfortunately, the humoral concentrations of most biotargets generally vary within rather limited scopes between normal and pathological states, while most literature-reported biosensors can detect large spans of targets concentrations, but are less sensitive to small concentration changes, which consequently make them mostly unsatisfactory or even unreliable in distinguishing positives from negatives. Herein, a novel strategy of precisely quantifying the small concentration changes of a certain biotarget by editing the dynamic ranges and sensitivities of a lanthanide-based metal-organic framework (Eu-ZnMOF) biosensor is reported. By elaborately tailoring the biosensor's structure and surface areas, the tunable Eu-ZnMOF is developed with remarkably enhanced response slope within the "optimized useful detection window," enabling it to serve as a powerful signal amplifier (87.2-fold increase) for discriminating the small concentration variation of urinary vanillylmandelic acid (an early pathological signature of pheochromocytoma) within only three times between healthy and diseased subjects. This study provides a facile approach to edit the biosensors' performances through structure engineering, and exhibits promising perspectives for future clinical application in the non-invasive and accurate diagnosis of severe diseases.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Engenharia , Európio/química , Estruturas Metalorgânicas/química , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/urina , Animais , Técnicas Biossensoriais , Linhagem Celular Tumoral , Humanos , Camundongos , Feocromocitoma/urina , Ácido Vanilmandélico/urina
7.
Nano Lett ; 19(12): 8690-8700, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31698897

RESUMO

Recent drug delivery nanosystems for cancer treatment still suffer from the poor tumor accumulation and low therapeutic efficacy due to the complex in vivo biological barriers. To resolve these problems, in this work, a novel gradient redox-responsive and two-stage rocket-mimetic drug nanocarrier is designed and constructed for improved tumor accumulation and safe chemotherapy. The nanocarrier is constructed on the basis of the disulfide-doped organosilica-micellar hybrid nanoparticles and the following dual-functional modification with disulfide-bonded polyethylene glycol (PEG) and amido-bonded polyethylenimine (PEI). First, prolonged circulation duration in the bloodstream is guaranteed due to the shielding of the outer PEG chains. Once the nanocarrier accumulates at the tumoral extracellular microenvironment with low glutathione (GSH) concentrations, the first-stage redox-responsive behavior with the separation of PEG and the exposure of PEI is triggered, leading to the improved tumor accumulation and cellular internalization. Furthermore, with their endocytosis by tumor cells, a high concentration of GSH induces the second-stage redox-responsiveness with the degradation of silsesquioxane framework and the release of the encapsulated drugs. As a result, the rocket-mimetic drug carrier displays longer circulation duration in the bloodstream, higher tumor accumulation capability, and improved antitumor efficacy (which is 2.5 times higher than that with inseparable PEG). It is envisioned that the rocket-mimetic strategy can provide new solutions for improving tumor accumulation and safety of nanocarriers in further cancer chemotherapy.


Assuntos
Doxorrubicina , Portadores de Fármacos , Nanopartículas , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Glutationa/química , Humanos , Micelas , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Polietilenoimina/química , Polietilenoimina/farmacocinética , Polietilenoimina/farmacologia
8.
J Biomed Nanotechnol ; 15(10): 2072-2089, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31462372

