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1.
Analyst ; 146(6): 1865-1871, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33480367

RESUMO

γ-Glutamyltranspeptidase (GGT) is an important aminopeptidase overexpressed in many malignant tumors, and accurate detection of its activity is useful for the diagnosis and treatment of tumors. Herein, we report a GGT-activatable ratiometric fluorescent probe (1) constructed by covalently linking an 'always-on' BODIPY fluorophore with a GGT-activatable near-infrared (NIR) fluorescent substrate. Upon interaction with GGT, the NIR fluorescence at 735 nm in probe 1 is significantly enhanced, while the fluorescence of BODIPY at 517 nm remains unchanged. Using BODIPY fluorescence as an internal standard, significantly enhanced ratiometric fluorescence between 735 nm and 517 nm could be achieved, allowing accurate detection of the activity of GGT in living subjects independent of probe concentration. We demonstrate that probe 1 is feasible for the evaluation of GGT levels in different tumor cells and differentiation of GGT-positive tumor cells from GGT-negative normal tissue cells. Moreover, probe 1 is further applied for the visualization of tumor via noninvasive ratiometric fluorescence imaging of GGT activity, which could facilitate the detection of GGT-positive tumor tissues and study of GGT-related pathological processes.

2.
Research (Wash D C) ; 2020: 4087069, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029587

RESUMO

Noninvasive in vivo imaging of hepatic glutathione (GSH) levels is essential to early diagnosis and prognosis of acute hepatitis. Although GSH-responsive fluorescence imaging probes have been reported for evaluation of hepatitis conditions, the low penetration depth of light in liver tissue has impeded reliable GSH visualization in the human liver. We present a liver-targeted and GSH-responsive trimodal probe (GdNPs-Gal) for rapid evaluation of lipopolysaccharide- (LPS-) induced acute liver inflammation via noninvasive, real-time in vivo imaging of hepatic GSH depletion. GdNPs-Gal are formed by molecular coassembly of a GSH-responsive Gd(III)-based MRI probe (1-Gd) and a liver-targeted probe (1-Gal) at a mole ratio of 5/1 (1-Gd/1-Gal), which shows high r 1 relaxivity with low fluorescence and fluorine magnetic resonance spectroscopic (19F-MRS) signals. Upon interaction with GSH, 1-Gd and 1-Gal are cleaved and GdNPs-Gal rapidly disassemble into small molecules 2-Gd, 2-Gal, and 3, producing a substantial decline in r 1 relaxivity with compensatory enhancements in fluorescence and 19F-MRS. By combining in vivo magnetic resonance imaging (1H-MRI) with ex vivo fluorescence imaging and 19F-MRS analysis, GdNPs-Gal efficiently detect hepatic GSH using three independent modalities. We noninvasively visualized LPS-induced liver inflammation and longitudinally monitored its remediation in mice after treatment with an anti-inflammatory drug, dexamethasone (DEX). Findings highlight the potential of GdNPs-Gal for in vivo imaging of liver inflammation by integrating molecular coassembly with GSH-driven disassembly, which can be applied to other responsive molecular probes for improved in vivo imaging.

3.
Biomater Sci ; 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32627767

RESUMO

Stimuli-responsive in situ self-assembly of small molecule probes into nanostructures has been promising for the construction of molecular probes for in vivo imaging. In the past few years, a number of intelligent molecular imaging probes with fluorescence, magnetic resonance imaging (MRI), positron electron tomography (PET) or photoacoustic imaging (PA) modality have been developed based on the in situ self-assembly strategy. In this minireview, we summarize the recent advances in the development of different modality imaging probes through controlling in situ self-assembly for in vivo imaging of enzymatic activity. This review starts from the brief introduction of two different chemical approaches amenable for in situ self-assembly, including (1) stimuli-mediated proteolysis and (2) stimuli-triggered biocompatible reaction. We then discuss their applications in the design of fluorescence, MRI, PET, PA, and bimodality imaging probes for in vivo imaging of different enzymes, such as caspase-3, furin, gelatinase and phosphatase. Finally, we discuss the current and prospective challenges in the stimuli-responsive in situ self-assembly strategy for in vivo imaging.

