Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
1.
Nano Lett ; 23(15): 7092-7099, 2023 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-37498114

RESUMEN

Venous malformations (VMs) consist of hugely enlarged and dysmorphic veins. These lesions cause significant disfigurement, pain, and complications such as bleeding and coagulopathy. Pharmacotherapy for the treatment of VMs has limited efficacy and potentially limiting toxicity. Current treatment for patients with VMs entails life-long pharmacotherapy or surgical procedures. Here we explored whether intravenously administered agents can be used to destroy VMs by photothermal therapy (PTT), using gold nanoshells (AuNSs) that generated heat following irradiation with near-infrared (NIR) light. In a murine model of VMs, intravenous AuNSs accumulated within the VMs. Irradiation of the VMs induced marked regression and even elimination. Nanoparticle-based photothermal therapy can provide effective therapy for VMs, which are otherwise relatively refractory to treatment.


Asunto(s)
Hipertermia Inducida , Nanocáscaras , Humanos , Ratones , Animales , Terapia Fototérmica , Oro/uso terapéutico , Nanocáscaras/uso terapéutico , Hipertermia Inducida/métodos , Fototerapia
2.
Mol Pharm ; 20(2): 1375-1381, 2023 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-36633440

RESUMEN

Drug delivery directly across the tympanic membrane (TM) could eliminate systemic exposure to antibiotics prescribed for otitis media, the most common reason for pediatricians to prescribe antibiotics. Here, we hypothesized that inducing inflammation of the TM could enhance drug flux across the TM. We demonstrated that the flux of ciprofloxacin across the TM was greatly increased by treatment with the proinflammatory agent histamine. That enhancement was blocked by concurrent treatment with blockers of histamine receptor 1. Treatment of the TM with histamine was able to enhance drug flux sufficiently to eradicate otitis media in vivo in chinchillas, but only if the histamine was applied prior to treatment with antibiotics.


Asunto(s)
Otitis Media , Membrana Timpánica , Humanos , Histamina/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Otitis Media/tratamiento farmacológico , Inflamación/tratamiento farmacológico
3.
Nano Lett ; 21(15): 6609-6616, 2021 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-34296614

RESUMEN

Pharmacotherapy of vascular anomalies has limited efficacy and potentially limiting toxicity. Targeted nanoparticle (NP) drug delivery systems have the potential to accumulate within tissues where the vasculature is impaired, potentially leading to high drug levels (increased efficacy) in the diseased tissue and less in off-target sites (less toxicity). Here, we investigate whether NPs can be used to enhance drug delivery to bioengineered human vascular networks (hVNs) that are a model of human vascular anomalies. We demonstrate that intravenously injected phototargeted NPs enhanced accumulation of NPs and the drug within hVNs. With phototargeting we demonstrate 17 times more NP accumulation within hVNs than was detected in hVNs without phototargeting. With phototargeting there was 10-fold more NP accumulation within hVNs than in any other organ. Phototargeting resulted in a 6-fold increase in drug accumulation (doxorubicin) within hVNs in comparison to animals injected with the free drug. Nanoparticulate approaches have the potential to markedly improve drug delivery to vascular anomalies.


Asunto(s)
Nanopartículas , Animales , Doxorrubicina , Sistemas de Liberación de Medicamentos , Humanos
4.
Pharm Res ; 36(12): 179, 2019 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-31705417