RESUMO

The development of hybrid particles for tumor diagnosis and therapy has received considerable attention because they are capable of combining tumor diagnosis and treatment concurrently. So far hybrid particles for efficient and safe tumor theranostics are still very limited. Herein we have designed a new type of hybrid particles and evaluated its potential to be used in image-guided cancer diagnosis and therapy without the need of any toxic anticancer or contrast agents. The hybrid particles, consist of magnetic nanoparticles which are embedded in the poly(methyl methacrylate) (PMMA) cores and gold shells on chitosan (CTS) (γ-Fe2O3 @PMMA/CTS@Au). The hybrid particles were synthesized through initial formation of the core-shell structured γ-Fe2O3 @PMMA/CTS particles containing approximately 20% loading of magnetic nanoparticles. A gold layer was then built on top of the core-shell magnetic particles via a reduction of gold salt by amines from the chitosan assisted with the reducing agent NaBH4, followed by growing to complete gold shells in the presence of ascorbic acid (42.6% Au content). The properties of the composite particles including their chemical composition, morphology, particle size, size distribution, surface charge, magnetic responsiveness and photothermal ability were systematically characterized. The potential application of the γ-Fe2O3 @PMMA/CTS@Au hybrid particles in tumor diagnosis and therapy was assessed in vitro and in vivo using 4T1 tumor cells and 4T1 tumor-bearing mice through combining magnetic targeting, photoacoustic (PA)/computed tomography (CT) imaging and photothermal therapy. Results suggest that the γ-Fe2O3 @PMMA/CTS@Au particles can serve as a multifunctional tumor theranostic nanoplatform for magnetically targeted photothermal therapy. Breast cancer has been effectively eliminated without the use of any anticancer drugs or contrast agents. Therefore, this type of core-shell hybrid particles represents a new composite particle design for effective and safe tumor theranostics.


Assuntos
Ouro , Magnetismo , Neoplasias/terapia , Fototerapia , Animais , Linhagem Celular Tumoral , Compostos Férricos , Camundongos , Nanomedicina Teranóstica
9.
Biomater Sci ; 7(7): 2951-2960, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31099352

RESUMO

Recently, block copolymer micelles have attracted widespread attention due to their controlled biodegradability and excellent loading capability. Unfortunately, the poor in vivo stability and low delivery efficiency of drug-loaded micelles greatly hampered their biomedical applications. Herein, we develop a new kind of biodegradable magnetite/doxorubicin (Fe3O4/DOX) co-loaded PEGylated organosilica micelles (designated as FDPOMs) with both high circulating stability and smart GSH-triggered biodegradability for magnetically targeted magnetic resonance imaging (MRI) and tumor chemotherapy. The FDPOMs are prepared by the self-assembly of biodegradable polycaprolactone-block-poly(glutamic acid) (PCL-b-PGA), a chemotherapeutic DOX drug and Fe3O4 nanoparticles in an oil/water system, subsequent organosilica cross-linking with 3-mercaptopropyltrimethoxysilane (MPTMS) molecules and surface PEGylation. The resultant FDPOMs exhibit excellent dispersity and stability in biological media, remarkable T2-weighted MR imaging capability, unique GSH-responsive release behavior and selective toxicity to tumor cells. The in vivo experiments show that the FDPOMs not only have improved MR tumor imaging capability, but also exhibit high anti-tumor efficacy due to the strong magnetic targeting ability under an external magnetic field. Consequently, the FDPOMs are promising candidates for magnetically targeted MR imaging and imaging-guided tumor chemotherapy.


Assuntos
Doxorrubicina/farmacologia , Glutationa/metabolismo , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Micelas , Compostos de Organossilício/química , Compostos de Organossilício/metabolismo , Animais , Linhagem Celular Tumoral , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Células NIH 3T3 , Poliésteres/química , Ácido Poliglutâmico/química , Segurança
10.
Macromol Rapid Commun ; 40(10): e1800869, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30828932

RESUMO

Heavy-metal-free fluorescent nanoparticles with high photostability and low toxicity are highly desirable as imaging probes for biological applications. Here, a novel synthetic strategy to prepare ultrabright multi-carbon dot cross-linked PEI particles, namely CDs@PEI, through self-assembly of hydrophobically modified PEI and in situ generations of carbon dots within residual monomer-swollen micelles is reported. The resulting particles consist of numerous carbon dots, which are individually and homogeneously embedded within the PEI network, and have an average hydrodynamic diameter of approximately 100 nm with ζ-potential above +35 mV. The CDs@PEI particles possess the synergistic effect of photoluminescent carbon dot and crosslink-enhanced emission of PEI, giving the particles superior optical properties such as high fluorescence quantum yield (up to 66%) in the aqueous system, excitation-dependent emission phenomenon, stable fluorescence in a wide pH range, and resistance to photobleaching.


