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The efficiency and durability of perovskite solar cells (PSCs) are closely related to the property and stability of each functional layer involved in device. Owing to the excellent hole transport properties, the additive-doped Spiro-OMeTAD (2,2',7,7'-tetrakis (N,N-di-p-methoxyphenylamine) 9,9'-spirobifluorene) has become an excellent hole-transporting material for obtaining highly efficient PSCs. However, the hygroscopic nature of additives and the pinholes caused by poor film-forming capability inevitably impair the performance and long-term stability of Spiro-OMeTAD and the resulting PSCs. In this study, the hydrophobic polymer polystyrene (PS) was incorporated to improve the hydrophobicity and film-forming capability of the additive-doped Spiro-OMeTAD films. Based on the PS-modified Spiro-OMeTAD and carbon electrodes, the derived planar carbon-based PSCs exhibited significantly enhanced long-term stability, which can maintain 92% of its initial efficiency after aging for 2500 h under ambient atmosphere without encapsulation. In addition, the PS-modified Spiro-OMeTAD exhibited improved morphology with reduced pinholes, contributing to significantly enhanced interfacial carrier transport. Finally, a champion power conversion efficiency of 21.06% was obtained, which is one of the highest efficiencies reported for the planar carbon-based PSCs to date.
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Magnetic resonance imaging (MRI) and photoacoustic tomography (PAT) offer two distinct image contrasts. To integrate these two modalities, we present a comprehensive hardware-software solution for the successive acquisition and co-registration of PAT and MRI images in in vivo animal studies. Based on commercial PAT and MRI scanners, our solution includes a 3D-printed dual-modality imaging bed, a 3-D spatial image co-registration algorithm with dual-modality markers, and a robust modality switching protocol for in vivo imaging studies. Using the proposed solution, we successfully demonstrated co-registered hybrid-contrast PAT-MRI imaging that simultaneously displays multi-scale anatomical, functional and molecular characteristics on healthy and cancerous living mice. Week-long longitudinal dual-modality imaging of tumor development reveals information on size, border, vascular pattern, blood oxygenation, and molecular probe metabolism of the tumor micro-environment at the same time. The proposed methodology holds promise for a wide range of pre-clinical research applications that benefit from the PAT-MRI dual-modality image contrast.
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In recent years, lead halide perovskite materials have attracted great interest and are widely used in solar cells and light-emitting devices due to their high photoelectronic quantum yield, high color purity, high defect tolerance, long diffusion length, high carrier mobility, and bandgap tunability. However, the application of lead halide perovskites is limited due to the presence of Pb, making lead-free perovskites an important substitute due to their same crystal structure and similar properties. Although some reports have been made on lead-free perovskite materials, there are still great challenges to realize their application due to their poor stability, easy phase transition, and low photoelectric conversion efficiency. Here, we mainly summarize the development and application of ABX3-type lead-free halide perovskite materials, especially in optoelectronic devices. The article first introduces the lattice and energy band structure, the optoelectronic properties of lead-free perovskites, including the research method of lead-free perovskites, and then analyzes the reasons for the low luminous efficiency and poor stability of lead-free perovskite materials. Second, the development history and current situation of lead-free perovskites in different optoelectronic device applications are summarized. Finally, we present the challenges and prospects for the future development of lead-free perovskites.
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Since their discovery, ferroelectric materials have shown excellent dielectric responses, pyroelectricity, piezoelectricity, electro-optical effects, nonlinear optical effects, etc. They are a class of functional materials with broad application prospects. Traditional pure inorganic piezoelectric materials have better piezoelectricity but higher rigidity; pure organic piezoelectric materials have better flexibility but havetoo small a piezoelectric coefficient. The material composite, on the other hand, can combine the advantages of both, so that it has both flexibility and a high piezoelectric coefficient. In this paper, a new molecular piezoelectric material (C5H11NO)2PbBr4 with a high Curie temperature Tc and a large piezoelectric voltage constant g33, referred to as (ATHP)2PbBr4, was used to prepare a 0-3 type piezoelectric composite film by compounding with an organic polymer material polyvinylidene fluoride (PVDF), and its ferroelectricity was investigated. The results show that the 0-3 type (ATHP)2PbBr4 piezoelectric composite film has good ferroelectricity and piezoelectricity, and the calculated piezoelectric voltage constant g33 after polarization is about 358.6 × 10-3 Vm/N, which is higher than that of PVDF material, and is important for the fabrication of high-performance piezoelectric sensors.
