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1.
Chem Commun (Camb) ; 52(67): 10305-8, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27476533

RESUMO

The adrenal glands (AGs) are relatively small yet require definitive identification during their resection, or more commonly their avoidance. To enable image-guided surgery involving the AGs, we have developed novel near-infrared (NIR) fluorophores that target the AGs after a single intravenous injection, which provided dual-NIR image-guided resection or avoidance of the AGs during both open and minimally-invasive surgery.


Assuntos
Glândulas Suprarrenais/cirurgia , Corantes Fluorescentes/química , Corantes Fluorescentes/administração & dosagem , Humanos , Raios Infravermelhos , Injeções Intravenosas , Cirurgia Assistida por Computador
2.
J Med Chem ; 59(11): 5311-23, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27100476

RESUMO

Our initial efforts to prepare tissue-specific near-infrared (NIR) fluorescent compounds generated successful correlation between physicochemical properties and global uptake in major organs after systemic circulation and biodistribution. Herein, we focus on the effects on biodistribution based on modulating electronic influencing moieties from donating to withdrawing moieties at both the heterocyclic site and through meso-substitution of pentamethine cyanine fluorophores. These selected modifications harnessed innate biodistribution pathways through the structure-inherent targeting, resulting in effective imaging of the adrenal glands, pituitary gland, lymph nodes, pancreas, and thyroid and salivary glands. These native-tissue contrast agents will arm surgeons with a powerful and versatile arsenal for intraoperative NIR imaging in real time.


Assuntos
Carbocianinas/farmacocinética , Corantes Fluorescentes/farmacocinética , Imagem Molecular/métodos , Cirurgia Assistida por Computador , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/cirurgia , Animais , Carbocianinas/análise , Carbocianinas/síntese química , Carbocianinas/química , Corantes Fluorescentes/análise , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Linfonodos/diagnóstico por imagem , Linfonodos/cirurgia , Masculino , Camundongos , Células NIH 3T3 , Pâncreas/diagnóstico por imagem , Pâncreas/cirurgia , Hipófise/diagnóstico por imagem , Hipófise/cirurgia , Glândulas Salivares/diagnóstico por imagem , Glândulas Salivares/cirurgia , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/cirurgia , Distribuição Tecidual
3.
Mol Imaging Biol ; 18(1): 52-61, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26084246

RESUMO

PURPOSE: The purpose of this study was to develop a family of 700-nm zwitterionic pentamethine indocyanine near-infrared fluorophores that would permit dual-channel image-guided surgery. PROCEDURES: Three complementary synthetic schemes were used to produce novel zwitterionic chemical structures. Physicochemical, optical, biodistribution, and clearance properties were compared to Cy5.5, a conventional pentamethine indocyanine now used for biomedical imaging. RESULTS: ZW700-1a, ZW700-1b, and ZW700-1c were synthesized, purified, and analyzed extensively in vitro and in vivo. All molecules had extinction coefficients ≥199,000 M(-1) cm(-1), emission ≥660 nm, and stability ≥99 % after 24 h in warm serum. In mice, rats, and pigs, ≥80 % of the injected dose was completely eliminated from the body via renal clearance within 4 h. Either alone or conjugated to a tumor targeting ligand, ZW700-1a permitted dual-channel, high SBR, and simultaneous imaging with 800-nm NIR fluorophores using the FLARE® imaging system. CONCLUSIONS: Novel 700-nm zwitterionic NIR fluorophores enable dual-NIR image-guided surgery.


Assuntos
Corantes Fluorescentes/química , Imagem Óptica/métodos , Fenômenos Ópticos , Cirurgia Assistida por Computador/métodos , Animais , Morte Celular , Linhagem Celular Tumoral , Feminino , Fluorescência , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Cuidados Intraoperatórios , Camundongos Nus , Espectroscopia de Luz Próxima ao Infravermelho , Sus scrofa , Distribuição Tecidual
4.
Angew Chem Int Ed Engl ; 54(30): 8648-52, 2015 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-26095685

RESUMO

A novel class of near-infrared fluorescent contrast agents was developed. These agents target cartilage with high specificity and this property is inherent to the chemical structure of the fluorophore. After a single low-dose intravenous injection and a clearance time of approximately 4 h, these agents bind to all three major types of cartilage (hyaline, elastic, and fibrocartilage) and perform equally well across species. Analysis of the chemical structure similarities revealed a potential pharmacophore for cartilage targeting. Our results lay the foundation for future improvements in tissue engineering, joint surgery, and cartilage-specific drug development.


