RESUMEN
The molecular diversity of aggregation-induced emission remains a challenge due to the limitation of conventional synthesis methods. Here, a series of novel neutral and cationic conjugated polymers composed of various ratios of tetraarylethylene (TAE) containing a bridged oxygen (O) and fluorene (F) units is designed and synthesized via the geminal cross-coupling (GCC) of 1,1-dibromoolefins. The incorporation of TAE segments into the conjugated backbone of polyfluorene produces pronounced aggregation-induced ratiometric fluorescence, i.e., aggregation-induced emission (AIE) at 520-600 nm and grows synergistically with aggregations-caused quenching (ACQ) at 400-450 nm. The content of fluorene unit in the polymer backbones determines the intensity of the initial fluorescence in the blue light region. The huge distinction (about 150 nm) in dual emission wavelengths caused by the environment change makes these conjugated polyelectrolytes particularly suitable for ratiometric fluorescence sensing. Based on electrostatic interaction mechanism, the gradual addition of heparin into the cationic conjugated polymers aqueous solutions can induce dual-color fluorescence changes with a detection limit of 9 × 10-9 m. This work exhibits the great facility of using GCC reaction to synthesis the conjugated TAE polymers with superior AIE properties and special functions.
Asunto(s)
Fluorenos , Polímeros , Cationes , Fluorescencia , Heparina , Oxígeno , Polielectrolitos , Espectrometría de FluorescenciaRESUMEN
The abundant and heterogeneous distribution of toxic phenol from plastics has drawn worldwide attention. However, the common analysis methods failed to identify the accurate species of these phenolic hazards from plastics in a direct and nondestructive approach. Herein, we demonstrate the layered double hydroxides (LDHs) as a novel matrix in matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) for low-molecular-weight phenols leaked from plastics. LDHs own abundant hydroxyl groups to facilitate chemoselectivity and ionization of phenols through the formation of hydrogen bonds with these phenols. More importantly, the LDH matrix could provide a distinguishable signal for the homolog and isomeride of these phenolic hazards. The developed method could realize nondestructive and in situ mapping of phenolic hazards in plastics. Our success could help to track the low-molecular-weight compounds liberated from plastics and supply spatial information for polluted plastics. We anticipated that the proposed approach could provide sufficient information to evaluate and alarm the safety of food packaging plastics.
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Fenoles , Plásticos , Diagnóstico por Imagen , Peso Molecular , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
It is of great significance to disclose the diverse aging pathways for polymers under multiple factors, so as to predict and control the potential aging evolution. However, the current methods fail to distinguish multiple pathways (multi-paths) of polymer aging due to the lack of spatiotemporal resolution. In this work, using polyimide as a model polymer, the hydroxyl, carboxyl, and amino groups from the polyimide aging process were labeled using specific fluorescent probes through boron-oxygen, imine, and thiourea linkages, respectively. When the excitation and emission wavelengths of each fluorescent probe were controlled, the multi-paths in polyimide aging can be visualized individually and simultaneously in three-dimensional fluorescent images. The overall aging process under hydrothermal treatment was destructured into the pyrolysis and hydrolysis pathways. Three-dimensional dynamic studies discovered that the increased humidity, along with the decreased oxygen content, could hamper the pyrolysis reaction and accelerate the hydrolysis reaction, leading to severe degradation of the overall polyimide aging. More importantly, the oxygen showed a higher regulation coefficient in accelerating the pyrolysis reaction, than the water vapor in motivating the hydrolysis reactions. Such a multidimensional identification methodology is able to guide the long-term use of polymers and control their aging process to a harmless direction in advance by tuning the contents of oxygen and water vapor.