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Carbon-based perovskite solar cells (C-PSCs) have attracted widespread research interest because of their excellent stability. However, the power conversion efficiency (PCE) of C-PSCs, especially planar C-PSCs, lags far behind the certified efficiency (25.5%) of metal-based PSCs. The simple architecture of planar C-PSCs imparts stringent requirements for device configuration. In this study, we fabricated high-performance planar C-PSCs through device configuration engineering in terms of the perovskite active layer and carbon electrode. Through the combination of component and additive engineering, the crystallization and absorption profiles of perovskite active layer have been improved, which afforded sufficient photogenerated carriers and decreased nonradiative recombination. Furthermore, the mechanical and physical properties of carbon electrode were evaluated comprehensively to regulate the back-interface contact. Based on the compromise of the flexibility and conductivity of carbon film, an excellent back-interface contact has been formed, which promoted fast interface charge transfer, thereby decreasing interface recombination and improving carrier collection efficiency. Finally, the as-prepared devices achieved a remarkable PCE of up to 20.04%, which is a record-high value for planar C-PSCs. Furthermore, the as-prepared devices exhibited excellent long-term stability. After storage for 1000 h at room temperature and 25% relative humidity without encapsulation, the as-prepared device retained 94% of its initial performance.
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The spatial resolution of photoacoustic tomography (PAT) can be characterized by the point spread function (PSF) of the imaging system. Due to the tomographic detection geometry, the PAT image degradation model could be generally described by using spatially variant PSFs. Deconvolution of the PAT image with these PSFs could restore image resolution and recover object details. Previous PAT image restoration algorithms assume that the degraded images can be restored by either a single uniform PSF, or some blind estimation of the spatially variant PSFs. In this work, we propose a PAT image restoration method to improve image quality and resolution based on experimentally measured spatially variant PSFs. Using photoacoustic absorbing microspheres, we design a rigorous PSF measurement procedure, and successfully acquire a dense set of spatially variant PSFs for a commercial cross-sectional PAT system. A pixel-wise PSF map is further obtained by employing a multi-Gaussian-based fitting and interpolation algorithm. To perform image restoration, an optimization-based iterative restoration model with two kinds of regularizations is proposed. We perform phantom and in vivo mice imaging experiments to verify the proposed method, and the results show significant image quality and resolution improvement.
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Algoritmos , Tomografía Computarizada por Rayos X , Animales , Estudios Transversales , Ratones , Fantasmas de Imagen , TomografíaRESUMEN
Endoscopic airway optical coherence tomography (OCT) is an advanced imaging modality capable of capturing the internal anatomy and geometry of the airway. Due to fiber-optic catheter bending and friction, the rotation speed of the endoscopic probe is usually non-uniform: at each B-scan image, the initial rotation angle of the probe is easily misaligned with that of the previous slices. During the pullback operation, this initial rotation angle error (IRAE) will be accumulated and will result in distortion and deformation of the reconstructed 3D airway structure. Previous attempts to correct this error were mainly manual corrections, which are time-consuming and suffered from observer variation. In this paper, we present a method to correct the IRAE for anatomically improved visualization of the airway. Our method derived the rotation angular difference of adjacent B-scans by measuring their contour similarity and then tracks the IRAE by formulating its continuous drift as a graph-based problem. The algorithm was tested on a simulated airway contour dataset, and also on experimental datasets acquired by two different long range endoscopic airway OCT platforms. Effective and smooth compensation of the frame-by-frame initial angle difference was achieved. Our method has real-time capability and thus has the potential to improve clinical imaging efficiency.