Assuntos
Cartilagem/metabolismo , Meios de Contraste/química , Meios de Contraste/farmacocinética , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Imagem Óptica , Administração Intravenosa , Animais , Meios de Contraste/administração & dosagem , Corantes Fluorescentes/administração & dosagem , Masculino , Camundongos , Imagem Óptica/métodos , Espectroscopia de Luz Próxima ao Infravermelho
5.
Theranostics ; 5(1): 1-11, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25553094

RESUMO

OBJECTIVE: Pancreas-related complications are some of the most serious ones in abdominal surgery. The goal of this study was to develop and validate novel near-infrared (NIR) fluorophores that would enable real-time pancreas imaging to avoid the intraoperative pancreatic injury. DESIGN: After initial screening of a large NIR fluorophore library, the performance of 3 selected pancreas-targeted 700 nm NIR fluorophores, T700-H, T700-F, and MB, were quantified in mice, rats, and pigs. Dose ranging using 25 and 100 nmol, and 2.5 µmol of T700-F, and its imaging kinetics over a 4 h period were tested in each species. Three different 800 nm NIR fluorophores were employed for dual-channel FLARE™ imaging in pigs: 2 µmol of ZW800-1 for vessels and kidney, 1 µmol of ZW800-3C for lymph nodes, and 2 µmol of ESNF31 for adrenal glands. RESULTS: T700-F demonstrated the highest signal to background ratio (SBR), with peak SBR at 4 h postinjection in mice. In pigs, T700-F produced an SBR≥2 against muscle, spleen, and lymph nodes for up to 8 h after a single intravenous injection. The combination of T700-F with each 800 nm NIR fluorophore provided simultaneous dual-channel intraoperative imaging of pancreas with surrounding organs in real time. CONCLUSION: Pancreas-targeted NIR fluorophores combined with the FLARE dual-channel imaging system enable the real-time intraoperative pancreas imaging which helps surgeons perform safer and more curative abdominal surgeries.


Assuntos
Corantes Fluorescentes/farmacocinética , Imagem Óptica/métodos , Pâncreas/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Coloração e Rotulagem/métodos , Cirurgia Assistida por Computador/métodos , Glândulas Suprarrenais/metabolismo , Animais , Rim/metabolismo , Linfonodos/metabolismo , Masculino , Camundongos , Ratos Sprague-Dawley , Suínos , Fatores de Tempo
6.
Theranostics ; 4(8): 823-33, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24955143

RESUMO

Nerve preservation is an important issue during most surgery because accidental transection or injury results in significant morbidity, including numbness, pain, weakness, or paralysis. Currently, nerves are still identified only by gross appearance and anatomical location during surgery, without intraoperative image guidance. Near-infrared (NIR) fluorescent light, in the wavelength range of 650-900 nm, has the potential to provide high-resolution, high-sensitivity, and real-time avoidance of nerve damage, but only if nerve-specific NIR fluorophores can be developed. In this study, we evaluated a series of Oxazine derivatives to highlight various peripheral nerve structures in small and large animals. Among the targeted fluorophores, Oxazine 4 has peak emission near into the NIR, which provided nerve-targeted signal in the brachial plexus and sciatic nerve for up to 12 h after a single intravenous injection. In addition, recurrent laryngeal nerves were successfully identified and highlighted in real time in swine, which could be preserved during the course of thyroid resection. Although optical properties of these agents are not yet optimal, chemical structure analysis provides a basis for improving these prototype nerve-specific NIR fluorophores even further.