RESUMEN

PURPOSE: It is unknown whether there are sex differences in response to free or encapsulated local anesthetics. METHODS: We examined nerve block duration and toxicity following peripheral nerve blockade in male and female rats. We studied the local anesthetic bupivacaine (free or encapsulated) as well as tetrodotoxin, which acts on a different site of the same voltage-gated channel. RESULTS: Sensory nerve blockade was 158.5 [139-190] minutes (median [interquartile range]) (males) compared to 173 [134-171] minutes (females) (p = 0.702) following bupivacaine injection, N = 8 male, 8 female. Motor nerve blockade was 157 [141-171] minutes (males) compared to 172 [146-320] minutes (females) (p = 0.2786). Micellar bupivacaine (N = 8 male, 8 female) resulted in sensory nerve blockade of 266 [227-320] minutes (males) compared to 285 [239-344] minutes (females) (p = 0.6427). Motor nerve blockade was 264 [251-264] minutes (males) compared to 287 [262-287] minutes (females) (p = 0.3823). Liposomal bupivacaine (N = 8 male, 8 female) resulted in sensory nerve blockade of 240 [207-277] minutes (males) compared to 289 [204-348] minutes (females) (p = 0.1654). Motor nerve blockade was 266 [237-372] minutes (males) compared to 317 [251-356] minutes (females) (p = 0.6671). Following tetrodotoxin injection (N = 12 male,12 female) sensory nerve blockade was 54.8 [5-117] minutes (males) compared to 54 [14-71] minutes (females) (p = 0.6422). Motor nerve blockade was 72 [40-112] minutes (males) compared to 64 [32-143] minutes (females) (p = 0.971). CONCLUSIONS: We found no statistically significant sex differences associated with the formulations tested. In both sexes, durations of nerve block were similar between micellar and liposomal bupivacaine formulations, despite the micellar formulation containing less drug.


Asunto(s)
Anestésicos Locales/farmacocinética , Bupivacaína/farmacocinética , Preparaciones de Acción Retardada/química , Bloqueo Nervioso/métodos , Tetrodotoxina/farmacocinética , Anestésicos Locales/administración & dosificación , Animales , Bupivacaína/administración & dosificación , Portadores de Fármacos/química , Composición de Medicamentos/métodos , Liberación de Fármacos , Femenino , Inyecciones , Masculino , Micelas , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Ratas , Ratas Sprague-Dawley , Factores Sexuales , Tetrodotoxina/administración & dosificación , Distribución Tisular
5.
Blood ; 118(6): 1579-90, 2011 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-21670468

RESUMEN

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy largely caused by aberrant activation of the TAL1/SCL, LMO1/2, and NOTCH1 oncogenes. Approximately 30% of T-ALL patients relapse, and evidence is emerging that relapse may result from a failure to eliminate leukemia-initiating cells (LICs). Thymic expression of the Tal1 and Lmo2 oncogenes in mice results in rapid development of T-ALL; and similar to T-ALL patients, more than half the leukemic mice develop spontaneous mutations in Notch1. Using this mouse model, we demonstrate that mouse T-ALLs are immunophenotypically and functionally heterogeneous with approximately 1 of 10,000 leukemic cells capable of initiating disease on transplantation. Our preleukemic studies reveal expansion of Notch-active double-negative thymic progenitors, and we find the leukemic DN3 population enriched in disease potential. To examine the role of Notch1 in LIC function, we measured LIC activity in leukemic mice treated with vehicle or with a γ-secretase inhibitor. In 4 of 5 leukemias examined, Notch inhibition significantly reduced or eliminated LICs and extended survival. Remarkably, in 2 mice, γ-secretase inhibitor treatment reduced LIC frequency below the limits of detection of this assay, and all transplanted mice failed to develop disease. These data support the continued development of Notch1 therapeutics as antileukemia agents.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Unión al ADN/genética , Metaloproteínas/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogénicas/genética , Receptor Notch1/genética , Proteínas Adaptadoras Transductoras de Señales , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proliferación Celular , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Citometría de Flujo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inmunofenotipificación , Estimación de Kaplan-Meier , Proteínas con Dominio LIM , Masculino , Metaloproteínas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Transgénicos , Mutación , Trasplante de Neoplasias , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas/metabolismo , Receptor Notch1/metabolismo , Proteína 1 de la Leucemia Linfocítica T Aguda , Timo/metabolismo , Timo/patología
6.
Nat Commun ; 14(1): 2444, 2023 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-37117194

RESUMEN

Delivery of hydrophilic small molecule therapeutics by traditional drug delivery systems is challenging. Herein, we have used the specific interaction between DNA aptamers and drugs to create simple and effective drug depot systems. The specific binding of a phosphorothioate-modified aptamer to drugs formed non-covalent aptamer/drug complexes, which created a sustained release system. We demonstrated the effectiveness of this system with small hydrophilic molecules, the site 1 sodium channel blockers tetrodotoxin and saxitoxin. The aptamer-based delivery system greatly prolonged the duration of local anesthesia and reduced systemic toxicity. The beneficial effects of the aptamers were restricted to the compounds they were specific to. These studies establish aptamers as a class of highly specific, modifiable drug delivery systems, and demonstrate potential usefulness in the management of postoperative pain.