Assuntos
Corantes Fluorescentes/síntese química , Nanopartículas/química , Polietilenoimina/síntese química , Pontos Quânticos/química , Carbono/química , Corantes Fluorescentes/química , Células HeLa , Humanos , Polietilenoimina/química , Espectrometria de Fluorescência , Água/química
11.
Int J Nanomedicine ; 14: 1519-1532, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880962

RESUMO

Introduction: In this work, we have developed a novel "confined-growth" strategy to synthesize PEGylated multiple gold nanorices-encapsulated dual-mesoporous silica nanospheres (designated as PEGylated MGNRs@DMSSs) containing both small mesopores (2.5 nm) in the shell and large mesopores (21.7 nm) in the core based on a well-established, seed-mediated growth method. The photothermal effect and CT imaging ability were also studied. Methods: The nanoparticles were characterized by Fourier transform infrared (FT-IR) spectra, N2 absorption isotherms, Field-emission scanning electron microscopy (FE-SEM), Transmission electron microscopy (TEM), Inductively coupled plasma atomic emission spectroscopy (ICP-AES) and Confocal microscopy. Results: The longitudinally-localized surface (LSPR) absorption properties of MGNRs@DMSSs can be easily tuned by altering the amount of HAuCl4 in the gold growth solution. Additionally, the resultant PEGylated MGNRs@DMSSs have monodispersed, spherical morphology and good colloidal stability in an aqueous solution. More importantly, when exposed to NIR irradiation, the PEGylated MGNRs@DMSSs exhibit both higher temperature increments and better photothermal effects than that of single PEGylated gold nanorods at nearly an equivalent LSPR absorption. In addition, as CT contrast agents, the PEGylated MGNRs@DMSSs display a better CT imaging performance, in comparison with single PEGylated gold nanorods at the same Au concentration. Conclusion: Taken together, results indicate the potential for MGNRs@DMSSs used in CT imaging-guided photothermal therapy. Such a simple "confined-growth" strategy within a porous matrix offers a promising platform to design and prepare novel metal(s) oxide@silica nanocomposites for use in further cancer bio-imaging and therapy.


Assuntos
Carcinoma Hepatocelular/terapia , Ouro/química , Neoplasias Hepáticas/terapia , Nanocompostos/administração & dosagem , Fototerapia , Dióxido de Silício/química , Tomografia Computadorizada por Raios X/métodos , Animais , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Nanocompostos/química , Células Tumorais Cultivadas
12.
Biomater Sci ; 7(5): 1825-1832, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30892297

RESUMO

As drug-delivery carriers for cancer chemotherapy, gatekeeper-capped mesoporous silica nanoparticles (MSNs) have been widely studied due to their high drug-loading capability, controlled drug release property and good biocompatibility. However, the currently reported gatekeeper-capped MSNs suffer from complex synthetic procedures, potential toxicity of gatekeepers, unsatisfactory control on drug stimuli-release, etc. In this work, we develop a simple but efficient approach to fabricate PEGylated organosilica-capped mesoporous silica nanoparticles (POMSNs) by employing a disulfide-doped organosilica coating as the gatekeeper formed by the hydrolysis and condensation of a silane coupling agent 3-(mercaptopropyl)trimethoxysilane (MPTMS) to block the mesopores of MSNs. Owing to the glutathione (GSH)-responsive biodegradation behavior of the disulfide-doped organosilica gatekeeper, the DOX-loaded POMSNs exhibit only 20% cell viability towards SMMC-7721 tumor cells, and almost no toxicity towards L-02 cells at a DOX concentration of 50 µg mL-1 was measured, demonstrating their selective cytotoxicity in vitro. More importantly, it is demonstrated that the DOX-loaded POMSNs exhibit a tumor inhibition rate of 71.3% and negligible systematic toxicity. Consequently, the resultant POMSNs show great potential as drug nanocarriers for redox-responsive drug release and passive-targeting tumor chemotherapy.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Nanoestruturas/química , Dióxido de Silício/química , Dióxido de Silício/síntese química , Animais , Transporte Biológico , Linhagem Celular Tumoral , Técnicas de Química Sintética , Doxorrubicina/química , Doxorrubicina/metabolismo , Portadores de Fármacos/metabolismo , Feminino , Glutationa/metabolismo , Humanos , Espaço Intracelular/metabolismo , Camundongos , Oxirredução , Porosidade , Dióxido de Silício/metabolismo
13.
Nanoscale ; 11(4): 2008-2016, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30644929