Assuntos
Corantes Fluorescentes/metabolismo , Tecido Nervoso/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Feminino , Corantes Fluorescentes/química , Cinética , Nervos Laríngeos/metabolismo , Masculino , Fenômenos Ópticos , Especificidade de Órgãos , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Sus scrofa
7.
Sci Rep ; 3: 1198, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23386968

RESUMO

Biodegradable scaffolds could revolutionize tissue engineering and regenerative medicine; however, in vivo matrix degradation and tissue ingrowth processes are not fully understood. Currently a large number of samples and animals are required to track biodegradation of implanted scaffolds, and such nonconsecutive single-time-point information from various batches result in inaccurate conclusions. To overcome this limitation, we developed functional biodegradable scaffolds by employing invisible near-infrared fluorescence and followed their degradation behaviors in vitro and in vivo. Using optical fluorescence imaging, the degradation could be quantified in real-time, while tissue ingrowth was tracked by measuring vascularization using magnetic resonance imaging in the same animal over a month. Moreover, we optimized the in vitro process of enzyme-based biodegradation to predict implanted scaffold behaviors in vivo, which was closely related to the site of inoculation. This combined multimodal imaging will benefit tissue engineers by saving time, reducing animal numbers, and offering more accurate conclusions.


Assuntos
Espectroscopia de Luz Próxima ao Infravermelho , Engenharia Tecidual , Alicerces Teciduais , Animais , Materiais Biocompatíveis/metabolismo , Colágeno/química , Colágeno/metabolismo , Colagenases/metabolismo , Raios Infravermelhos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Compostos de Amônio Quaternário/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Ácidos Sulfônicos/química , Suínos
8.
Nat Biotechnol ; 31(2): 148-53, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23292608

RESUMO

The signal-to-background ratio (SBR) is the key determinant of sensitivity, detectability and linearity in optical imaging. As signal strength is often constrained by fundamental limits, background reduction becomes an important approach for improving the SBR. We recently reported that a zwitterionic near-infrared (NIR) fluorophore, ZW800-1, exhibits low background. Here we show that this fluorophore provides a much-improved SBR when targeted to cancer cells or proteins by conjugation with a cyclic RGD peptide, fibrinogen or antibodies. ZW800-1 outperforms the commercially available NIR fluorophores IRDye800-CW and Cy5.5 in vitro for immunocytometry, histopathology and immunoblotting and in vivo for image-guided surgery. In tumor model systems, a tumor-to-background ratio of 17.2 is achieved at 4 h after injection of ZW800-1 conjugated to cRGD compared to ratios of 5.1 with IRDye800-CW and 2.7 with Cy5.5. Our results suggest that introducing zwitterionic properties into targeted fluorophores may be a general strategy for improving the SBR in diagnostic and therapeutic applications.


Assuntos
Neoplasias/patologia , Imagem Óptica/métodos , Compostos de Amônio Quaternário , Ácidos Sulfônicos , Animais , Anticorpos/isolamento & purificação , Linhagem Celular Tumoral , Fibrinogênio/isolamento & purificação , Corantes Fluorescentes/química , Humanos , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Neoplasias/diagnóstico , Peptídeos Cíclicos/isolamento & purificação , Compostos de Amônio Quaternário/química , Razão Sinal-Ruído , Ácidos Sulfônicos/química , Cirurgia Assistida por Computador
9.
Biomed Mater ; 8(1): 014109, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23353870

RESUMO

Biodegradable scaffolds have been extensively used in the field of tissue engineering and regenerative medicine. However, noninvasive monitoring of in vivo scaffold degradation is still lacking. In order to develop a real-time trafficking technique, a series of meso-brominated near-infrared (NIR) fluorophores were synthesized and conjugated to biodegradable gelatin scaffolds. Since the pentamethine cyanine core is highly lipophilic, the side chain of each fluorophore was modified with either quaternary ammonium salts or sulfonate groups. The physicochemical properties such as lipophilicity and net charge of fluorophores played a key role in the fate of NIR-conjugated scaffolds in vivo after biodegradation. The positively charged fluorophore-conjugated scaffold fragments were found in salivary glands, lymph nodes, and most of the hepatobiliary excretion route. However, halogenated fluorophores intensively accumulated into lymph nodes and the liver. Interestingly, balanced-charged gelatin scaffolds were degraded into urine in a short period of time. These results demonstrate that the noninvasive optical imaging using NIR fluorophores can be useful for the translation of biodegradable scaffolds into the clinic.