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Colorantes Fluorescentes , Polímeros , Hidrólisis , Oxígeno , PirólisisRESUMEN
Dysfunctional uterine bleeding is menstrual bleeding in abnormal volume, duration, or time, and it is a common problem in women. A wide range of drug therapies, with varying efficacy, is available for women with dysfunctional uterine bleeding. The use of herbal and traditional medicine is one of the ways to treat this disease, which has fewer side effects than chemical drugs. On the other hand, these medicines have less effect on treatment than chemical drugs. Therefore, increasing their effectiveness in the treatment of diseases has always been important. For this purpose, in this study, a comparison was done between direct use and PLGA nanocapsules containing Tiaojing Zhixue, in the treatment of dysfunctional uterine bleeding. First, PLGA nanocapsules containing Tiaojing Zhixue were synthesized by the electrospray technique. Then 80 women with dysfunctional uterine bleeding were treated with this medicine. These people were divided into two groups of 40 people. The first group was treated with 20mg of Tiaojing Zhixue and the other group was treated with PLGA nanocapsules containing Tiaojing Zhixue for eight months. The duration and frequency of bleeding from one month before the start of treatment and during the eight months after the start of treatment (second, fourth, and eighth month) were assessed in two groups. The two groups were homogeneous in terms of mean frequency of bleeding and mean duration of bleeding before starting treatment. The positive response in the PLGA nanocapsules treatment group (75%) was higher than the direct use drug treatment group (42.5%) (P < 0.01). The rate of side effects was the same in each group. Due to the effectiveness of PLGA nanocapsules in the treatment of dysfunctional uterine bleeding and the lack of side effects, it can be considered as an alternative medicine for the treatment of this disorder.
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Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China/métodos , Metrorragia/tratamiento farmacológico , Nanocápsulas/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Adulto , Femenino , Humanos , Microscopía Electrónica de Rastreo , Nanocápsulas/química , Nanocápsulas/ultraestructura , Factores de Tiempo , Resultado del TratamientoRESUMEN
A rapid, simple, inexpensive fluorescence analysis method for determination of famotidine based on polyethyleneimine (PEI)-capped Ag nanoclusters (PEI-Ag NCs) was developed. The study showed that addition of famotidine could cause efficient quenching of PEI-Ag NC fluorescence, as the presence of famotidine could cause aggregation of Ag NCs and quench its fluorescence. The sensitivity and selectivity of the method were investigated and experimental conditions such as buffer type, pH, temperature, and reaction time were optimized. Under optimized conditions, the results showed a linear profile from 3.7 × 10-8 to 3.7 × 10-5 mol/L, and had a detection limit of 1.6 × 10-9 mol/L (S/N = 3).
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Nanopartículas del Metal , Plata , Famotidina , Polietileneimina , Espectrometría de FluorescenciaRESUMEN
Although chitosan-based hydrogel has been widely used as a gene carrier material, further improvement in this aspect is still needed. Herein a new method was proposed for preparing the effective chitosan-based gene carrier nanogel. The new method based on the fact that supra-molecular interactions between silica, polyethylenimine (PEI) and chitosan could be used to self-assemble them together to form a rigid and stable gene carrier material in the reverse microemulsion system. When compared with chemical cross-linking route, the proposed method is simple and easy to adjust components of the resulting nanogel and, therefore, can improve its gene carrying ability. Our results showed that, doping of the PEI and silica into the chitosan hydrogel obviously increased its strength, stability and gene carrying ability.
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Quitosano/química , ADN/genética , Leucemia Linfoide/genética , Nanocápsulas/química , Polietileneimina/química , Transfección/métodos , Animales , Línea Celular Tumoral , ADN/administración & dosificación , ADN/química , Geles/química , Inestabilidad Genómica/genética , Ratones , Nanocápsulas/ultraestructura , Tamaño de la Partícula , Dióxido de Silicio/químicaRESUMEN
A multiple-unit floating alginate bead drug delivery system with prolonged stomach retention time was developed in this study. The floating alginate beads were prepared by ionic cross-linking method, using CaCO3 as the gas-forming agent. Over 92% of the beads remained floating after 9 h. In order to prepare sustained-release dosage forms of dipyridamole, the solid dispersion technique was applied using a blend of Eudragit L100 and Eudragit RLPO. Afterwards, the solid dispersions of dipyridamole were incorporated into the floating alginate beads. The drug release was modified by changing the ratio of Eudragit RLPO and Eudragit L100 in the solid dispersions. The in vivo results showed that the relative bioavailability of alginate beads was enhanced by approximately 2.52-fold compared with that of the commercial tablet. Therefore, our study illustrated the potential use of floating alginate beads combined with the solid dispersion technique for the delivery of acid-soluble compounds, such as dipyridamole.