RESUMO

Bone morphogenetic protein (BMP)-9 has been associated with insulin resistance and type 2 diabetes mellitus. However, methods for delivering exogenous BMP-9 genes in vivo are lacking. In this study, we developed a gene delivery system using polyethyleneimine (PEI)-based core-shell nanoparticles (PCNs) as gene delivery carriers, and investigated the effectiveness and safety for delivery of the shBMP-9 gene. PCNs possessed a well-defined core-shell nanostructure with hydrophobic polymer cores and dense PEI shells of uniform particle size and highly positively charged surfaces. In vitro evaluation suggested that PCNs had high loading capacity for exogenous genes and low cytotoxicity toward hepatocytes. The transfection efficiency of PCNs/pENTR-shBMP9 complexes was higher than that of commercial lipofectamine 2000/shBMP9. In vivo studies showed that PCNs/pENTR-shBMP9 transfection led to a significant decrease in hepatic BMP9 expression compared with pENTR-shBMP9 transfection. Under high fat diet (HFD) feeding, PCNs/pENTR-shBMP9 mice exhibited aggravated glucose and insulin tolerance. At a molecular level, PCNs/pENTR-shBMP9 mice displayed elevated PEPCK protein levels and lower levels of InsR and Akt phosphorylation than pENTR-shBMP9 mice. These results suggest that the biological effects of PCNs/pENTR-shBMP9 in vivo are much more effective than those of pENTR-shBMP9. Therefore, the polyethyleneimine (PEI)-based core-shell nanoparticle can be applied as promising nanocarriers for effective and safe gene delivery.


Assuntos
Portadores de Fármacos/química , Fator 2 de Diferenciação de Crescimento/metabolismo , Nanopartículas/química , Polietilenoimina/química , RNA Interferente Pequeno/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Dieta Hiperlipídica , Modelos Animais de Doenças , Fator 2 de Diferenciação de Crescimento/antagonistas & inibidores , Fator 2 de Diferenciação de Crescimento/genética , Células Hep G2 , Humanos , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/toxicidade , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Transfecção
14.
Adv Mater ; 30(30): e1704490, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29889325

RESUMO

Chemotherapy suffers numbers of limitations including poor drug solubility, nonspecific biodistribution, and inevitable adverse effects on normal tissues. Tumor-targeted delivery and intratumoral stimuli-responsive release of drugs by nanomedicines are considered to be highly promising in solving these problems. Compared with traditional chemotherapeutic drugs, high concentration of nitric oxide (NO) exhibits unique anticancer effects. The development of tumor-targeting and intratumoral microenvironment-responsive NO-releasing nanomedicines is highly desired. Here a novel kind of organic-inorganic composite nanomedicine (QM-NPQ@PDHNs) is presented by encapsulating a glutathione S-transferases π (GSTπ)-responsive drug O2 -(2,4-dinitro-5-{[2-(ß-d-galactopyranosyl olean-12-en-28-oate-3-yl)-oxy-2-oxoethyl] piperazine-1-yl} phenyl) 1-(methylethanolamino)diazen-1-ium-1,2-dilate (NPQ) as NO donor and an aggregation-induced-emission (AIE) red fluorogen QM-2 into the cores of the hybrid nanomicelles (PEGylated disulfide-doped hybrid nanocarriers (PDHNs)) with glutathione (GSH)-responsive shells. The QM-NPQ@PDHN nanomedicine is able to respond to the intratumoral over-expressed GSH and GSTπ, resulting in the responsive biodegradation of the protective organosilica shell and NPQ release, and subsequent NO release within the tumor, respectively, and thus normal organs remain unaffected. This work demonstrates a paradigm of dual intratumoral redox/enzyme-responsive NO-release nanomedicine for tumor-specific and high-efficacy cancer therapy.