Asunto(s)
Aptámeros de Nucleótidos , Sistemas de Liberación de Medicamentos , Preparaciones de Acción Retardada , Aptámeros de Nucleótidos/química , Tetrodotoxina/farmacología , Bloqueadores de los Canales de Sodio
7.
Blood ; 113(24): 6172-81, 2009 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-19246562

RESUMEN

Mutations in NOTCH1 are frequently detected in patients with T-cell acute lymphoblastic leukemia (T-ALL) and in mouse T-ALL models. Treatment of mouse or human T-ALL cell lines in vitro with gamma-secretase inhibitors (GSIs) results in growth arrest and/or apoptosis. These studies suggest GSIs as potential therapeutic agents in the treatment of T-ALL. To determine whether GSIs have antileukemic activity in vivo, we treated near-end-stage Tal1/Ink4a/Arf+/- leukemic mice with vehicle or with a GSI developed by Merck (MRK-003). We found that GSI treatment significantly extended the survival of leukemic mice compared with vehicle-treated mice. Notch1 target gene expression was repressed and increased numbers of apoptotic cells were observed in the GSI-treated mice, demonstrating that Notch1 inhibition in vivo induces apoptosis. T-ALL cell lines also exhibit PI3K/mTOR pathway activation, indicating that rapamycin may also have therapeutic benefit. When GSIs are administered in combination with rapamycin, mTOR kinase activity is ablated and apoptosis induced. Moreover, GSI and rapamycin treatment inhibits human T-ALL growth and extends survival in a mouse xenograft model. This work supports the idea of targeting NOTCH1 in T-ALL and suggests that inhibition of the mTOR and NOTCH1 pathways may have added efficacy.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Óxidos S-Cíclicos/farmacología , Modelos Animales de Enfermedad , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Receptor Notch1/metabolismo , Tiadiazoles/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Apoptosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Western Blotting , Proteínas Portadoras/genética , Proliferación Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/fisiología , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones Transgénicos , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Proteínas Proto-Oncogénicas/fisiología , Receptor Notch1/genética , Transducción de Señal , Proteína 1 de la Leucemia Linfocítica T Aguda , Serina-Treonina Quinasas TOR , Células Tumorales Cultivadas
8.
Drug Deliv Transl Res ; 10(5): 1507-1516, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32307675

RESUMEN

The effect of local anesthetics, particularly those which are hydrophilic, such as tetrodotoxin, is impeded by tissue barriers that restrict access to individual nerve cells. Methods of enhancing penetration of tetrodotoxin into nerve include co-administration with chemical permeation enhancers, nanoencapsulation, and insonation with very low acoustic intensity ultrasound and microbubbles. In this study, we examined the effect of acoustic intensity on nerve block by tetrodotoxin and compared it to the effect on nerve block by bupivacaine, a more hydrophobic local anesthetic. Anesthetics were applied in peripheral nerve blockade in adult Sprague-Dawley rats. Insonation with 1-MHz ultrasound at acoustic intensity greater than 0.5 W/cm2 improved nerve block effectiveness, increased nerve block reliability, and prolonged both sensory and motor nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. These effects were not enhanced by microbubbles. There was minimal or no tissue injury from ultrasound treatment. Insonation did not enhance nerve block from bupivacaine. Using an in vivo model system of local anesthetic delivery, we studied the effect of acoustic intensity on insonation-mediated drug delivery of local anesthetics to the peripheral nerve. We found that insonation alone (at intensities greater than 0.5 W/cm2) enhanced nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. Graphical abstract.