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Dipiridamol/administración & dosificación , Sistemas de Liberación de Medicamentos , Excipientes/química , Jugo Gástrico/química , Inhibidores de Agregación Plaquetaria/administración & dosificación , Alginatos/química , Animales , Animales Endogámicos , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Fenómenos Químicos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/análisis , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Dipiridamol/análisis , Dipiridamol/química , Dipiridamol/farmacocinética , Perros , Composición de Medicamentos , Liberación de Fármacos , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Concentración de Iones de Hidrógeno , Tamaño de la Partícula , Inhibidores de Agregación Plaquetaria/análisis , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Ácidos Polimetacrílicos/química , SolubilidadRESUMEN
Selective fractionation of hemicelluloses is of great significance for realizing high-value application of hemicelluloses and comprehensive utilization of lignocellulosic biomass. Tetramethylammonium hydroxide (TMAH) solvent has been confirmed as a promising solvent to selectively fractionate hemicelluloses from holocellulose. Herein, TMAH solvent was adopted to pretreat poplar thermomechanical pulp (PTMP) for the selective fractionation of hemicelluloses and enhancement of enzymatic hydrolysis performance of residues. The maximal hemicelluloses yield (65.0 %) and excellent cellulose retention rate (93.3 %) were achieved after pretreatment by the 25 wt% TMAH solvent, while the delignification was only 33.9 %. The hemicelluloses fractions could be selectively fractionated with high molecular weights (109,800-118,500 g/mol), the contents of Klason lignin in them were low (3.2-5.9 %), and the dominating structure of them was 4-O-methylglucurono-ß-D-xylan. Compared to the H2SO4 and NaOH methods, the hemicelluloses fractionated by TMAH method exhibited higher yields, more complete structures and higher molecular weights. Furthermore, the crystalline structure of cellulose practically remained stable, and the highest yield of enzymatic hydrolysis glucose was 57.5 %, which was 3.3 times of that of PTMP. The fractionation effectiveness of TMAH solvent was not significantly reduced after repeatedly recycling. This work demonstrated TMAH solvent could selectively fractionate hemicelluloses from PTMP and efficiently promote sustainable poplar-based biorefinery.
Asunto(s)
Lignina , Polisacáridos , Populus , Compuestos de Amonio Cuaternario , Peso Molecular , Lignina/química , Celulosa/química , Solventes , Hidrólisis , BiomasaRESUMEN
The fractionation of hemicelluloses is a promising method to improve the comprehensive utilization of lignocellulosic biomass. However, the effective fractionation of hemicelluloses is always limited by the structural complexity and easy degradability. In this study, tetramethylammonium hydroxide (TMAH) was developed to fractionate hemicelluloses from poplar holocellulose with high molecular weights and high yields at room temperature. Approximately 90% of hemicelluloses could be dissolved at room temperature in 1 h, and the yield was up to 81.9%. Compared with the fractionation using NaOH solution, the hemicelluloses isolated by TMAH solvent showed a more complete structure and higher purity. Meanwhile, the retention rate of cellulose after treatment with TMAH was up to 90.2%, and the crystal structure of cellulose in the residues was practically unchanged. Moreover, the TMAH solvent could be recycled to fractionate hemicelluloses. The work provides an elegant and significantly efficient method towards hemicelluloses fractionation and cellulose purification.