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BACKGROUND AND OBJECTIVE: In acoustic inversion of photoacoustic tomography (PAT), an imaging model that precisely describes both the ultrasonic wave propagation and the detector properties is of crucial importance. Inspired by the multi-stripe integration model in clinical X-ray computed tomography systems, in this work, we introduce the Multi-Curve-Integration-based acoustic inversion for cross-sectional Photoacoustic Tomography (MCI-PAT). METHODS: We assumed that in cross-sectional PAT system, the three-dimensional (3-D) wave propagation problem could be reduced to a two-dimensional (2-D) problem in a limited, yet sufficient field of view. Under such condition, the MCI-PAT imaging model is generated by integrating several circular acoustic curves, the centers of which are points evenly distributed on the finite-size ultrasonic transducer surface. In this way, the spatial detector response is taken into account, while its computational burden does not largely increase because the integration process is performed only on a 2-D plane. RESULTS: As proven by simulation, phantom and in vivo small animal experiments, the MCI-PAT method leads to promising improvement in PAT image quality. Comparing to traditional imaging models that considered only a single acoustic curve, our proposed method successfully improved the visibility of small structures and achieved evident enhancement on signal-to-noise ratio. CONCLUSIONS: The performance of the MCI-PAT method demonstrates that for cross-sectional PAT, a 2-D simplification of the propagation of multiple photoacoustic waves is feasible. Due to its simplicity, our method can be used as an add-on to current system models considering only a single acoustic curve.
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Técnicas Fotoacústicas , Tomografía , Animales , Estudios Transversales , Procesamiento de Imagen Asistido por Computador , Fantasmas de Imagen , Tomografía Computarizada por Rayos XRESUMEN
Multispectral photoacoustic tomography (PAT) is capable of resolving tissue chromophore distribution based on spectral un-mixing. It works by identifying the absorption spectrum variations from a sequence of photoacoustic images acquired at multiple illumination wavelengths. Due to multispectral acquisition, this inevitably creates a large dataset. To cut down the data volume, sparse sampling methods that reduce the number of detectors have been developed. However, image reconstruction of sparse sampling PAT is challenging because of insufficient angular coverage. During spectral un-mixing, these inaccurate reconstructions will further amplify imaging artefacts and contaminate the results. To solve this problem, we present the interlaced sparse sampling (ISS) PAT, a method that involved: 1) a novel scanning-based image acquisition scheme in which the sparse detector array rotates while switching illumination wavelength, such that a dense angular coverage could be achieved by using only a few detectors; and 2) a corresponding image reconstruction algorithm that makes use of an anatomical prior image created from the ISS strategy to guide PAT image computation. Reconstructed from the signals acquired at different wavelengths (angles), this self-generated prior image fuses multispectral and angular information, and thus has rich anatomical features and minimum artefacts. A specialized iterative imaging model that effectively incorporates this anatomical prior image into the reconstruction process is also developed. Simulation, phantom, and in vivo animal experiments showed that even under 1/6 or 1/8 sparse sampling rate, our method achieved comparable image reconstruction and spectral un-mixing results to those obtained by conventional dense sampling method.
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Algoritmos , Tomografía Computarizada por Rayos X , Animales , Artefactos , Simulación por Computador , Procesamiento de Imagen Asistido por Computador , Fantasmas de ImagenRESUMEN
One of the advantages of photoacoustic imaging (PAI) is that its image contrast may come from exogenous agents. Such advantage leads to the development of a great number of exogenous probes. However, the biosafety of most of these contrast agents has not yet been confirmed, thus hindering their clinical translation. In this work, we report on the utilization of a clinically commonly used nutritional medicine, the Intralipid, as a new contrast agent for photoacoustic imaging. Intralipid consists of soybean oil, lecithin and glycerin and has long been adapted in clinical practices, mainly as a parenteral nutrition. In our study, we found that with Intralipid, the imaging sensitivity of PAI can be effectively enhanced, as demonstrated in in vivo imaging of different organs of nude mice. Further imaging studies on cancerous mice showed not only a twofold PA signal enhancement, but also a strong and long-lasting signal aggregation in the tumor region. Our result revealed the potential of Intralipid to be used in clinical PAI applications, since it is clinically safe, and can be easily prepared at very low cost.
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Due to complication factors such as blood-brain barrier (BBB), integrating high efficiency of brain target ability with specific cargo releasing into one nanocarrier seems more important. A brain targeting nanoscale system is developed using dehydroascorbic acid (DHA) as targeting moiety. DHA has high affinity with GLUT1 on BBB. More importantly, the GLUT1 transportation of DHA represents a "one-way" accumulative priority from blood into brain. The artificial micelles are fabricated by a disulfide linkage, forming a bio-responsive inner barrier, which can maintain micelles highly stable in circulation and shield the leakage of entrapped drug before reaching the targeting cells. The designed micelles can cross BBB and be further internalized by brain cells. Once within the cells, the drug release can be triggered by high intracellular level of glutathione (GSH). Itraconazole (ITZ) is selected as the model drug because of its poor brain permeability and low stability in blood. It demonstrates that the functionalized nanoscale micelles can achieve highly effective direct drug delivery to targeting site. Based on the markedly increased stability in blood circulation and improved brain delivery efficiency of ITZ, DHA-modified micelles show highly effective in anti-intracranial infection. Therefore, this smart nanodevice shows a promising application for the treatment of brain diseases.
