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1.
Small ; 15(40): e1902776, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31402576

RESUMEN

The vascular endothelial growth factor (VEGF) induces pathological angiogenetic ocular diseases. It is a scientific challenge to develop carriers for the controlled release of inhibitors for VEGF present in the back of the eye domain. Carbon dots (C-dots) functionalized with the VEGF aptamer are introduced and the hybrid nanoparticles are used for ocular nanomedicine. The C-dots are applied as effective carriers of the anti-VEGF aptamer across the cornea, yielding therapeutic levels upon topical administration. The hybrids show no toxicity for both in vitro and in vivo murine animal model, and further enable noninvasive intraocular concentration monitoring through the C-dots inherent fluorescence. In addition, the hybrid C-dots effectively inhibit VEGF-stimulated angiogenesis in choroidal blood vessels. This inhibition is comparable to two commercially available anti-VEGF drugs, bevacizumab and aflibercept. The hybrid aptamer-modified C-dots provide a versatile nanomaterial to treat age-related macular degeneration and diabetic retinopathy.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Aptámeros de Péptidos/administración & dosificación , Aptámeros de Péptidos/uso terapéutico , Carbono/química , Oftalmopatías/tratamiento farmacológico , Nanocompuestos/química , Enfermedades Vasculares/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Tópica , Inhibidores de la Angiogénesis/farmacología , Animales , Aptámeros de Péptidos/farmacología , Línea Celular , Humanos , Ratas Long-Evans , Factor A de Crecimiento Endotelial Vascular/metabolismo
2.
Sci Rep ; 8(1): 8271, 2018 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-29844463

RESUMEN

Microalgae-based metabolic engineering has been proven effective for producing valuable substances such as food supplements, pharmaceutical drugs, biodegradable plastics, and biofuels in the past decade. The ability to accurately visualize and quantify intracellular metabolites in live microalgae is essential for efficient metabolic engineering, but remains a major challenge due to the lack of characterization methods. Here we demonstrate it by synthesizing fluorogenic peptide aptamers with specific binding affinity to a target metabolite and delivering them into live microalgae by femtosecond laser photoporation at single-cell resolution. As a proof-of-principle demonstration of our method, we use it to characterize Euglena gracilis, a photosynthetic unicellular motile microalgal species, which is capable of producing paramylon (a carbohydrate granule similar to starch). Specifically, we synthesize a peptide aptamer containing a paramylon-binding fluorescent probe, 7-nitrobenzofurazan, and introduce it into E. gracilis cells one-by-one by suppressing their mobility with mannitol and transiently perforating them with femtosecond laser pulses at 800 nm for photoporation. To demonstrate the method's practical utility in metabolic engineering, we perform spatially and temporally resolved fluorescence microscopy of single live photoporated E. gracilis cells under different culture conditions. Our method holds great promise for highly efficient microalgae-based metabolic engineering.


Asunto(s)
Aptámeros de Péptidos/administración & dosificación , Ingeniería Metabólica/métodos , Microalgas/metabolismo , Biocombustibles/microbiología , Citoplasma/metabolismo , Euglena gracilis/metabolismo , Colorantes Fluorescentes/metabolismo , Glucanos , Rayos Láser , Microscopía Fluorescente/métodos , Fotosíntesis
3.
Theranostics ; 8(21): 6008-6024, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30613278

RESUMEN

Extra domain B of fibronectin (FN-EDB) is upregulated in the extracellular matrix during tissue remodeling and has been postulated as a potential biomarker for atherosclerosis, yet no systematic test for FN-EDB in plaques has been reported. We hypothesized that FN-EDB expression would intensify in advanced plaques. Furthermore, engineering of FN-EDB-targeted nanoparticles (NPs) could enable imaging/diagnosis and local delivery of payloads to plaques. Methods: The amount of FN-EDB in human atherosclerotic and normal arteries (ages: 40 to 85 years) was assessed by histological staining and quantification using an FN-EDB-specific aptide (APTFN-EDB). FN-EDB-specific NPs that could serve as MRI beacons were constructed by immobilizing APTFN-EDB on the NP surface containing DTPA[Gd]. MRI visualized APTFN-EDB-[Gd]NPs administered to atherosclerotic apolipoprotein E-deficient mice in the brachiocephalic arteries. Analysis of the ascending-to-descending thoracic aortas and the aortic roots of the mice permitted quantitation of Gd, FN-EDB, and APTFN-EDB-[Gd]NPs. Cyanine, a model small molecule drug, was used to study the biodistribution and pharmacokinetics of APTFN-EDB-NPs to evaluate their utility for drug delivery. Results: Atherosclerotic tissues had significantly greater FN-EDB-positive areas than normal arteries (P < 0.001). This signal pertained particularly to Type III (P < 0.01), IV (P < 0.01), and V lesions (P < 0.001) rather than Type I and II lesions (AHA classification). FN-EDB expression was positively correlated with macrophage accumulation and neoangiogenesis. Quantitative analysis of T1-weighted images of atherosclerotic mice revealed substantial APTFN-EDB-[Gd]NPs accumulation in plaques compared to control NPs, conventional MRI contrast agent (Gd-DTPA) or accumulation in wild-type C57BL/6J mice. Additionally, the APTFN-EDB-NPs significantly prolonged the blood-circulation time (t1/2: ~ 6 h) of a model drug and increased its accumulation in plaques (6.9-fold higher accumulation vs. free drug). Conclusions: Our findings demonstrate augmented FN-EDB expression in Type III, IV, and V atheromata and that APTFN-EDB-NPs could serve as a platform for identifying and/or delivering agents locally to a subset of atherosclerotic plaques.