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Celulosa , Polisacáridos , Celulosa/química , Temperatura , Polisacáridos/química , SolventesRESUMEN
Bamboo (Phyllostachys pubescens) is an attractive biomass block to develop biorefining industry, however, less emphasis has been placed on elucidating the chemical linkage variations of lignin and LCC between different bamboo cell walls. Here, purified milled wood lignin (MWLp) and lignin-carbohydrate complex (LCC) were isolated from bamboo (Phyllostachys pubescens) fibers (BF) and parenchyma cells (PC), respectively. The variations of structure features and chemical linkages of lignin and LCC were investigated via FT-IR, 2D HSQC NMR, and 31P NMR techniques. 2D HSQC NMR revealed that ß-O-4 alkyl-aryl ether linkages and resinol (ß-ß) substructure were the main substructures in BF-MWLp and PC-MWLp. ß-1 linkages existed in the PC-MWLp (3.18/100 Ar), but not in BF-MWLp. Moreover, tricin, as a flavonoid compound, was only detected in the BF-MWLp. The amount of the syringyl (S) units of PC-MWLp was higher than BF-MWLp. The results indicated that phenyl glycoside (PhGlc) bonds (mainly lignin and xylan) were the predominant chemical linkage type of LCC bonds in BF-LCC and PC-LCC, and the high contents of PhGlc bonds (45.53/100 Ar) were presented in PC. Our finding can provide a reference for the structural variations of lignin and LCC between the different bamboo cell walls.
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Glicósidos Cardíacos , Lignina , Lignina/química , Espectroscopía Infrarroja por Transformada de Fourier , Poaceae/química , Espectroscopía de Resonancia Magnética , Glicósidos , Xilanos/químicaRESUMEN
To provide lifecycle monitoring for degradable polymers, we have proposed a three-dimensional fluorescence monitoring and quantification method to simultaneously study the thermal and photothermal degradation by combining the intrinsic conjugation and probe-labelled carboxyl of poly(butylene adipate-co-terephthalate) (PBAT).
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Poliésteres , Polímeros , FluorescenciaRESUMEN
Exploration of lignocellulosic biomass provides a sustainable and eco-friendly route for producing liquid fuels, materials, and chemicals. However, direct utilization of lignocelluloses is limited by the stable and complicated cross-linking structure of the plant cell wall. Hydrothermal pretreatment (HTP) is a green and cost-effective technology because it can disrupt lignin-carbohydrate complex (LCC) linkages, dissolve hemicelluloses and lignin, and redistribute lignin in the cell wall layers without utilization of any chemicals. Thus, HTP is expected to achieve industrial scale in second-generation biorefineries and circular bioeconomies. This review analyzed the deconstruction of lignocelluloses by HTP, with particular emphasis on the formation mechanism of hemicellulose degradation products and the structural evolution of hemicelluloses and lignin accompanying HTP. Meanwhile, the formation mechanism of pseudolignin and its effect on the enzymatic hydrolysis of cellulose as well as strategies for inhibiting lignin recondensation were discussed.
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Lignina , Polisacáridos , Biomasa , Hidrólisis , Lignina/química , SolubilidadRESUMEN
Nanomedicines with photodynamic therapy and reactive oxygen species (ROS)-triggered drug release capabilities are promising for cancer therapy. However, most of the nanomedicines based on ROS-responsive nanocarriers still suffer from serious ROS consumption during the triggered drug release process. Herein, a photodynamic-chemodynamic cascade strategy for the design of drug delivery nanosystem is proposed. A doxorubicin hydrochloride-loaded ROS-responsive polymersome (DOX-RPS) is prepared via the self-assembly of amphiphilic poly(ethylene glycol)-poly(linoleic acid) and poly(ethylene glycol)-(2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-α)-iron chelate (PEG-HPPH-Fe). The RPS can effectively deliver a drug to tumor site through passive targeting effect. Upon laser irradiation, the photosensitizer HPPH can efficiently generate ROS, which further causes in situ oxidation of linoleic acid chain and subsequent RPS structural destruction, permitting triggered drug release. Intriguingly, catalyzed by HPPH-Fe, ROS will be regenerated from linoleic acid peroxide through a chemodynamic process. Therefore, ROS-triggered drug release can be achieved without ROS over-consumption. The in vitro and in vivo results confirmed ROS generation, triggered drug release behavior, and potent antitumor effect of the DOX-RPS. This photodynamic-chemodynamic cascade strategy provides a promising approach for enhanced combination therapy.
