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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.
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
3.
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
4.
Nat Commun ; 10(1): 5742, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848334

RESUMO

Small animals support a wide range of pathological phenotypes and genotypes as versatile, affordable models for pathogenesis of cardiovascular diseases and for exploration of strategies in electrotherapy, gene therapy, and optogenetics. Pacing tools in such contexts are currently limited to tethered embodiments that constrain animal behaviors and experimental designs. Here, we introduce a highly miniaturized wireless energy-harvesting and digital communication electronics for thin, miniaturized pacing platforms weighing 110 mg with capabilities for subdermal implantation and tolerance to over 200,000 multiaxial cycles of strain without degradation in electrical or optical performance. Multimodal and multisite pacing in ex vivo and in vivo studies over many days demonstrate chronic stability and excellent biocompatibility. Optogenetic stimulation of cardiac cycles with in-animal control and induction of heart failure through chronic pacing serve as examples of modes of operation relevant to fundamental and applied cardiovascular research and biomedical technology.


Assuntos
Engenharia Biomédica/métodos , Dispositivos de Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca/etiologia , Miniaturização , Optogenética/métodos , Animais , Modelos Animais de Doenças , Fontes de Energia Elétrica , Feminino , Humanos , Preparação de Coração Isolado , Masculino , Camundongos , Camundongos Transgênicos , Tecnologia sem Fio
5.
Clin Cancer Res ; 25(4): 1331-1342, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30420445

RESUMO

PURPOSE: Response to toxicity in chemotherapies varies considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug-induced toxicity on an individual basis. EXPERIMENTAL DESIGN: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate, or cisplatin. In vivo whole-body imaging data were acquired using 99mTc-duramycin, which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared with standard blood and serum panels for toxicology. RESULTS: The in vivo whole-body imaging data detected widespread changes, where spatially heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared with conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females. CONCLUSIONS: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis.Toxicity to normal tissues is a significant limitation in chemotherapies. This work demonstrated an in vivo imaging-based approach for characterizing toxicity-induced tissue injury in a systemic, dynamic, and near-real time fashion. This novel approach shows promise in optimizing therapeutic decisions by monitoring drug toxicity on a personalized basis.


Assuntos
Apoptose/efeitos dos fármacos , Bacteriocinas/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico por imagem , Compostos de Organotecnécio/farmacologia , Imagem Corporal Total , Animais , Morte Celular/efeitos dos fármacos , Cisplatino/farmacologia , Ciclofosfamida/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Ratos
6.
Chem Sci ; 8(6): 4424-4430, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28979760

RESUMO

We demonstrate the ability of a molecular Fe2 complex to enable magnetic resonance (MR)-based ratiometric quantitation of redox status, namely through redox-dependent paramagnetic chemical exchange saturation transfer (PARACEST). Metalation of a tetra(carboxamide) ligand with FeII and/or FeIII in the presence of etidronate ion affords analogous FeII2, FeIIFeIII, and FeIII2 complexes. Both FeII2 and FeIIFeIII complexes give highly-shifted, sharp, and non-overlapping NMR spectra, with multiple resonances for each complex corresponding to exchangeable carboxamide protons. These protons can be selectively irradiated to give CEST peaks at 74 and 83 ppm vs. H2O for the FeIIFeIII complex and at 29, 40 and 68 ppm for the FeII2 complex. The CEST spectra obtained from a series of samples containing mixtures of FeII2 and FeIIFeIII are correlated with independently-determined open-circuit potentials to construct a Nernstian calibration curve of potential vs. CEST peak intensity ratio. In addition, averaged intensities of phantom images collected on a 9.4 T MRI scanner show analogous Nernstian behavior. Finally, both the FeII2 and FeIIFeIII forms of the complex are stable to millimolar concentrations of H2PO4-/HPO42-, CO32-, SO42-, CH3COO-, and Ca2+ ions, and the FeIII2 form is air-stable in aqueous buffer and shows >80% viability in melanoma cells at millimolar concentration. The stability suggests the possible application of this or related complexes for in vivo studies. To our knowledge, this concentration-independent method based on a single Fe2 probe provides the first example of MR-based ratiometric quantitation of redox environment.