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Antiinfecciosos/farmacología , Encéfalo/metabolismo , Encéfalo/patología , Microambiente Celular , Micelas , Nanopartículas/química , Animales , Transporte Biológico/efectos de los fármacos , Encéfalo/citología , Encéfalo/efectos de los fármacos , Línea Celular Tumoral , Ácido Deshidroascórbico/química , Ácido Deshidroascórbico/metabolismo , Sistemas de Liberación de Medicamentos , Endocitosis/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/metabolismo , Fluorescencia , Glucosa/metabolismo , Glutatión/metabolismo , Humanos , Terapia de Inmunosupresión , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Ratones , Microscopía de Fuerza Atómica , Distribución Tisular/efectos de los fármacosRESUMEN
Malignant glioma, a highly aggressive tumor, is one of the deadliest types of cancer associated with dismal outcome despite optimal chemotherapeutic regimens. One explanation for this is the failure of most chemotherapeutics to accumulate in the tumors, additionally causing serious side effects in periphery. To solve these problems, we sought to develop a smart therapeutic nanodevice with cooperative dual characteristics of high tumor-targeting ability and selectively controlling drug deposition in tumor cells. This nanodevice was fabricated with a cross-linker, containing disulfide linkage to form an inner cellular microenvironment-responsive "-S-S-" barrier, which could shield the entrapped drug leaking in blood circulation. In addition, dehydroascorbic acid (DHA), a novel small molecular tumor-specific vector, was decorated on the nanodevice for tumor-specific recognition via GLUT1, a glucose transporter highly expressed on tumor cells. The drug-loaded nanodevice was supposed to maintain high integrity in the bloodstream and increasingly to specifically bind with tumor cells through the association of DHA with GLUT1. Once within the tumor cells, the drug release was triggered by a high level of intracellular glutathione. When these two features were combined, the smart nanodevice could markedly improve the drug tumor-targeting delivery efficiency, meanwhile decreasing systemic toxicity. Herein, this smart nanodevice showed promising potential as a powerful platform for highly effective antiglioma treatment.
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Neoplasias Encefálicas/terapia , Portadores de Fármacos , Glioma/terapia , Nanoestructuras , Microambiente Tumoral , Animales , Xenoinjertos , Humanos , RatonesRESUMEN
Among all the malignant brain tumors, glioma is the deadliest and most common form with poor prognosis. Gene therapy is regarded as a promising way to halt the progress of the disease or even cure the tumor and RNA interference (RNAi) stands out. However, the existence of the blood-brain barrier (BBB) and blood tumor barrier (BTB) limits the delivery of these therapeutic genes. In this work, the delivery system targeting to the transferrin (Tf) receptor highly expressed on both BBB and glioma was successfully synthesized and would not compete with endogenous Tf. U87 cells stably express luciferase were employed here to simulate tumor and the RNAi experiments in vitro and in vivo validated that the gene silencing activity was 2.17-fold higher with the targeting ligand modification. The dual-targeting gene delivery system exhibits a series of advantages, such as high efficiency, low toxicity, stability and high transaction efficiency, which may provide new opportunities in RNAi therapeutics and nanomedicine of brain tumors.
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Neoplasias Encefálicas/terapia , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Glioma/terapia , Nanopartículas , Oligopéptidos/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Animales , Transporte Biológico , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Permeabilidad Capilar , Línea Celular Tumoral , Dendrímeros/química , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Nanotecnología , Oligopéptidos/química , Polietilenglicoles/química , Polilisina/química , Receptores de Transferrina/metabolismo , Factores de Tiempo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson's disease (PD). METHODS: Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations. RESULTS: The successful synthesis of DPA was demonstrated via (1)H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119 ± 12 nm and zeta potential of 8.2 ± 0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups. CONCLUSION: This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.
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Técnicas de Transferencia de Gen , Terapia Genética/métodos , Nanoconjugados/química , Enfermedad de Parkinson/terapia , Péptidos/química , Animales , Línea Celular Tumoral , Expresión Génica , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Humanos , Proteínas Relacionadas con Receptor de LDL/metabolismo , Masculino , Enfermedad de Parkinson/genética , Unión Proteica , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
A tumor targeting nanoparticle system has been successfully developed to response to the lowered tumor extracellular pH (pHe) and upregulated matrix metalloproteinase 2 (MMP2) in the tumor microenvironment. The nanoparticles are modified with activatable cell-penetrating peptide (designated as dtACPP) that's dual-triggered by the lowered pHe and MMP2. In dtACPP, the internalization function of cell-penetrating peptide (CPP) is quenched by a pH-sensitive masking peptide, linking by a MMP2 substrate. The masking peptide is negatively charged to quench the cationic CPP well after systemic administration. Hence, dtACPP-modified nanoparticles possesses passive tumor targetability via the enhanced permeability and retention (EPR) effect. Once reaching the tumor microenvironment, the pre-existing attraction would be eliminated due to the lowered pHe, accompanying the linker cleaved by MMP2, dtACPP would be activated to expose CPP to drive the nanoparticles' internalization into the intratumoral cells. The studies of plasmid DNA loading, toxicity assessment, cellular uptake, tumor targeting delivery, and gene transfection demonstrate that dtACPP-modified nanoparticle system is a potential candidate for tumor targeting gene delivery.
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Técnicas de Transferencia de Gen , Nanopartículas/química , Neoplasias/metabolismo , Neoplasias/patología , Microambiente Tumoral , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Péptidos de Penetración Celular/síntesis química , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , ADN/metabolismo , Portadores de Fármacos/química , Electroforesis , Endocitosis/efectos de los fármacos , Fluorescencia , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Desnudos , Nanopartículas/toxicidad , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Polietilenglicoles/farmacología , Polilisina/síntesis química , Polilisina/química , Polilisina/farmacología , Distribución Tisular/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Gadolinium (Gd) chelate contrast-enhanced magnetic resonance imaging (MRI) is a preferred method of glioma detection and preoperative localisation because it offers high spatial resolution and non-invasive deep tissue penetration. Gd-based contrast agents, such as Gd-diethyltriaminepentaacetic acid (DTPA-Gd, Magnevist), are widely used clinically for tumor diagnosis. However, the Gd-based MRI approach is limited for patients with glioma who have an uncompromised blood-brain barrier (BBB). Moreover, the rapid renal clearance and non-specificity of such contrast agents further hinders their prevalence. We present a choline derivate (CD)-modified nanoprobe with BBB permeability, glioma specificity and a long blood half-life. Specific accumulation of the nanoprobe in gliomas and subsequent MRI contrast enhancement are demonstrated in vitro in U87 MG cells and in vivo in a xenograft nude model. BBB and glioma dual targeting by this nanoprobe may facilitate precise detection of gliomas with an uncompromised BBB and may offer better preoperative and intraoperative tumor localization.
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Neoplasias Encefálicas/patología , Colina , Glioma/patología , Aumento de la Imagen/métodos , Imagen por Resonancia Magnética/métodos , Nanopartículas/química , Animales , Colina/química , Medios de Contraste/síntesis química , Ratones , Ratones Desnudos , Nanopartículas/ultraestructura , Tamaño de la PartículaRESUMEN
Tumor microenvironment, such as the lowered tumor extracellular pH (pHe) and matrix metalloproteinase 2 (MMP2), has been extensively explored, which promotes the development of the microenvironment-responsive drug delivery system. Utilizing these unique features, an activatable cell-penetrating peptide (designated as dtACPP) that is dual-triggered by the lowered pHe and MMP2 has been constructed, and a smart nanoparticle system decorating with dtACPP has been successfully developed, which could dual-load gene drug and chemotherapeutics simultaneously. After systemic administration, dtACPP-modified nanoparticles possess passive tumor targetability via the enhanced permeability and retention effect. Then dtACPP would be activated to expose cell-penetrating peptide to drive the nanoparticles' internalization into the intratumoral cells. As angiogenesis and tumor cells might be mutually improved in tumor growth, so combining antiangiogenesis and apoptosis is meaningful for oncotherapy. Vascular endothelial growth factor (VEGF) is significant in angiogenesis, and anti-VEGF therapy could decrease blood vessel density and delay tumor growth obviously. Chemotherapy using doxorubicin (DOX) could kill off tumor cells efficiently. Here, utilizing dtACPP-modified nanoparticles to co-deliver plasmid expressing interfering RNA targeting VEGF (shVEGF) and DOX (designated as dtACPPD/shVEGF-DOX) results in effective shutdown of blood vessels and cell apoptosis within the tumor. On the premise of effective drug delivery, dtACPPD/shVEGF-DOX has demonstrated good tumor targetability, little side effects after systemic administration, and ideal antitumor efficacy.
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Inhibidores de la Angiogénesis/administración & dosificación , Doxorrubicina/administración & dosificación , Nanopartículas/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Transporte Biológico Activo , Línea Celular Tumoral , Péptidos de Penetración Celular/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Desnudos , Nanopartículas/administración & dosificación , Nanopartículas/química , Nanotecnología , Neovascularización Patológica/tratamiento farmacológico , Microambiente Tumoral/fisiología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
One of the most common life-threatening infections in immunosuppressive patients, like AIDs patients, is cryptococcal meningitis or meningoencephalitis. Current therapeutic options are mostly ineffective and mortality rates remain high. Hydrophobic antifungal drug Amphotericin B (AmB), has become a golden standard in severe systemic fungal infection therapy. However, most AmB commercial formulations, including deoxycholate AmB and lipid formulations of AmB, show poor penetration into the CNS and difficulty to reach the therapeutic levels. To improve the CNS permeability of AmB, we have successfully developed an effective brain-targeting polymeric micellar system with angiopep-2 modified, named Angiopep-PEG-PE/AmB polymeric micelles. An immunosuppressive murine model with Cryptococcus neoformans meningoencephalitis (CNME) was established to evaluate the CNS penetration efficiency and antifungal treatment efficacy of the AmB-incorporated brain-vectored polymeric micellar formulation, compared with the AmB commercial formulations. After three consecutive days of i.v. administration, the results showed that the group treated with Angiopep-PEG-PE/AmB achieved the greatest treatment efficacy, which reached the highest AmB level in brain, reduced the brain fungal burden significantly, decreased histopathological severity and prolonged the median survival time. The increased treatment efficacy could be attributed to the brain-targeting delivery system promoted AmB crossing the BBB and penetrating into the brain to reach the therapeutic concentration. The underlying mechanism was also explored in this work. Therefore, the brain-targeting delivery system could have potential and promising implications for treatment of intracerebral fungal infection.
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Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Portadores de Fármacos/química , Meningitis Criptocócica/tratamiento farmacológico , Péptidos/administración & dosificación , Péptidos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Anfotericina B/sangre , Anfotericina B/química , Animales , Antifúngicos/sangre , Antifúngicos/química , Barrera Hematoencefálica/metabolismo , Cryptococcus neoformans/efectos de los fármacos , Cryptococcus neoformans/aislamiento & purificación , Portadores de Fármacos/administración & dosificación , Humanos , Masculino , Meningoencefalitis/tratamiento farmacológico , Ratones , Micelas , Microscopía Confocal , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Espectrometría de Fluorescencia , Verapamilo/farmacologíaRESUMEN
The combination of gene therapy and chemotherapy is a promising treatment strategy for brain gliomas. In this paper, we designed a co-delivery system (DGDPT/pORF-hTRAIL) loading chemotherapeutic drug doxorubicin and gene agent pORF-hTRAIL, and with functions of pH-trigger and cancer targeting. Peptide HAIYPRH (T7), a transferrin receptor-speciï¬c peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. T7-modiï¬ed co-delivery system showed higher efï¬ciency in cellular uptake and gene expression than unmodiï¬ed co-delivery system in U87 MG cells, and accumulated in tumor more efï¬ciently in vivo. DOX was covalently conjugated to carrier though pH-trigged hydrazone bond. In vitro incubation of the conjugates in buffers led to a fast DOX release at pH 5.0 (intracellular environment) while at pH 7.4 (blood) the conjugates are relatively stable. The combination treatment resulted in a synergistic growth inhibition (combination index, CI < 1) in U87 MG cells. The synergism effect of DGDPT/pORF-hTRAIL was verified in vitro and in vivo. In vivo anti-glioma efï¬cacy study confirmed that DGDPT/pORF-hTRAIL displayed anti-glioma activity but was less toxic.