Asunto(s)
Anestesia Local , Bupivacaína , Bloqueo Nervioso/métodos , Ultrasonido , Anestésicos Locales/administración & dosificación , Animales , Bupivacaína/administración & dosificación , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados
9.
Transl Vis Sci Technol ; 8(5): 28, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31637108

RESUMEN

PURPOSE: Topical corneal local anesthetics are short acting and may impair corneal healing. In this study we compared corneal anesthesia and toxicity of topically applied N-ethyl lidocaine (QX-314) versus the conventional local anesthetic, proparacaine (PPC). METHODS: Various concentrations of QX-314 and 15 mM (0.5%) PPC were topically applied to rat corneas. Corneal anesthesia was assessed with a Cochet-Bonnet esthesiometer at predetermined time points. PC12 cells were exposed to the same solutions to assess cytotoxicity. Repeated topical corneal administration in rats was then used to assess for histologic evidence of toxicity. Finally, we created uniform corneal epithelial defects in rats and assessed the effect of repeated administration of these compounds on the defect healing rate. RESULTS: QX-314 (15 mM) and PPC (15 mM) caused similar total duration (114 ± 17 and 87 ± 16 minutes, respectively; P = 0.06) of anesthesia. The depth of anesthesia was similar between these low-dose groups at 15 minutes after application (1.8 ± 0.3- and 2.0 ± 0.8-cm filament lengths). QX-314 (100 mM) provided more prolonged corneal anesthesia (174 ± 13 minutes; P < 0.0001), with improved depth at 15 minutes (0.7 ± 0.3-cm filament length; P = 0.007). All tested concentrations of QX-314 demonstrated similar or less toxicity than 0.5% PPC. CONCLUSIONS: Topical administration of QX-314 is effective for corneal anesthesia and demonstrates no histologic signs of local toxicity in a rodent model. In higher concentrations, QX-314 provides more than twofold the duration of anesthetic effect than does 0.5% PPC. TRANSLATIONAL RELEVANCE: Our study reveals a clinically relevant compound providing prolonged duration topical corneal anesthesia.

10.
Adv Mater ; 29(37)2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28752600

RESUMEN

The delivery of drugs to a target site frequently involves crossing biological barriers. The degree and nature of the impediment to flux, as well as the potential approaches to overcoming it, depend on the tissue, the drug, and numerous other factors. Here an overview of approaches that have been taken to crossing biological barriers is presented, with special attention to transdermal drug delivery. Technology and knowledge pertaining to addressing these issues in a variety of organs could have a significant clinical impact.


Asunto(s)
Preparaciones Farmacéuticas/metabolismo , Animales , Transporte Biológico , Sistemas de Liberación de Medicamentos , Humanos , Preparaciones Farmacéuticas/química , Reproducibilidad de los Resultados , Distribución Tisular
14.
Biochem Biophys Res Commun ; 344(3): 834-44, 2006 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-16631614

RESUMEN

Castor is a zinc finger transcription factor that controls cell fate within neuroblast cell lineages in Drosophila melanogaster. Here, we describe the cloning and characterization of a human castor gene (CASZ1) that is structurally homologous to Drosophila castor. We find the expression of castor gene is increased when cells of neural origin as well as mesenchymal origin are induced to differentiation. CASZ1 is expressed in a number of normal tissues and exists in at least two mRNA species of 4.4 and 8.0kb. They are named hCasz5 and hCasz11 because the predicted proteins have 5 and 11 zinc fingers, respectively. Deletion analysis of the proximal 5'-flanking sequences delineates sequences sufficient to drive transcription in cells of neural and non-neural origin. Both hCasz5 and hCasz11 localize predominantly in the nucleus, consistent with their role as Zn-finger containing transcription factor. CASZ1 is expressed in a number of human tumors and localizes to a chromosomal region frequently lost in tumors of neuroectodermal origin.


Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Diferenciación Celular , Línea Celular Tumoral , Clonación Molecular , Humanos , Datos de Secuencia Molecular , Neuroblastoma/genética , Homología de Secuencia de Aminoácido , Regulación hacia Arriba/fisiología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA