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1.
Nat Mater ; 20(11): 1559-1570, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34326506

RESUMO

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic-tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.

2.
Pharmaceutics ; 12(10)2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33092175

RESUMO

Ephrin receptor A2 (EphA2) is a member of the Ephrin/Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, and its expression is in many cases associated with poor prognosis. We recently developed a novel EphA2-targeting antibody-directed nanotherapeutic encapsulating a labile prodrug of docetaxel (EphA2-ILs-DTXp) for the treatment of EphA2-expressing malignancies. Here, we characterized the expression of EphA2 in bladder cancer using immunohistochemistry in 177 human bladder cancer samples and determined the preclinical efficacy of EphA2-ILs-DTXp in four EphA2-positive patient-derived xenograft (PDX) models of the disease, either as a monotherapy, or in combination with gemcitabine. EphA2 expression was detected in 80-100% of bladder cancer samples and correlated with shorter patient survival. EphA2 was found to be expressed in tumor cells and/or tumor-associated blood vessels in both primary and metastatic lesions with a concordance rate of approximately 90%. The EphA2-targeted antibody-directed nanotherapeutic EphA2-ILs-DTXp controlled tumor growth, mediated greater regression, and was more active than free docetaxel at equitoxic dosing in all four EphA2-positive bladder cancer PDX models. Combination of EphA2-ILs-DTXp and gemcitabine in one PDX model led to improved tumor growth control compared to monotherapies or the combination of free docetaxel and gemcitabine. These data demonstrating the prevalence of EphA2 in bladder cancers and efficacy of EphA2-ILs-DTXp in PDX models support the clinical exploration of EphA2 targeting in bladder cancer.

3.
Adv Healthc Mater ; 9(16): e2000942, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32597568

RESUMO

Measurements of regional internal body temperatures can yield important information in the diagnosis of immune response-related anomalies, for precisely managing the effects of hyperthermia and hypothermia therapies and monitoring other transient body processes such as those associated with wound healing. Current approaches rely on permanent implants that require extraction surgeries after the measurements are no longer needed. Emerging classes of bioresorbable sensors eliminate the requirements for extraction, but their use of percutaneous wires for data acquisition leads to risks for infection at the suture site. As an alternative, a battery-free, wireless implantable device is reported here, which is constructed entirely with bioresorbable materials for monitoring regional internal body temperatures over clinically relevant timeframes. Ultimately, these devices disappear completely in the body through natural processes. In vivo demonstrations indicate stable operation as subcutaneous and intracranial implants in rat models for up to 4 days. Potential applications include monitoring of healing cascades associated with surgical wounds, recovery processes following internal injuries, and the progression of thermal therapies for various conditions.


Assuntos
Implantes Absorvíveis , Temperatura Corporal , Animais , Ratos , Temperatura , Tecnologia sem Fio , Cicatrização
4.
Cancer Discov ; 10(9): 1388-1409, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32444465

RESUMO

Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL. SIGNIFICANCE: Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery.This article is highlighted in the In This Issue feature, p. 1241.


Assuntos
Processamento Alternativo/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fosfoproteínas/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Peptidase 7 Específica de Ubiquitina/metabolismo , Processamento Alternativo/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sinergismo Farmacológico , Éxons/genética , Humanos , Células Jurkat , Masculino , Camundongos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Estudo de Prova de Conceito , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Exp Eye Res ; 195: 108030, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32272114

RESUMO

Retinopathy of prematurity (ROP) is a growing cause of lifelong blindness and visual defects as improved neonatal care worldwide increases survival in very-low-birthweight preterm newborns. Advancing ROP is managed by laser surgery or a single intravitreal injection of anti-VEGF, typically at 33-36 weeks gestational age. While newer methods of scanning and telemedicine improve monitoring ROP, the above interventions are more difficult to deliver in developing countries. There is also concern as to laser-induced detachment and adverse developmental effects in newborns of anti-VEGF treatment, spurring a search for alternative means of mitigating ROP. Pigment epithelium-derived factor (PEDF), a potent angiogenesis inhibitor appears late in gestation, is undetected in 25-28 week vitreous, but present at full term. Its absence may contribute to ROP upon transition from high-to-ambient oxygen environment or with intermittent hypoxia. We recently described antiangiogenic PEDF-derived small peptides which inhibit choroidal neovascularization, and suggested that their target may be laminin receptor, 67LR. The latter has been implicated in oxygen-induced ischemic retinopathy (OIR). Here we examined the effect of a nonapeptide, PEDF 336, in a newborn mouse OIR model. Neovascularization was significantly decreased in a dose-responsive manner by single intravitreal (IVT) injections of 1.25-7.5 µg/eye (1.0-6.0 nmol/eye). By contrast, anti-mouse VEGFA164 was only effective at 25 ng/eye, with limited dose-response. Combination of anti-VEGFA164 with PEDF 336 gave only the poorer anti-VEGF response while abrogating the robust inhibition seen with peptide-alone, suggesting a need for VEGF in sensitizing the endothelium to the peptide. VEGF stimulated 67LR presentation on endothelial cells, which was decreased in the presence of PEDF 336. Mouse and rabbit eyes showed no histopathology or inflammation after IVT peptide injection. Thus, PEDF 336 is a potential ROP therapeutic, but is not expected to be beneficial in combination with anti-VEGF.


Assuntos
Animais Recém-Nascidos , Bevacizumab/administração & dosagem , Proteínas do Olho/metabolismo , Isquemia/tratamento farmacológico , Fatores de Crescimento Neural/metabolismo , Neovascularização Retiniana/tratamento farmacológico , Serpinas/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Injeções Intravítreas , Isquemia/metabolismo , Isquemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/toxicidade , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
6.
Proc Natl Acad Sci U S A ; 117(6): 2835-2845, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974306

RESUMO

Recording cell-specific neuronal activity while monitoring behaviors of freely moving subjects can provide some of the most significant insights into brain function. Current means for monitoring calcium dynamics in genetically targeted populations of neurons rely on delivery of light and recording of fluorescent signals through optical fibers that can reduce subject mobility, induce motion artifacts, and limit experimental paradigms to isolated subjects in open, two-dimensional (2D) spaces. Wireless alternatives eliminate constraints associated with optical fibers, but their use of head stages with batteries adds bulk and weight that can affect behaviors, with limited operational lifetimes. The systems introduced here avoid drawbacks of both types of technologies, by combining highly miniaturized electronics and energy harvesters with injectable photometric modules in a class of fully wireless, battery-free photometer that is fully implantable subdermally to allow for the interrogation of neural dynamics in freely behaving subjects, without limitations set by fiber optic tethers or operational lifetimes constrained by traditional power supplies. The unique capabilities of these systems, their compatibility with magnetic resonant imaging and computed tomography and the ability to manufacture them with techniques in widespread use for consumer electronics, suggest a potential for broad adoption in neuroscience research.


Assuntos
Encéfalo/fisiologia , Fotometria/métodos , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Desenho de Equipamento , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Fotometria/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação
7.
Cancer Cell ; 36(5): 483-497.e15, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31679823

RESUMO

Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/farmacologia , Descoberta de Drogas/métodos , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Antígeno B7-H1/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Estudos de Viabilidade , Feminino , Humanos , Masculino , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Treonina/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nat Biomed Eng ; 3(8): 644-654, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391594

RESUMO

Capabilities in real-time monitoring of internal physiological processes could inform pharmacological drug-delivery schedules, surgical intervention procedures and the management of recovery and rehabilitation. Current methods rely on external imaging techniques or implantable sensors, without the ability to provide continuous information over clinically relevant timescales, and/or with requirements in surgical procedures with associated costs and risks. Here, we describe injectable classes of photonic devices, made entirely of materials that naturally resorb and undergo clearance from the body after a controlled operational lifetime, for the spectroscopic characterization of targeted tissues and biofluids. As an example application, we show that the devices can be used for the continuous monitoring of cerebral temperature, oxygenation and neural activity in freely moving mice. These types of devices should prove useful in fundamental studies of disease pathology, in neuroscience research, in surgical procedures and in monitoring of recovery from injury or illness.


Assuntos
Implantes Absorvíveis , Técnicas Biossensoriais/instrumentação , Óptica e Fotônica/instrumentação , Análise Espectral/métodos , Animais , Materiais Biocompatíveis , Engenharia Biomédica/instrumentação , Análise Química do Sangue/instrumentação , Análise Química do Sangue/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Desenho de Equipamento , Feminino , Camundongos , Modelos Animais , Neurociências , Fibras Ópticas , Silício/química , Temperatura
9.
Sci Adv ; 5(7): eaaw1899, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31281889

RESUMO

Continuous measurements of pressure and temperature within the intracranial, intraocular, and intravascular spaces provide essential diagnostic information for the treatment of traumatic brain injury, glaucoma, and cardiovascular diseases, respectively. Optical sensors are attractive because of their inherent compatibility with magnetic resonance imaging (MRI). Existing implantable optical components use permanent, nonresorbable materials that must be surgically extracted after use. Bioresorbable alternatives, introduced here, bypass this requirement, thereby eliminating the costs and risks of surgeries. Here, millimeter-scale bioresorbable Fabry-Perot interferometers and two dimensional photonic crystal structures enable precise, continuous measurements of pressure and temperature. Combined mechanical and optical simulations reveal the fundamental sensing mechanisms. In vitro studies and histopathological evaluations quantify the measurement accuracies, operational lifetimes, and biocompatibility of these systems. In vivo demonstrations establish clinically relevant performance attributes. The materials, device designs, and fabrication approaches outlined here establish broad foundational capabilities for diverse classes of bioresorbable optical sensors.


Assuntos
Implantes Absorvíveis , Técnicas Biossensoriais , Pressão Intracraniana/fisiologia , Monitorização Fisiológica , Humanos , Interferometria/métodos , Imageamento por Ressonância Magnética/métodos , Dispositivos Ópticos , Fótons , Silício/química , Temperatura
10.
Nat Biomed Eng ; 3(1): 37-46, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30932064

RESUMO

Pressures in the intracranial, intraocular and intravascular spaces are clinically useful for the diagnosis and management of traumatic brain injury, glaucoma and hypertension, respectively. Conventional devices for measuring these pressures require surgical extraction after a relevant operational time frame. Bioresorbable sensors, by contrast, eliminate this requirement, thereby minimizing the risk of infection, decreasing the costs of care and reducing distress and pain for the patient. However, the operational lifetimes of bioresorbable pressure sensors available at present fall short of many clinical needs. Here, we present materials, device structures and fabrication procedures for bioresorbable pressure sensors with lifetimes exceeding those of previous reports by at least tenfold. We demonstrate measurement accuracies that compare favourably to those of the most sophisticated clinical standards for non-resorbable devices by monitoring intracranial pressures in rats for 25 days. Assessments of the biodistribution of the constituent materials, complete blood counts, blood chemistry and magnetic resonance imaging compatibility confirm the biodegradability and clinical utility of the device. Our findings establish routes for the design and fabrication of bioresorbable pressure monitors that meet requirements for clinical use.


Assuntos
Implantes Absorvíveis , Doença Crônica , Pressão Intracraniana , Monitorização Fisiológica/instrumentação , Dióxido de Silício/química , Temperatura , Cicatrização , Animais , Feminino , Cinética , Imageamento por Ressonância Magnética , Masculino , Camundongos , Ratos Endogâmicos Lew , Distribuição Tecidual
11.
Sci Adv ; 5(3): eaaw0873, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30873435

RESUMO

Monitoring regional tissue oxygenation in animal models and potentially in human subjects can yield insights into the underlying mechanisms of local O2-mediated physiological processes and provide diagnostic and therapeutic guidance for relevant disease states. Existing technologies for tissue oxygenation assessments involve some combination of disadvantages in requirements for physical tethers, anesthetics, and special apparatus, often with confounding effects on the natural behaviors of test subjects. This work introduces an entirely wireless and fully implantable platform incorporating (i) microscale optoelectronics for continuous sensing of local hemoglobin dynamics and (ii) advanced designs in continuous, wireless power delivery and data output for tether-free operation. These features support in vivo, highly localized tissue oximetry at sites of interest, including deep brain regions of mice, on untethered, awake animal models. The results create many opportunities for studying various O2-mediated processes in naturally behaving subjects, with implications in biomedical research and clinical practice.


Assuntos
Fontes de Energia Elétrica , Oximetria/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação , Animais , Substitutos Sanguíneos/análise , Corpo Estriado/metabolismo , Corpo Estriado/cirurgia , Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Oxigênio/análise , Ratos , Ratos Sprague-Dawley , Materiais Inteligentes
12.
Clin Cancer Res ; 25(1): 222-239, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30224337

RESUMO

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. EXPERIMENTAL DESIGN: To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models. RESULTS: We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. CONCLUSIONS: These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.


Assuntos
Histona Desmetilases com o Domínio Jumonji/genética , Leucemia de Células T/genética , Receptor Notch1/genética , Peptidase 7 Específica de Ubiquitina/genética , Animais , Carcinogênese/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Terapia Genética , Humanos , Células Jurkat , Leucemia de Células T/patologia , Leucemia de Células T/terapia , Camundongos , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Invest Ophthalmol Vis Sci ; 59(10): 4071-4081, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098194

RESUMO

Purpose: Drug delivery by intravitreal injection remains problematic, small agents and macromolecules both clearing rapidly. Typical carriers use microparticles (>2 µm), with size-related liabilities, to slow diffusion. We recently described cationic nanoparticles (NP) where conjugated Arg peptides prolonged residence in rat eyes, through ionic interaction with vitreal poly-anions. Here we extended this strategy to in vivo tracking of NP-conjugate (NPC) clearance from rabbit eyes. Relating t1/2 to zeta potential, and varied dose, we estimated the limits of this charge-based delivery system. Methods: NPC carried covalently attached PEG8-2Arg or PEG8-3Arg pentapeptides, having known sequences from human eye proteins. Peptides were conjugated (61-64 per NPC); each NP/NPC also carried a cyanine7 tag (<0.5 dye/particle). In vivo imaging system (IVIS), after intravitreal injection, estimated NPC loss by 800-nm photon emission (745-nm excitation) at 1 to 3-week intervals following initial scan at day 10. Results: NPC of 2Arg-peptides or 3Arg-peptides showed clearance t1/2 of 7 days and 17 days respectively, unconjugated NP t1/2 was <<5 days. Doses of 90, 180, and 360 µg of PEG8-2Arg NPC were compared. The lower doses showed dose-proportional day-10 concentration, and similar clearance. Higher early loss was seen with a 360-µg dose, exceeding rabbit vitreal binding capacity. No inflammation was observed. Conclusions: This type of cationic NPC can safely increase residence t1/2 in a 1 to 3-week range, with dose <100 µg per mL vitreous. Human drug load may then range from 10 to 100 µg/eye, usefulness depending on individual drug potency and release rate, superimposed on extended intravitreal residence.


Assuntos
Arginina/farmacocinética , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Injeções Intravítreas , Nanopartículas , Peptídeos , Corpo Vítreo/metabolismo , Animais , Arginina/administração & dosagem , Portadores de Fármacos/química , Modelos Animais , Nanopartículas/administração & dosagem , Nanopartículas/química , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Coelhos , Ratos
14.
Adv Mater ; 30(32): e1801584, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29944186

RESUMO

Optical technologies offer important capabilities in both biological research and clinical care. Recent interest is in implantable devices that provide intimate optical coupling to biological tissues for a finite time period and then undergo full bioresorption into benign products, thereby serving as temporary implants for diagnosis and/or therapy. The results presented here establish a silicon-based, bioresorbable photonic platform that relies on thin filaments of monocrystalline silicon encapsulated by polymers as flexible, transient optical waveguides for accurate light delivery and sensing at targeted sites in biological systems. Comprehensive studies of the mechanical and optical properties associated with bending and unfurling the waveguides from wafer-scale sources of materials establish general guidelines in fabrication and design. Monitoring biochemical species such as glucose and tracking physiological parameters such as oxygen saturation using near-infrared spectroscopic methods demonstrate modes of utility in biomedicine. These concepts provide versatile capabilities in biomedical diagnosis, therapy, deep-tissue imaging, and surgery, and suggest a broad range of opportunities for silicon photonics in bioresorbable technologies.


Assuntos
Técnicas Biossensoriais , Animais , Camundongos , Óptica e Fotônica , Fótons , Polímeros , Silício
15.
Sci Transl Med ; 10(441)2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769289

RESUMO

Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.


Assuntos
Nucléolo Celular/patologia , Metástase Neoplásica/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Animais , Linhagem Celular Tumoral , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/metabolismo , Nucléolo Celular/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Cromatina/metabolismo , DNA Ribossômico/genética , Humanos , Masculino , Camundongos , Invasividade Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fator 1 de Elongação de Peptídeos/metabolismo , Regiões Promotoras Genéticas/genética , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , RNA Polimerase I/metabolismo , Precursores de RNA/biossíntese , Análise de Sobrevida , Transcrição Genética/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
PeerJ ; 6: e4661, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29682426

RESUMO

In 2015, as part of the Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative, we published a Registered Report (Shan et al., 2015) that described how we intended to replicate selected experiments from the paper "Androgen Receptor Splice Variants Determine Taxane Sensitivity in Prostate Cancer" (Thadani-Mulero et al., 2014). Here we report the results of those experiments. Growth of tumor xenografts from two prostate cancer xenograft lines, LuCaP 86.2, which expresses wild-type androgen receptor (AR) and AR variant 567, and LuCaP 23.1, which expresses wild-type AR and AR variant 7, were not affected by docetaxel treatment. The LuCaP 23.1 tumor xenografts grew slower than in the original study. This result is different from the original study, which reported significant reduction of tumor growth in the LuCaP 86.2. Furthermore, we were unable to detect ARv7 in the LuCaP 23.1, although we used the antibody as stated in the original study and ensured that it was detecting ARv7 via a known positive control (22rv1, Hörnberg et al., 2011). Finally, we report a meta-analysis of the result.

18.
FASEB J ; 31(12): 5453-5465, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28821631

RESUMO

Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide, and its incidence is increasing rapidly in the United States, tripling over the past 3 decades. The current chemotherapeutic strategies against localized and metastatic HCC are ineffective. Here we report that 6-methoxyethylamino-numonafide (MEAN) is a potent growth inhibitor of murine xenografts of 2 human HCC cell lines. At the same dose and with the same treatment strategies, MEAN was more efficacious in inhibiting tumor growth in mice than sorafenib, the only approved drug for HCC. Treatment by MEAN at an effective dose for 6 wk was well tolerated by animals. Combined therapy using both sorafenib and MEAN enhanced tumor growth inhibition over monotherapy with either agent. Additional experiments revealed that MEAN inhibited tumor growth through mechanisms distinct from those of either its parent compound, amonafide, or sorafenib. MEAN suppressed C-MYC expression and increased expression of several tumor suppressor genes, including Src homology region 2 domain-containing phosphatase-1 (SHP-1) and TXNIP (thioredoxin-interacting protein). As an encouraging feature for envisioned clinical application, the IC50 of MEAN was not significantly changed in several drug-resistant cell lines with activated P-glycoprotein drug efflux pumps compared to drug-sensitive parent cells, demonstrating the ability of MEAN to be effective in cells resistant to existing chemotherapy regimens. MEAN is a promising candidate for clinical development as a single-agent therapy or in combination with sorafenib for the management of HCC.-Liu, Y., Lou, G., Norton, J. T., Wang, C., Kandela, I., Tang, S., Shank, N. I., Gupta, P., Huang, M., Avram, M. J., Green, R., Mazar, A., Appella, D., Chen, Z., Huang, S. 6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Naftalimidas/uso terapêutico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Western Blotting , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Niacinamida/uso terapêutico , Sorafenibe , Ensaios Antitumorais Modelo de Xenoenxerto
19.
ACS Med Chem Lett ; 8(7): 705-709, 2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28740602

RESUMO

A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the ß-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups. Pz 285 is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.

20.
Mol Pharm ; 14(5): 1831-1839, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28355489

RESUMO

Although ibuprofen is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs), it exhibits poor solubility in aqueous and physiological environments as a free acid. In order to improve its oral bioavailability and rate of uptake, extensive research into the development of new formulations of ibuprofen has been undertaken, including the use of excipients as well as ibuprofen salts, such as ibuprofen lysinate and ibuprofen, sodium salt. The ultimate goals of these studies are to reduce the time required for maximum uptake of ibuprofen, as this period of time is directly proportional to the rate of onset of analgesic/anti-inflammatory effects, and to increase the half-life of the drug within the body; that is, the duration of action of the effects of the drug. Herein, we present a pharmaceutical cocrystal of ibuprofen and the biocompatible metal-organic framework called CD-MOF. This metal-organic framework (MOF) is based upon γ-cyclodextrin (γ-CD) tori that are coordinated to alkali metal cations (e.g., K+ ions) on both their primary and secondary faces in an alternating manner to form a porous framework built up from (γ-CD)6 cubes. We show that ibuprofen can be incorporated within CD-MOF-1 either by (i) a crystallization process using the potassium salt of ibuprofen as the alkali cation source for production of the MOF or by (ii) absorption and deprotonation of the free-acid, leading to an uptake of 23-26 wt % of ibuprofen within the CD-MOF. In vitro viability studies revealed that the CD-MOF is inherently not affecting the viability of the cells with no IC50 value determined up to a concentration of 100 µM. Bioavailability investigations were conducted on mice, and the ibuprofen/CD-MOF pharmaceutical cocrystal was compared to control samples of the potassium salt of ibuprofen in the presence and absence of γ-CD. From these animal studies, we observed that the ibuprofen/CD-MOF-1 cocrystal exhibits the same rapid uptake of ibuprofen as the ibuprofen potassium salt control sample with a peak plasma concentration observed within 20 min, and the cocrystal has the added benefit of a 100% longer half-life in blood plasma samples and is intrinsically less hygroscopic than the pure salt form.


Assuntos
Ciclodextrinas/química , Ibuprofeno/análogos & derivados , Ibuprofeno/química , Lisina/análogos & derivados , gama-Ciclodextrinas/química , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Lisina/química , Solubilidade
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