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Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Glioma/terapia , Nanopartículas/administración & dosificación , Fotoquimioterapia/métodos , Polietilenglicoles/química , Especies Reactivas de Oxígeno/metabolismo , Animales , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Terapia Combinada , Liberación de Fármacos , Glioma/metabolismo , Glioma/patología , Humanos , Ratones Desnudos , Nanopartículas/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Tensoactivos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The COVID-19 pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused great impact on the global economy and people's daily life. In the clinic, most patients with COVID-19 show none or mild symptoms, while approximately 20% of them develop severe pneumonia, multiple organ failure, or septic shock due to infection-induced cytokine release syndrome (the so-called "cytokine storm"). Neutralizing antibodies targeting inflammatory cytokines may potentially curb immunopathology caused by COVID-19; however, the complexity of cytokine interactions and the multiplicity of cytokine targets make attenuating the cytokine storm challenging. Nonspecific in vivo biodistribution and dose-limiting side effects further limit the broad application of those free antibodies. Recent advances in biomaterials and nanotechnology have offered many promising opportunities for infectious and inflammatory diseases. Here, potential mechanisms of COVID-19 cytokine storm are first discussed, and relevant therapeutic strategies and ongoing clinical trials are then reviewed. Furthermore, recent research involving emerging biomaterials for improving antibody-based and broad-spectrum cytokine neutralization is summarized. It is anticipated that this work will provide insights on the development of novel therapeutics toward efficacious management of COVID-19 cytokine storm and other inflammatory diseases.
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Materiales Biocompatibles/química , COVID-19/patología , Síndrome de Liberación de Citoquinas/terapia , Citocinas/química , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Materiales Biocompatibles/metabolismo , COVID-19/complicaciones , COVID-19/virología , Síndrome de Liberación de Citoquinas/etiología , Citocinas/inmunología , Citocinas/metabolismo , Vesículas Extracelulares/química , Humanos , Nanopartículas/química , Polímeros/química , SARS-CoV-2/aislamiento & purificaciónRESUMEN
Immunogenic cell death (ICD) and tumour-infiltrating T lymphocytes are severely weakened by elevated reactive oxygen species (ROS) in the tumour microenvironment. It is therefore of critical importance to modulate the level of extracellular ROS for the reversal of immunosuppressive environment. Here, we present a tumour extracellular matrix (ECM) targeting ROS nanoscavenger masked by pH sensitive covalently crosslinked polyethylene glycol. The nanoscavenger anchors on the ECM to sweep away the ROS from tumour microenvironment to relieve the immunosuppressive ICD elicited by specific chemotherapy and prolong the survival of T cells for personalized cancer immunotherapy. In a breast cancer model, elimination of the ROS in tumour microenvironment elicited antitumour immunity and increased infiltration of T lymphocytes, resulting in highly potent antitumour effect. The study highlights a strategy to enhance the efficacy of cancer immunotherapy by scavenging extracellular ROS using advanced nanomaterials.
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Antineoplásicos/farmacología , Espacio Extracelular/metabolismo , Depuradores de Radicales Libres/metabolismo , Muerte Celular Inmunogénica , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular Tumoral , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Proteína HMGB1/metabolismo , Muerte Celular Inmunogénica/efectos de los fármacos , Ratones Endogámicos BALB C , Tamaño de la Partícula , Polietilenglicoles/química , Microambiente Tumoral/efectos de los fármacosRESUMEN
Combination therapy that could better balance immune activation and suppressive signals holds great potential in cancer immunotherapy. Herein, we serendipitously found that the pH-responsive nanovesicles (pRNVs) self-assembled from block copolymer polyethylene glycol-b-cationic polypeptide can not only serve as a nanocarrier but also cause immunogenic cell death (ICD) through preapoptotic exposure of calreticulin. After coencapsulation of a photosensitizer, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) and an indoleamine 2,3-dioxygenase inhibitor, indoximod (IND), pRNVs/HPPH/IND at a single low dose elicited significant antitumor efficacy and abscopal effect following laser irradiation in a B16F10 melanoma tumor model. Treatment efficacy attributes to three key factors: (i) singlet oxygen generation by HPPH-mediated photodynamic therapy (PDT); (ii) increased dendritic cell (DC) recruitment and immune response provocation after ICD induced by pRNVs and PDT; and (iii) tumor microenvironment modulation by IND via enhancing P-S6K phosphorylation for CD8+ T cell development. This study exploited the nanocarrier to induce ICD for the host's immunity activation. The "all-in-one" smart nanovesicles allow the design of multifunctional materials to strengthen cancer immunotherapy efficacy.
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Antineoplásicos/farmacología , Muerte Celular Inmunogénica/efectos de los fármacos , Inmunoterapia , Melanoma/terapia , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Concentración de Iones de Hidrógeno , Muerte Celular Inmunogénica/inmunología , Melanoma/inmunología , Melanoma/patología , Ratones , Estructura Molecular , Tamaño de la Partícula , Péptidos/química , Péptidos/farmacología , Fármacos Fotosensibilizantes/química , Polietilenglicoles/química , Polietilenglicoles/farmacología , Propiedades de Superficie , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Zwitterionic surface modification is a promising strategy for nanomedicines to achieve prolonged circulation time and thus effective tumor accumulation. However, zwitterion modified nanoparticles suffer from reduced cellular internalization efficiency. Methods: A polyprodrug-based nanomedicine with zwitterionic-to-cationic charge conversion ability (denoted as ZTC-NMs) was developed for enhanced chemotherapeutic drug delivery. The polyprodrug consists of pH-responsive poly(carboxybetaine)-like zwitterionic segment and glutathione-responsive camptothecin prodrug segment. Results: The ZTC-NMs combine the advantages of zwitterionic surface and polyprodrug. Compared with conventional zwitterionic surface, the ZTC-NMs can respond to tumor microenvironment and realize ZTC surface charge conversion, thus improve cellular internalization efficiency of the nanomedicines. Conclusions: This ZTC method offers a strategy to promote the drug delivery efficiency and therapeutic efficacy, which is promising for the development of cancer nanomedicines.
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Camptotecina/farmacología , Cationes/química , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas/química , Polímeros/química , Profármacos/farmacología , Animales , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Nanomedicina , Nanopartículas/administración & dosificación , Profármacos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumor-lymph node (LN) metastasis is the dominant prognostic factor for tumor staging and therapeutic decision-making. However, concurrently visualizing metastasis and performing imaging-guided lymph node surgery is challenging. Here, a multiplexed-near-infrared-II (NIR-II) in vivo imaging system using nonoverlapping NIR-II probes with markedly suppressed photon scattering and zero-autofluorescence is reported, which enables visualization of the metastatic tumor and the tumor metastatic proximal LNs resection. A bright and tumor-seeking donor-acceptor-donor (D-A-D) dye, IR-FD, is screened for primary/metastatic tumor imaging in the NIR-IIa (1100-1300 nm) window. This optimized D-A-D dye exhibits greatly improved quantum yield of organic D-A-D fluorophores in aqueous solutions (≈6.0%) and good in vivo performance. Ultrabright PbS/CdS core/shell quantum dots (QDs) with dense polymer coating are used to visualize cancer-invaded sentinel LNs in the NIR-IIb (>1500 nm) window. Compared to clinically used indocyanine green, the QDs show superior brightness and photostability (no obvious bleaching even after continuous laser irradiation for 5 h); thus, only a picomolar dose is required for sentinel LNs detection. This combination of dual-NIR-II image-guided surgery can be performed under bright light, adding to its convenience and appeal in clinical use.
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Colorantes Fluorescentes/química , Metástasis Linfática/diagnóstico por imagen , Imagen Óptica/métodos , Puntos Cuánticos/química , Ganglio Linfático Centinela/diagnóstico por imagen , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Compuestos de Cadmio/química , Línea Celular Tumoral , Femenino , Plomo/química , Metástasis Linfática/terapia , Ratones , Polímeros/química , Compuestos de Selenio/química , Ganglio Linfático Centinela/cirugía , Espectroscopía Infrarroja Corta/métodos , Cirugía Asistida por Computador/métodosRESUMEN
Persistent high-risk HPV infection is the main factor for cervical cancer. HPV E7 oncogene plays an important role in HPV carcinogenesis. Down-regulation of E7 oncogene expression could induce growth inhibition in HPV-positive cells and thus treats HPV related cervical cancer. Here we developed a non-virus gene vector based on poly(amide-amine)-poly(ß-amino ester) hyperbranched copolymer (hPPC) for the delivery of CRISPR/Cas9 system to specifically cleave HPV E7 oncogene in HPV-positive cervical cancer cells. The diameter of polyplex nanoparticles (NPs) formed by hPPCs/linear poly(ß-amino ester) (PBAE) and plasmids were approximately 300 nm. These hPPCs/PBAE-green fluorescence protein plasmids polyplex NPs showed high transfection efficiency and low toxicity in cells and mouse organs. By cleaving HPV16 E7 oncogene, reducing the expression of HPV16 E7 protein and increasing intracellular retinoblastoma 1 (RB1) amount, hPPCs/PBAE-CRISPR/Cas9 therapeutic plasmids polyplex NPs, especially highly branched hPPC1-plasmids polyplex NPs, exhibited strong growth inhibition of cervical cancer cells in vitro and xenograft tumors in nude mice. Together, the hPPCs/PBAE polyplex NPs to deliver HPV16 E7 targeted CRISPR/Cas9 system in this study could potentially be applied to treat HPV-related cervical cancer.
Asunto(s)
Infecciones por Papillomavirus , Polímeros , Neoplasias del Cuello Uterino , Animales , Sistemas CRISPR-Cas , Sistemas de Liberación de Medicamentos , Ésteres , Femenino , Humanos , Ratones , Ratones Desnudos , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/terapia , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/terapiaRESUMEN
BACKGROUND: Gene therapy has held promises for treating specific genetic diseases. However, the key to clinical application depends on effective gene delivery. METHODS: Using a large animal model, we developed two pharmaceutical formulations for gene delivery in the pigs' vagina, which were made up of poly (ß-amino ester) (PBAE)-plasmid polyplex nanoparticles (NPs) based two gel materials, modified montmorillonite (mMMT) and hectorite (HTT). FINDINGS: By conducting flow cytometry of the cervical cells, we found that PBAE-GFP-NPs-mMMT gel was more efficient than PBAE-GFP-NPs-HTT gel in delivering exogenous DNA intravaginally. Next, we designed specific CRISPR/SpCas9 sgRNAs targeting porcine endogenous retroviruses (PERVs) and evaluated the genome editing efficacy in vivo. We discovered that PERV copy number in vaginal epithelium could be significantly reduced by the local delivery of the PBAE-SpCas9/sgRNA NPs-mMMT gel. Comparable genome editing results were also obtained by high-fidelity version of SpCas9, SpCas9-HF1 and eSpCas9, in the mMMT gel. Further, we confirmed that the expression of topically delivered SpCas9 was limited to the vagina/cervix and did not diffuse to nearby organs, which was relatively safe with low toxicity. INTERPRETATION: Our data suggested that the PBAE-NPs mMMT vaginal gel is an effective preparation for local gene therapy, yielding insights into novel therapeutic approaches to sexually transmitted disease in the genital tract. FUNDING: This work was supported by the National Science and Technology Major Project of the Ministry of science and technology of China (No. 2018ZX10301402); the National Natural Science Foundation of China (81761148025, 81871473 and 81402158); Guangzhou Science and Technology Programme (No. 201704020093); National Ten Thousand Plan-Young Top Talents of China, Fundamental Research Funds for the Central Universities (17ykzd15 and 19ykyjs07); Three Big Constructions-Supercomputing Application Cultivation Projects sponsored by National Supercomputer Center In Guangzhou; the National Research FFoundation (NRF) South Africa under BRICS Multilateral Joint Call for Proposals; grant 17-54-80078 from the Russian Foundation for Basic Research.