Asunto(s)
Aterosclerosis/diagnóstico por imagen , Aterosclerosis/tratamiento farmacológico , Fibronectinas/metabolismo , Imagen Molecular/métodos , Terapia Molecular Dirigida/métodos , Nanopartículas/metabolismo , Placa Aterosclerótica/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Animales , Aptámeros de Péptidos/administración & dosificación , Aptámeros de Péptidos/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibronectinas/análisis , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Unión Proteica
4.
Int J Nanomedicine ; 11: 3891-905, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27574422

RESUMEN

Liver cancer is the fifth most commonly diagnosed malignancy, of which hepatocellular carcinoma (HCC) represents the dominating histological subtype. Antiangiogenic therapy aimed at vascular endothelial growth factor (VEGF) has shown promising but deficient clinical prospects on account of vasculogenic mimicry, a highly patterned vascular channel distinguished from the endothelium-dependent blood vessel, which may function as blood supply networks occurring in aggressive tumors including HCC. In this study, we used a new cationic peptide, disulfide cross-linked stearylated polyarginine peptide modified with histidine (H3R5), as a reducible vector, cell penetrating peptide-modified aptamer (ST21) with specific binding to HCC cells to conjugate to peptide H3R5 as the targeting probe, miRNA-195 (miR195) as a powerful gene drug to inhibit VEGF, and fasudil to suppress vasculogenic mimicry by blocking ROCK2, all of which were simultaneously encapsulated in the same nanoparticles. Fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient and miR195 was condensed through electrostatic interaction. ST21-H3R5-polyethylene glycol (PEG) exhibited excellent loading capacities for both fasudil and miR195 with adjustable dosing ratios. Western blot analysis showed that (Fasudil)ST21-H3R5-PEGmiR195 had strong silencing activity of ROCK2 and VEGF, as compared with (Fasudil)H3R5-PEGmiR195. In vitro and in vivo experiments confirmed that ST21-modified nanoparticles showed significantly higher cellular uptake and therapeutic efficacy in tumor cells or tumor tissues than the unmodified counterparts. These findings suggest that aptamer-conjugated peptide holds great promise for delivering chemical drugs and gene drugs simultaneously to overcome HCC.


Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Inhibidores de la Angiogénesis/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Hepáticas/tratamiento farmacológico , MicroARNs/administración & dosificación , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/administración & dosificación , Sulfato de Amonio/química , Inhibidores de la Angiogénesis/farmacología , Animales , Aptámeros de Péptidos/administración & dosificación , Aptámeros de Péptidos/química , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Péptidos de Penetración Celular/química , Estabilidad de Medicamentos , Humanos , Neoplasias Hepáticas/patología , Ratones Desnudos , Nanopartículas/administración & dosificación , Nanopartículas/química , Péptidos/química , Polietilenglicoles/química , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
PLoS One ; 9(10): e110930, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25329893

RESUMEN

HIV-associated cardiomyopathy (HIVCM) is of clinical concern in developing countries because of a high HIV-1 prevalence, especially subtype C, and limited access to highly active antiretroviral therapy (HAART). For these reasons, we investigated the direct and indirect effects of HIV-1 subtype C infection of cultured human cardiomyocytes and the mechanisms leading to cardiomyocytes damage; as well as a way to mitigate the damage. We evaluated a novel approach to mitigate HIVCM using a previously reported gp120 binding and HIV-1 neutralizing aptamer called UCLA1. We established a cell-based model of HIVCM by infecting human cardiomyocytes with cell-free HIV-1 or co-culturing human cardiomyocytes with HIV-infected monocyte derived macrophages (MDM). We discovered that HIV-1 subtype C unproductively (i.e. its life cycle is arrested after reverse transcription) infects cardiomyocytes. Furthermore, we found that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway. CXCR4 receptor-using viruses were stronger inducers of apoptosis than CCR5 utilizing variants. Importantly, we discovered that HIV-1 induced apoptosis of cardiomyocytes was mitigated by UCLA1. However, UCLA1 had no protective effective on cardiomyocytes when apoptosis was triggered by HIV-infected MDM. When HIV-1 was treated with UCLA1 prior to infection of MDM, it failed to induce apoptosis of cardiomyocytes. These data suggest that HIV-1 causes a mitochondrial initiated apoptotic cascade, which signal through caspase-9, whereas HIV-1 infected MDM causes apoptosis predominantly via the death-receptor pathway, mediated by caspase-8. Furthermore the data suggest that UCLA1 protects cardiomyocytes from caspase-mediated apoptosis, directly by binding to HIV-1 and indirectly by preventing infection of MDM.


Asunto(s)
Aptámeros de Péptidos/metabolismo , Cardiomiopatías/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/complicaciones , Apoptosis/efectos de los fármacos , Aptámeros de Péptidos/administración & dosificación , Cardiomiopatías/etiología , Cardiomiopatías/virología , Sistema Libre de Células , Proteína gp120 de Envoltorio del VIH/genética , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , VIH-1/patogenicidad , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/patología , Macrófagos/virología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/virología , Receptores CXCR4/metabolismo
6.
Curr Pharm Biotechnol ; 14(13): 1105-17, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24725129

RESUMEN

OBJECTIVE: A multifunctional tumor-targeting drug delivery system employing single-walled carbon nanotubes (SWCNT) as drug carriers, AS1411 as targeting ligand and doxorubicine (DOX) as a model chemotherapy drug was constructed. METHODS: Firstly, SWCNT were modified with F68 (4.0 mg/ml) by ultrasonic dispersing technology due to the action of hydrophobic force and Van der Waals force, endowing SWCNT water dispersions and biocompatibility. Meanwhile, DOX could be easily absorbed on the surface of SWCNT by the π-π stacking, electrostatic adsorption and hydrophobic interactions. Finally, AS1411 was attached to the surface of DOX-SWCNT by the π-π stacking and electrostatic adsorption to obtain a tumor-targeting delivery system. Cellular uptake, anti-tumor effect in vitro and in vivo, cell cycle and apoptosis and biodistribution of AS1411-DOX-SWCNT were investigated, compared with the DOX solution. CONCLUSION: This AS1411-mediated DOX-loaded SWCNT (AS1411-DOX-SWCNT) delivery system not only retained both optical properties of SWCNT and cytotoxicity of DOX but also could accumulate in tumors, which facilitated combination of chemotherapy and photothermal therapy. AS1411-DOX-SWCNT could effectively promote DOX cellular uptake and then increase intracellular accumulation as a targeting delivery system. AS1411-DOX-SWCNT by NIR laser excited could trigger S phase arrest and the late stage apoptotic on PC3 cancer cells. The investigation in vivo further confirmed that this system possessed higher tumor targeting capacity and antitumor efficacy than DOX, especially with NIR laser irradiation.


Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Aptámeros de Péptidos/administración & dosificación , Aptámeros de Péptidos/uso terapéutico , Nanotubos de Carbono , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Área Bajo la Curva , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Ratones , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Macromol Biosci ; 13(10): 1413-21, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23868860

RESUMEN

It is of paramount importance to study the cellular uptake processes of particles with defined surface property, especially the uptake pathways and intracellular transportation. In this study, aptamer AS1411 molecules, which are known to specifically bind the over-expressed nucleolin on cancer cell membrane, were conjugated onto bovine serum albumin-decorated poly(D,L-lactide-co-glycolide; PLGA, Φ400 nm) particles with a density of 1-1.7 molecule/10 nm(2). The aptamer-modified PLGA particles were preferably ingested by liver cancer cells with higher amount and faster rate. The clathrin-mediated endocytosis and macropinocytosis pathways played a more important role in uptake of the aptamer modified particles.


Asunto(s)
Aptámeros de Péptidos/administración & dosificación , Ácido Láctico/administración & dosificación , Hígado/efectos de los fármacos , Ácido Poliglicólico/administración & dosificación , Albúmina Sérica Bovina/química , Animales , Aptámeros de Péptidos/química , Bovinos , Línea Celular , Clatrina/metabolismo , Endocitosis/efectos de los fármacos , Ácido Láctico/química , Hígado/citología , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Pinocitosis/efectos de los fármacos , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/metabolismo , Albúmina Sérica Bovina/administración & dosificación , Propiedades de Superficie , Nucleolina
8.
J Drug Target ; 21(5): 427-34, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23350808

RESUMEN

BACKGROUND: The use of mesoporous silica for cancer targeting is increasing rapidly. The association between rigid model of nanoparticles such as mesoporous silica and biological compounds with affinity for oncological diseases is a very promising drug targeting system nowadays. METHODS: In this study, we used the mesoporous silica (SBA-15) associated with aptamer (functionalized for the tumor marker MUC-1). RESULTS: The results obtained in the characterization were quite interesting and demonstrated that the silica produced were very uniform and with a size range of 50-100 nm. Thus, the results of cytotoxicity demonstrated that there is no cytotoxicity related to the nanoparticle. CONCLUSION: We conclude that although further studies are required, the nanoparticle mesoporous silica model loaded with aptamer is very functional and its use can be widespread for other application especially in nuclear medicine.


Asunto(s)
Aptámeros de Péptidos/administración & dosificación , Aptámeros de Péptidos/química , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/administración & dosificación , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Humanos , Ratones , Mucina-1/metabolismo , Neoplasias/metabolismo , Tamaño de la Partícula , Porosidad , Técnica SELEX de Producción de Aptámeros/métodos , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/química , Distribución Tisular
9.
Arterioscler Thromb Vasc Biol ; 32(4): 902-9, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22282355

RESUMEN

OBJECTIVE: We investigated the stability, pharmacokinetic, and pharmacodynamic profile of the 2(nd) generation anti-von Willeband factor aptamer ARC15105. METHODS AND RESULTS: Platelet plug formation was measured by collagen/adenosine diphosphate-induced closure time with the platelet function analyzer-100 and platelet aggregation by multiple electrode aggregometry. Platelet adhesion was measured on denuded porcine aortas and in a flow chamber. Aptamer stability was assessed by incubation in nuclease rich human, monkey, and rat serum for up to 72 hours. Pharmacokinetic and pharmacodynamic profiles were tested in cynomolgus monkeys after IV and SC administration. The median IC(100) and IC(50) to prolong collagen/adenosine diphosphate-induced closure timewere 27 nmol/L and 12 nmol/L, respectively. ARC15105 (1.3 µmol/L) completely inhibited ristocetin-induced platelet aggregation in whole blood (P<0.001), but also diminished collagen, ADP, arachidonic acid, and thrombin receptor activating peptide-induced platelet aggregation to some extent (P<0.05). ARC15105 (40 nmol/L) decreased platelet adhesion by >90% on denuded porcine aortas (P<0.001), which was comparable to the degree of inhibition obtained with abciximab. ARC15105 (100 nmol/L) also inhibited platelet adhesion to collagen under arterial shear in a flow chamber by >90% (P<0.001). The IV and SC terminal half-lives in cynomolgus monkeys were 67 and 65 hours, respectively, and the SC bioavailability was ≈98%. Allometric scaling estimates the human T(1/2) would be ≈217 hours. Pharmacodynamic analysis confirms that ARC15105 inhibits von Willeband factor activity >90% in blood samples taken 300 hours after a 20 mg/kg IV or SC dose in monkeys. CONCLUSIONS: The potency, pharmacokinetic profile, and SC bioavailability of ARC15105 support its clinical investigation for chronic inhibition of von Willeband factor -mediated platelet activation.


Asunto(s)
Aptámeros de Nucleótidos/uso terapéutico , Aptámeros de Péptidos/farmacología , Plaquetas/efectos de los fármacos , Infarto del Miocardio/sangre , Activación Plaquetaria/efectos de los fármacos , Adhesividad Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Factor de von Willebrand/antagonistas & inhibidores , Anciano , Animales , Aptámeros de Nucleótidos/administración & dosificación , Aptámeros de Nucleótidos/farmacocinética , Aptámeros de Péptidos/administración & dosificación , Aptámeros de Péptidos/farmacocinética , Austria , Disponibilidad Biológica , Plaquetas/metabolismo , Boston , Estudios de Casos y Controles , Colágeno/metabolismo , Estudios Transversales , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Macaca fascicularis , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacocinética , Pruebas de Función Plaquetaria , Unión Proteica , Quebec , Ratas , Porcinos , Factor de von Willebrand/metabolismo
10.
Nanomedicine (Lond) ; 5(9): 1435-45, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21128724

RESUMEN

Aptamers are an interesting class of molecules that have potential in many facets of human health. They are characterized by high affinity and specificity to their targets, are small in size, have similar properties to antibodies, but are made synthetically. All of these properties, among others, give aptamers the potential to diagnose, image and treat like no other molecules. By combining the unique properties of aptamers with the ever expanding field of nanotechnology and all it has to offer, we are entering a very promising new area of targeted nanodelivery treatments. These treatments have found success in the complex disease processes of cancer, eye and inflammatory diseases.


Asunto(s)
Aptámeros de Nucleótidos/administración & dosificación , Aptámeros de Péptidos/administración & dosificación , Oftalmopatías/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Nanotecnología/métodos , Neoplasias/tratamiento farmacológico , Animales , Aptámeros de Nucleótidos/química , Aptámeros de Péptidos/química , Humanos , Ratones
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