Assuntos
Implantes Absorvíveis , Carbocianinas/química , Corantes Fluorescentes/química , Alicerces Teciduais , Animais , Compostos de Bis-Trimetilamônio/química , Compostos de Bis-Trimetilamônio/farmacocinética , Carbocianinas/farmacocinética , Corantes Fluorescentes/farmacocinética , Gelatina/química , Teste de Materiais , Camundongos , Camundongos Nus , Imagem Óptica , Espectroscopia de Luz Próxima ao Infravermelho , Distribuição Tecidual , Engenharia Tecidual , Alicerces Teciduais/química
10.
Biomed Mater ; 8(1): 014110, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23353894

RESUMO

Longitudinal monitoring of cell migration, division and differentiation is of paramount importance in cell-based medical treatment. However, currently available optical techniques for tracing cell growth and tissue development are limited in applications due to genetic modification, toxicity and inaccurate detection when utilizing the visible spectrum. We have developed lipophilic near-infrared (NIR) fluorophores with high optical properties and a low background signal that allows longitudinal monitoring of cell proliferation and differentiation. Intracellular labeling efficacy was highly dependent on the physicochemical properties of fluorophores such as lipophilicity, charge, polar surface area and rotational bonds. Among the series of NIR cyanine fluorophores, ESNF 13 showed high solubility in aqueous buffer, high membrane penetration, low cytotoxicity and a long-term signal maintainability with a high signal intensity. This study will guide tissue engineers in designing long-term cell trafficking agents with better physicochemical and optical properties.


Assuntos
Corantes Fluorescentes/química , Engenharia Tecidual/métodos , Animais , Compostos de Bis-Trimetilamônio/química , Compostos de Bis-Trimetilamônio/farmacocinética , Carbocianinas/química , Carbocianinas/farmacocinética , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Condrócitos/citologia , Condrócitos/metabolismo , Corantes Fluorescentes/farmacocinética , Camundongos , Mioblastos/citologia , Mioblastos/metabolismo , Imagem Óptica , Solubilidade , Espectroscopia de Luz Próxima ao Infravermelho , Sus scrofa
11.
Quant Imaging Med Surg ; 2(4): 266-73, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23289086

RESUMO

Optical fluorescence imaging with the right combination of imaging modality and targeted contrast agents offers tremendous improvement in intraoperative imaging and clinical output (i.e., image-guided cancer surgery). Therefore, it is of paramount importance to gain an in-depth knowledge in the design of targeted contrast agents to meet clinical requirements. Currently, there are several clinically approved contrast agents available; however, none perform optimally in vivo by providing optimum sensitivity, stability, specificity, and safety for target imaging, diagnosis, and therapy. In this review, we discuss basic design considerations for targeted contrast agents in terms of optical and physicochemical properties, biological and physiological interactions, and biodistribution and targeting.

12.
Free Radic Res ; 44(4): 454-61, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20187708

RESUMO

Morin is a flavone that has anti-inflammatory effects through a mechanism that is not well understood. Based on the extreme sensitive nature of the transcription factor, NF-kB to redox change, it is postulated that morin's anti-NF-kappaB activation likely depends on its ability to scavenge excessive reactive species [RS]. The present study assessed the extent of morin's ability to modulate RS-induced NF-kappaB activation through its scavenging activity. Results indicate that morin neutralized RS in vitro and inhibited t-BHP-induced RS generation. It also examined morin for suppressed redox-sensitive transcription factor NF-kappaB activation via reduced DNA binding activity, I kappaB alpha phosphorylation and p65/p50 nuclear translocation. The more important finding was that suppression of the NF-kappaB cascade by morin was modulated through the ERK and p38 MAPKs signal transduction pathways in endothelial cells. As a consequence, morin's anti-oxidant effect extended expression level of NF-kappaB dependent pro-inflammatory genes, thereby reducing COX-2, iNOS and 5-LOX. The data indicate that morin has strong anti-oxidative power against RS-induced NF-kappaB modulation through the ERK and p38 MAPKs signalling pathways by its RS scavenging activity. The significance of the current study is the new revelation that morin may have potential as an effective anti-inflammatory therapeutic agent.


Assuntos
Anti-Inflamatórios/farmacologia , Células Endoteliais/efeitos dos fármacos , Flavonoides/farmacologia , Sequestradores de Radicais Livres/farmacologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Sítios de Ligação , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , DNA/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase I-kappa B , Mediadores da Inflamação/metabolismo , Molsidomina/análogos & derivados , Molsidomina/farmacologia , Subunidade p50 de NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Ratos , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , terc-Butil Hidroperóxido/farmacologia
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