7.
Circulation ; 136(16): 1477-1491, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-28778945

RESUMO

BACKGROUND: Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing. METHODS: Whole-genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of Mybphl. RESULTS: Whole-genome sequencing identified a premature stop codon, R255X, in the MYBPHL gene encoding MyBP-HL (myosin-binding protein-H like), a novel member of the myosin-binding protein family. MYBPHL was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant MYBPHL allele. Echocardiography of Mybphl heterozygous and null mouse hearts exhibited a 36% reduction in fractional shortening and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in Mybphl heterozygous and null mice. Using a reporter system, we detected robust expression of Mybphl in the atria, and in discrete puncta throughout the right ventricular wall and septum, as well. Telemetric electrocardiogram recordings in Mybphl mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice. CONCLUSIONS: The findings of reduced ventricular function and conduction system defects in Mybphl mice support that MYBPHL truncations may increase risk for human arrhythmias and cardiomyopathy.


Assuntos
Arritmias Cardíacas/metabolismo , Cardiomiopatia Dilatada/metabolismo , Proteínas do Citoesqueleto/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Animais , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Função Atrial , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Células Cultivadas , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Predisposição Genética para Doença , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Miocárdica , Fenótipo , Função Ventricular
8.
Nano Lett ; 16(12): 7551-7564, 2016 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-27960515

RESUMO

The ability to track labeled cancer cells in vivo would allow researchers to study their distribution, growth, and metastatic potential within the intact organism. Magnetic resonance (MR) imaging is invaluable for tracking cancer cells in vivo as it benefits from high spatial resolution and the absence of ionizing radiation. However, many MR contrast agents (CAs) required to label cells either do not significantly accumulate in cells or are not biologically compatible for translational studies. We have developed carbon-based nanodiamond-gadolinium(III) aggregates (NDG) for MR imaging that demonstrated remarkable properties for cell tracking in vivo. First, NDG had high relaxivity independent of field strength, a finding unprecedented for gadolinium(III) [Gd(III)]-nanoparticle conjugates. Second, NDG demonstrated a 300-fold increase in the cellular delivery of Gd(III) compared to that of clinical Gd(III) chelates without sacrificing biocompatibility. Further, we were able to monitor the tumor growth of NDG-labeled flank tumors by T1- and T2-weighted MR imaging for 26 days in vivo, longer than was reported for other MR CAs or nuclear agents. Finally, by utilizing quantitative maps of relaxation times, we were able to describe tumor morphology and heterogeneity (corroborated by histological analysis), which would not be possible with competing molecular imaging modalities.


Assuntos
Gadolínio , Imagem Molecular , Nanodiamantes , Neoplasias Experimentais/diagnóstico por imagem , Animais , Meios de Contraste , Feminino , Imageamento por Ressonância Magnética , Camundongos , Camundongos SCID
10.
J Am Chem Soc ; 137(28): 9108-16, 2015 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-26083313

RESUMO

Multiple imaging modalities are often required for in vivo imaging applications that require both high probe sensitivity and excellent spatial and temporal resolution. In particular, MR and optical imaging are an attractive combination that can be used to determine both molecular and anatomical information. Herein, we describe the synthesis and in vivo testing of two multimeric NIR-MR contrast agents that contain three Gd(III) chelates and an IR-783 dye moiety. One agent contains a PEG linker and the other a short alkyl linker. These agents label cells with extraordinary efficacy and can be detected in vivo using both imaging modalities. Biodistribution of the PEGylated agent shows observable fluorescence in xenograft MCF7 tumors and renal clearance by MR imaging.


Assuntos
Quelantes/química , Corantes/química , Meios de Contraste/química , Gadolínio/química , Imageamento por Ressonância Magnética , Imagem Multimodal , Imagem Óptica , Animais , Quelantes/síntese química , Quelantes/farmacocinética , Corantes/síntese química , Corantes/farmacocinética , Meios de Contraste/síntese química , Meios de Contraste/farmacocinética , Feminino , Gadolínio/farmacocinética , Humanos , Raios Infravermelhos , Células MCF-7 , Camundongos Nus , Neoplasias/diagnóstico , Distribuição Tecidual
11.
ACS Nano ; 8(7): 7325-32, 2014 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-24937195

RESUMO

Bioactive supramolecular nanostructures are of great importance in regenerative medicine and the development of novel targeted therapies. In order to use supramolecular chemistry to design such nanostructures, it is extremely important to track their fate in vivo through the use of molecular imaging strategies. Peptide amphiphiles (PAs) are known to generate a wide array of supramolecular nanostructures, and there is extensive literature on their use in areas such as tissue regeneration and therapies for disease. We report here on a series of PA molecules based on the well-established ß-sheet amino acid sequence V3A3 conjugated to macrocyclic Gd(III) labels for magnetic resonance imaging (MRI). These conjugates were shown to form cylindrical supramolecular assemblies using cryogenic transmission electron microscopy and small-angle X-ray scattering. Using nuclear magnetic relaxation dispersion analysis, we observed that thermal annealing of the nanostructures led to a decrease in water exchange lifetime (τm) of hundreds of nanoseconds only for molecules that self-assemble into nanofibers of high aspect ratio. We interpret this decrease to indicate more solvent exposure to the paramagnetic moiety on annealing, resulting in faster water exchange within angstroms of the macrocycle. We hypothesize that faster water exchange in the nanofiber-forming PAs arises from the dehydration and increase in packing density on annealing. Two of the self-assembling conjugates were selected for imaging PAs after intramuscular injections of the PA C16V3A3E3-NH2 in the tibialis anterior muscle of a murine model. Needle tracts were clearly discernible with MRI at 4 days postinjection. This work establishes Gd(III) macrocycle-conjugated peptide amphiphiles as effective tracking agents for peptide amphiphile materials in vivo over the timescale of days.


Assuntos
Gadolínio/química , Nanofibras/química , Peptídeos/química , Peptídeos/metabolismo , Animais , Cloreto de Cálcio/química , Meios de Contraste/química , Interações Hidrofóbicas e Hidrofílicas , Imageamento por Ressonância Magnética , Camundongos , Modelos Moleculares , Músculos/metabolismo , Estrutura Secundária de Proteína , Transporte Proteico
12.
Contrast Media Mol Imaging ; 9(4): 313-22, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24706615

RESUMO

Porphyrazines (Pz), or tetraazaporphyrins, are being studied for their potential use in detection and treatment of cancer. Here, an amphiphilic Cu-Pz-Gd(III) conjugate has been prepared via azide-alkyne Huisgen cycloaddition or 'click' chemistry between an azide functionalized Pz and alkyne functionalized DOTA-Gd(III) analog for use as an MRI contrast agent. This agent, Cu-Pz-Gd(III), is synthesized in good yield and exhibits solution-phase ionic relaxivity (r1 = 11.5 mM(-1) s(-1)) that is approximately four times higher than that of a clinically used monomeric Gd(III) contrast agent, DOTA-Gd(III). Breast tumor cells (MDA-MB-231) associate with Cu-Pz-Gd(III) in vitro, where significant contrast enhancement (9.336 ± 0.335 contrast-to-noise ratio) is observed in phantom cell pellet MR images. This novel contrast agent was administered in vivo to an orthotopic breast tumor model in athymic nude mice and MR images were collected. The average T1 of tumor regions in mice treated with 50 mg kg(-1) Cu-Pz-Gd(III) decreased relative to saline-treated controls. Furthermore, the decrease in T1 was persistent relative to mice treated with the monomeric Gd(III) contrast agent. An ex vivo biodistribution study confirmed that Cu-Pz-Gd(III) accumulates in the tumors and is rapidly cleared, primarily through the kidneys. Differential accumulation and T1 enhancement by Cu-Pz-Gd(III) in the tumor's core relative to the periphery offer preliminary evidence that this agent would find application in the imaging of necrotic tissue.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Meios de Contraste , Gadolínio , Imageamento por Ressonância Magnética , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Meios de Contraste/química , Feminino , Gadolínio/química , Humanos , Camundongos , Porfirinas/química , Radiografia
13.
Arthritis Rheum ; 65(9): 2279-89, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23740612

RESUMO

OBJECTIVE: The ability to noninvasively monitor the development of inflammatory arthritis longitudinally has become increasingly important in experimental rheumatology. Magnetic resonance imaging (MRI) allows for detailed examination of anatomic structures, as well as the assessment of joint and soft tissue inflammation. The aim of this study was to extend the use of MRI to include quantitative measurements of bone destruction in murine ankle joints. METHODS: Joint disease was measured serially using clinical, histologic, in vivo imaging system (IVIS), micro-computed tomography (micro-CT), and MRI techniques in mouse ankle joints, using the K/BxN serum transfer-induced acute arthritis and K/BxA(g7) chronic arthritis models. Ankle joint MRI was performed using a gradient-echo pulse sequence to evaluate bone destruction and a spin-echo sequence to evaluate inflammation (long T2 signal). RESULTS: Arthritic mice, as compared to control mice, demonstrated increased disease severity according to clinical, histologic, IVIS, and MRI measures. Following induction of arthritis, the majority of volume expansion of the long T2 signal occurred in a juxtaarticular, rather than intrarticular, manner within the ankle joints. Bone destruction in K/BxA(g7) mouse ankle joints was readily detectible by MRI. Linear regression analyses demonstrated significant correlations between the clinical score and joint radiance intensity assessed by IVIS, between the ankle joint width and increased long T2 signal on MRI, and between the bone volume obtained by micro-CT and bone volume obtained by MRI. CONCLUSION: MRI is an optimal technology for anatomic localization of articular and soft tissue changes during the development and progression of inflammatory arthritis. Future studies may combine MRI with in vivo labeling agents to investigate joint disease in a cell type-specific manner.


Assuntos
Articulação do Tornozelo/patologia , Artrite Experimental/patologia , Reabsorção Óssea/patologia , Inflamação/patologia , Animais , Articulação do Tornozelo/diagnóstico por imagem , Artrite Experimental/diagnóstico por imagem , Reabsorção Óssea/diagnóstico por imagem , Progressão da Doença , Inflamação/diagnóstico por imagem , Imageamento por Ressonância Magnética , Camundongos , Radiografia
14.
Ann Rheum Dis ; 72(1): 89-95, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22736097

RESUMO

OBJECTIVES: Patients with rheumatoid arthritis (RA) have a reduced life expectancy due to increased cardiovascular disease. The lack of a suitable animal model resembling both RA and atherosclerosis has hindered studies demonstrating a direct link between systemic inflammation in RA and the development of atherosclerosis. Our objective was to overcome this barrier by generating an animal model (K/BxA(g7)) that spontaneously develops both RA-like disease and atherosclerosis. METHODS: Arthritis severity was evaluated using clinical indices and immunohistochemical staining of ankle joint specimens. Aortic atherosclerosis was delineated via Sudan IV staining and immunohistochemical analysis. Serum cholesterol and lipoprotein levels were measured using enzymatic assays. Serum levels of cytokines, chemokines and adipokines were determined by Luminex assays. RESULTS: K/BxA(g7) mice developed a destructive arthropathy followed by prominent aortic atherosclerosis. These animals also displayed dyslipidaemia, characterised by reduced serum levels of total cholesterol and high-density lipoprotein, and increased low-density lipoprotein (LDL)/vLDL compared with control mice. Further, there were higher levels of circulating inflammatory mediators, such as interleukin-6, sRANKL and CCL5 in atherosclerotic K/BxA(g7) mice compared with controls. Treatment with etanercept reduced arthritis and atherosclerosis development in K/BxA(g7) mice. CONCLUSIONS: K/BxA(g7) mice recapitulate the same sequence of events occurring in patients with RA, namely an erosive, inflammatory arthritis followed by atherosclerosis. These data suggest that the K/BxA(g7) mouse is a novel system for investigating the interplay between systemic inflammation occurring in RA and the development of atherosclerosis.


Assuntos
Artrite Reumatoide/complicações , Aterosclerose/complicações , Modelos Animais de Doenças , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Aterosclerose/genética , Aterosclerose/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
15.
Magn Reson Med ; 65(1): 220-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20740653

RESUMO

Despite recent advances in tissue engineering to regenerate biological function by combining cells with material supports, development is hindered by inadequate techniques for characterizing biomaterials in vivo. Magnetic resonance imaging is a tomographic technique with high temporal and spatial resolution and represents an excellent imaging modality for longitudinal noninvasive assessment of biomaterials in vivo. To distinguish biomaterials from surrounding tissues for magnetic resonance imaging, protein polymer contrast agents were developed and incorporated into hydrogels. In vitro and in vivo images of protein polymer hydrogels, with and without covalently incorporated protein polymer contrast agents, were acquired by magnetic resonance imaging. T(1) values of the labeled gels were consistently lower when protein polymer contrast agents were included. As a result, the protein polymer contrast agent hydrogels facilitated fate tracking, quantification of degradation, and detection of immune response in vivo. For the duration of the in vivo study, the protein polymer contrast agent-containing hydrogels could be distinguished from adjacent tissues and from the foreign body response surrounding the gels. The hydrogels containing protein polymer contrast agent have a contrast-to-noise ratio 2-fold greater than hydrogels without protein polymer contrast agent. In the absence of the protein polymer contrast agent, hydrogels cannot be distinguished by the end of the gel lifetime.


Assuntos
Materiais Biocompatíveis/análise , Materiais Biocompatíveis/química , Meios de Contraste/síntese química , Imageamento por Ressonância Magnética/métodos , Polímeros/química , Proteínas/química , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Teste de Materiais , Fatores de Tempo
16.
Bioconjug Chem ; 21(12): 2267-75, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21062033

RESUMO

Magnetic resonance imaging (MRI) has long been used clinically and experimentally as a diagnostic tool to obtain three-dimensional, high-resolution images of deep tissues. These images are enhanced by the administration of contrast agents such as paramagnetic Gd(III) complexes. Herein, we describe the preparation of a series of multimodal imaging agents in which paramagnetic Gd(III) complexes are conjugated to a fluorescent tetrapyrrole, namely, a porphyrazine (pz). Zinc metalated pzs conjugated to one, four, or eight paramagnetic Gd(III) complexes are reported. Among these conjugates, Zn-Pz-8Gd(III) exhibits an ionic relaxivity four times that of the monomeric Gd(III) agent, presumably because of increased molecular weight and a molecular relaxivity that is approximately thirty times larger, while retaining the intense electronic absorption and emission of the unmodified pz. Unlike current clinical MR agents, Zn-Pz-1Gd(III) is taken up by cells. This probe demonstrates intracellular fluorescence by confocal microscopy and provides significant contrast enhancement in MR images, as well as marked phototoxicity in assays of cellular viability. These results suggest that pz agents possess a new potential for use in cancer imaging by both MRI and near-infrared (NIR) fluorescence, while acting as a platform for photodynamic therapy.


Assuntos
Complexos de Coordenação/síntese química , Gadolínio/metabolismo , Imageamento por Ressonância Magnética/métodos , Tetrapirróis/síntese química , Adenocarcinoma/diagnóstico , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/radioterapia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Fibroblastos/efeitos dos fármacos , Fluorescência , Gadolínio/química , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Espectrometria de Massas , Microscopia Confocal , Técnicas de Diagnóstico Molecular , Peso Molecular , Fotoquimioterapia/métodos , Radiografia , Tetrapirróis/metabolismo , Tetrapirróis/farmacologia
17.
Biomacromolecules ; 11(6): 1429-36, 2010 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-20420441

RESUMO

Magnetic resonance imaging is a noninvasive imaging modality with high spatial and temporal resolution. Contrast agents (CAs) are frequently used to increase the contrast between tissues of interest. To increase the effectiveness of MR agents, small molecule CAs have been attached to macromolecules. We have created a family of biodegradable, macromolecular CAs based on protein polymers, allowing control over the CA properties. The protein polymers are monodisperse, random coil, and contain evenly spaced lysines that serve as reactive sites for Gd(III) chelates. The exact sequence and length of the protein can be specified, enabling controlled variation in lysine spacing and molecular weight. Relaxivity could be modulated by changing protein polymer length and lysine spacing. Relaxivities of up to approximately 14 mM(-1) s(-1) per Gd(III) and approximately 461 mM(-1) s(-1) per conjugate were observed. These CAs are biodegradable by incubation with plasmin, such that they can be easily excreted after use. They do not reduce cell viability, a prerequisite for future in vivo studies. The protein polymer CAs can be customized for different clinical diagnostic applications, including biomaterial tracking, as a balanced agent with high relaxivity and appropriate molar mass.


Assuntos
Materiais Biocompatíveis/química , Meios de Contraste/química , Imageamento por Ressonância Magnética , Proteínas Recombinantes/química , Sequência de Aminoácidos , Sítios de Ligação , Materiais Biocompatíveis/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Meios de Contraste/toxicidade , Eletroforese em Gel de Poliacrilamida , Fibrinolisina/química , Gadolínio/química , Modelos Moleculares , Dados de Sequência Molecular , Peso Molecular , Proteínas Recombinantes/genética , Proteínas Recombinantes/toxicidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
18.
Chem Commun (Camb) ; 46(1): 73-5, 2010 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-20024297

RESUMO

A one-pot reaction process was developed to synthesize highly dispersible, superparamagnetic Fe(3)O(4) nanoflowers; the potential of these nanoflowers as MRI contrast agents was investigated.


Assuntos
Óxido Ferroso-Férrico/química , Indicadores e Reagentes/química , Imageamento por Ressonância Magnética , Magnetismo , Nanopartículas Metálicas/química , Animais , Nanopartículas Metálicas/ultraestrutura , Camundongos , Células NIH 3T3 , Tamanho da Partícula
19.
Nano Lett ; 10(2): 484-9, 2010 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-20038088

RESUMO

A Gd(III)-nanodiamond conjugate [Gd(III)-ND] was prepared and characterized, enabling detection of nanodiamonds by MR imaging. The Gd(III)-ND particles significantly reduced the T(1) of water protons with a per-Gd(III) relaxivity of 58.82 +/- 1.18 mM(-1) s(-1) at 1.5 T (60 MHz). This represents a 10-fold increase compared to the monomer Gd(III) complex (r(1) = 5.42 +/- 0.20 mM(-1) s(-1)) and is among the highest per-Gd(III) relaxivities reported.


Assuntos
Meios de Contraste/farmacologia , Gadolínio/química , Imageamento por Ressonância Magnética/métodos , Nanomedicina/métodos , Nanoestruturas/química , Nanotecnologia/métodos , Animais , Calorimetria/métodos , Diamante , Células HeLa , Humanos , Camundongos , Microscopia Eletrônica de Transmissão/métodos , Conformação Molecular , Células NIH 3T3
20.
J Phys Chem C Nanomater Interfaces ; 113(49): 20855-20860, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24991303

RESUMO

Ultrasmall (3, 4, 5, and 6 nm), water-soluble Fe3O4 magnetic nanoparticles were synthesized in diethylene glycol (DEG) via a facile one-pot reaction. Hydrodynamic size and relaxation time measurements did not show particle aggregation when Fe3O4 nanoparticles were dispersed in phosphate buffered saline, fetal bovine serum, or calf bovine serum for 1 week. Furthermore, the new Fe3O4 nanoparticles tolerated high salt concentrations (≤1 M NaCl) and a wide pH range from 5 to 11. Surface modification of the nanoparticles with poly(ethylene glycol) bis(carboxymethyl) ether (HOOC-PEG-COOH, 600 g/mol) was accomplished through a ligand-exchange reaction. The effects of PEG modification on magnetization and relaxivity of the Fe3O4 nanoparticles were investigated, and the results indicate that the increase in transverse relaxivity after PEG modification may be due to the increased volume of slowly diffusing water surrounding each nanoparticle. In vitro experiments showed that the DEG- and PEG-coated Fe3O4 nanoparticles have little effect on NIH/3T3 cell viability.

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