Assuntos
Nanomedicina , Humanos , Neoplasias , Óxido Nítrico , Oxirredução , Distribuição Tecidual
15.
Biomacromolecules ; 19(7): 2923-2930, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29787265

RESUMO

A pillar[5]arene-based nonionic polyrotaxane (PR) with star-poly(ε-caprolactone) ( S-PCL) as the axle, pillar[5]arene (DEP5) as the wheel and adamantane as the end-capped group is designed and synthesized. The resulting PR is subsequently assembled with ß-cyclodextrin end-capped pH-stimulated poly(acrylic acid) (CD-PAA) via a host-guest interaction to form the supramolecular pseudoblock polymer PR-PAA. This supramolecular pseudoblock polymer could self-assemble in aqueous solution to produce PR-PAA-based supramolecular vesicular nanoparticles (PR-SVNPs), which present significantly enhanced drug loading capacity (DLC, 45.6%) of DOX, much higher than those of superamphiphiles (PCL-PAA, 17.1%). Such a high DLC of PR-SVNPs can be most probably attributed to the greatly decreased crystallinity of PCL in PR. Moreover, the loaded drugs could be selectively released in an acidic microenvironment-responsive manner. Compared to free DOX, the DOX-loaded PR-SVNPs (DOX@PR-SVNPs) shows much enhanced cellular uptake and cytotoxicity against the SMMC-7721. More importantly, thanks to the enhanced permeability and retention (EPR) effect, DOX@PR-SVNPs exhibits appealing features such as extremely low toxicity, highly efficient intratumoral accumulation and substantial antitumor efficacy in vivo.


Assuntos
Nanoconjugados/química , Rotaxanos/química , Tensoativos/síntese química , Resinas Acrílicas/química , Adamantano/análogos & derivados , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Caproatos/química , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Lactonas/química , Camundongos , Camundongos Endogâmicos BALB C , beta-Ciclodextrinas/química
16.
J Hazard Mater ; 328: 160-169, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28126477

RESUMO

A novel type of adsorbent for the selective recognition and adsorption of trace Pb2+ from aqueous solutions has been successfully constructed simply by grafting molecularly imprinted polymers (MIPs) onto hollow mesoporous silica (HMS). Attractively, the HMS loaded with MIPs (H-MIPs) exhibits a fast adsorption kinetics, marked adsorption capacity of 40.52mg/g and extremely high selectivity toward Pb2+ over Cu2+, Zn2+, Co2+, Mn2+ and Ni2+, and the selectivity coefficients have been determined to be as high as 50. Moreover, such high adsorptive capability and selectivity were retained for at least 6 runs, indicating the stability and reusability of H-MIPs. Lead ion contaminants in real water samples were successfully concentrated and approximately 100% recovered using H-MIPs. Theoretical analysis shows that the adsorption process of H-MIPs follows the pseudo-second-order kinetic and Langmuir isotherm models. These demonstrate that H-MIPs are greatly potential for the rapid and highly efficient removal of trace Pb2+ ions in complicated matrices.

17.
Chem Soc Rev ; 46(3): 569-585, 2017 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-27805705

RESUMO

As a member of the organic-inorganic hybrid family, silica/organosilica cross-linked block copolymer micelles are becoming increasingly attractive due to the combined features of excellent self-assembly properties of amphiphilic block copolymers and the high stability and the easy surface modification of silica/organosilica components. Compared to the traditional cross-linking route with organic components, the silica/organosilica cross-linking approach could offer more advantages, such as quick reaction under mild conditions, a much stronger barrier to the diffusion of both encapsulated small molecules and functional nanoparticles and the substantial improvement in the stability of the whole micelles against the ambient environment. In this tutorial review, we will focus on the recent developments in the design, synthesis and biomedical applications of silica/organosilica cross-linked block copolymer micelles based on the self-assembly of amphiphilic block copolymers and the hydrolysis and condensation of silanes in aqueous solution. First, we will summarize the synthesis of three typical kinds of silica/organosilica cross-linked block copolymer micelles based on the self-assembly of non-ionic polyethylene oxide (PEO)-based, cationic and anionic poly(acrylic acid) (PAA)-based block copolymer micelles. Then, a series of multifunctional silica/organosilica cross-linked block copolymer micelles by encapsulating various functional nanoparticles/molecules in the hydrophobic polymer cores or hydrophilic silica/organosilica cross-linked shells are introduced and their biomedical applications in controlled drug delivery, bio-imaging (magnetic resonance, fluorescence and multimodal imaging) and imaging-guided therapies (photothermal and high intensity focused ultrasound therapies) will be discussed. Finally, the challenges and prospects of silica/organosilica cross-linked micellar nanostructures and their biological applications are discussed and assessed. It is highly expected that the silica/organosilica cross-linked micelles may provide a new and promising kind of carrier system for enhanced bio-imaging and efficient cancer therapy.

18.
J Mater Chem B ; 5(8): 1642-1649, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32263936

RESUMO

Gold-based nanocomposites have attracted intensive attention due to their unique optical properties and great potential in biomedical applications. Herein, we report a simple route for the synthesis of multiple gold nanorods encapsulated, hierarchically porous silica nanospheres (MGNRs@HPSNs) based on the cooperative self-assembly of amphiphilic block copolymer polystyrene-b-poly (acrylic acid) (PS-b-PAA), cetyl trimethyl ammonium bromide (CTAB), gold nanorods and the organosilane of tetraethyl orthosilicate (TEOS) in an oil/water system. Multiple gold nanorods have been loaded successfully into the interior of the hierarchically porous silica nanospheres, which consist of large, interconnected pores of 13.2 nm throughout the whole sphere and small pores of 2.7 nm in the silica framework. Moreover, the loading amount (or number) of gold nanorods in the silica matrix can be tuned by simply changing the initial concentration of preformed gold nanorods. Due to the presence of the hierarchically porous structure, the PEGylated MGNRs@HPSNs display high loading capability for both small anti-tumor drugs (i.e., doxorubicin hydrochloride, 69.2 ± 7.2 mg g-1) and bio-macromolecules (i.e., bovine serum albumin, 248.1 ± 12.3 mg g-1). More importantly, MGNRs@HPSNs present better photothermal effect than that of hierarchically porous silica nanoparticles containing less (one or two) gold nanorods at the same Au concentration. It is thus demonstrated that MGNRs@HPSNs can not only act as promising drug/protein nanocarriers, but also can be used as photoabsorbers for photothermal tumor therapy under NIR laser irradiation.

19.
J Mater Chem B ; 5(22): 4214-4220, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-32264151

RESUMO

Natural antibodies are used widely for various applications such as in biomedical analysis, protein separation, and targeted-drug delivery, but they suffer from high cost and low stability. In this study, we developed a facile approach for the construction of antibody-like binding sites in a porous silica solid for efficient separation of bovine serum albumin (BSA) based on large-pore silica particles (LPSPs). This was accomplished by grafting two types of organosilane monomers, 3-aminopropyltriethoxylsilane (APTES) and octyltrimethoxysilane (OTMS), to provide hydrogen bonds or hydrophobic interactions with BSA through molecular imprinting technology. The resulting molecularly imprinted, large-pore silica particles (MI-LPSPs) were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TG), X-ray diffraction (XRD) and N2 sorption analysis. Results showed that the as-synthesized MI-LPSPs exhibited a spherical morphology, favorable stability and large pore structure. The kinetic adsorption experiments showed that the MI-LPSPs could reach equilibrium within one hour and were described well by the pseudo second-order model, indicating that chemical adsorption might be the rate-limiting step. Meanwhile, the MI-LPSPs had a large binding capacity up to 162.82 mg g-1 and high selectivity for the recognition of BSA. Moreover, such a high binding capacity and selectivity was retained after six runs, indicating a good stability and reusability of MI-LPSPs. Thus, it is expected that a simple synthetic methodology in the present study provides a promising pathway to prepare novel imprinted materials for efficient purification and separation of target proteins.

20.
J Mater Chem B ; 5(30): 5931-5936, 2017 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32264349

RESUMO

We present a simple route to fabricate peptide modified spherical gold nanoparticles (AuNPs@Pep1/Pep2) with enhanced retention performance in tumor sites for improved photothermal treatment (PTT), which was achieved through its in vivo self-assembly triggered by matrix metalloproteinase-2 (MMP-2).

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