4.
Angew Chem Int Ed Engl ; 59(46): 20636-20644, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-32686894

RESUMO

Stimuli-responsive smart photosensitizer (PS) nanoassemblies that allow enhanced delivery and controlled release of PSs are promising for imaging-guided photodynamic therapy (PDT) of tumors. However, the lack of high-sensitivity and spatial-resolution signals and fast washout of released PSs from tumor tissues have impeded PDT efficacy in vivo. Herein, we report tumor targeting, redox-responsive magnetic and fluorogenic PS nanoassemblies (NP-RGD) synthesized via self-assembly of a cRGD- and disulfide-containing fluorogenic and paramagnetic small molecule (1-RGD) for fluorescence/magnetic resonance bimodal imaging-guided tumor PDT. NP-RGD show high r1 relaxivity but quenched fluorescence and PDT activity; disulfide reduction by glutathione (GSH) promotes efficient disassembly into a small-molecule probe (2-RGD) and an organic PS (PPa-SH), which could further bind with intracellular albumin, allowing prolonged retention and cascade activation of fluorescence and PDT to ablate tumors.

5.
Chem Asian J ; 15(7): 1147-1155, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32030909

RESUMO

When the 1,1,4,4-tetraanilinobutadiene skeleton is attached with two halogenated aryl units at the 2,3-positions, they undergo facile two-electron oxidation to give stable dicationic dyes which exhibit a near-infrared (NIR) absorption whereas the neutral dienes show only pale color. Therefore, a distinct electrochromic response with an absorption change in the NIR region is achieved, which is attracting considerable recent attention from the viewpoint of bioimaging. Herein, we demonstrate that the redox potentials of the 1,1,4,4-tetraanilinobutadiene can be precisely controlled by the donating properties of the amino group on the aniline unit as well as the number of halogen atoms on the aryl units at 2,3-positions on the butadiene. In contrast, the NIR absorption bands mainly depend on the number of halogen atoms irrespective to the donating properties of aniline unit. Thus, the hexaarylbutadiene skeleton is proven to be a versatile scaffold to develop less-explored organic NIR electrochromic materials, whose redox and spectroscopic properties can be finely tuned by modifying/attaching the proper substituents.

6.
Nat Commun ; 11(1): 446, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974383

RESUMO

Afterglow luminescent probes with high signal-to-background ratio show promise for in vivo imaging; however, such probes that can be selectively delivered into target sites and switch on afterglow luminescence remain limited. We optimize an organic electrochromic material and integrate it into near-infrared (NIR) photosensitizer (silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) and (poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene]) containing nanoparticles, developing an H2S-activatable NIR afterglow probe (F12+-ANP). F12+-ANP displays a fast reaction rate (1563 ± 141 M-1 s-1) and large afterglow turn-on ratio (~122-fold) toward H2S, enabling high-sensitivity and -specificity measurement of H2S concentration in bloods from healthy persons, hepatic or colorectal cancer patients. We further construct a hepatic-tumor-targeting and H2S-activatable afterglow probe (F12+-ANP-Gal) for noninvasive, real-time imaging of tiny subcutaneous HepG2 tumors (<3 mm in diameter) and orthotopic liver tumors in mice. Strikingly, F12+-ANP-Gal accurately delineates tumor margins in excised hepatic cancer specimens, which may facilitate intraoperative guidance of hepatic cancer surgery.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Sulfeto de Hidrogênio/análise , Neoplasias Hepáticas/diagnóstico por imagem , Substâncias Luminescentes/química , Imagem Molecular/métodos , Animais , Neoplasias Colorretais/sangue , Cistationina beta-Sintase/análise , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/análise , Cistationina gama-Liase/metabolismo , Células Hep G2 , Humanos , Sulfeto de Hidrogênio/sangue , Sulfeto de Hidrogênio/química , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Substâncias Luminescentes/síntese química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Polímeros/química , Compostos de Vinila/química , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Am Chem Soc ; 142(6): 2787-2794, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31944682

RESUMO

Near-infrared (NIR) probes are ideal for fluorescence labeling and imaging of biological targets in living animals. However, the instability of common NIR dyes hampers the construction of NIR probes bearing multiple functional components such as biomolecules for specific targeting and imaging reagents for multimodality imaging. To overcome these limitations, we designed a novel NIR scaffold bearing two terminal alkynes as clickable handles and a chloride on the heptamethine backbone that allows nucleophilic substitution with an azide to generate the third clickable handle. This unique scaffold allows for facile installation of multiple functional arms for the construction of multifunctional NIR probes. Various biomacromolecules or imaging reagents can be introduced to the NIR scaffold by sequential one-pot click reactions under biocompatible conditions. The preclickable handle chloride on the NIR backbone does not interfere with the initial click reactions, and it can be easily transformed into an azide for a following click reaction. On the basis of this unique NIR scaffold, we developed a highly efficient method to construct diverse NIR probes containing multiple functional biomolecules including peptides, antibodies, nucleic acids, and NIR/PET (positron emission tomography) dual-modality imaging probes bearing tumor-targeting groups. NIR imaging or multimodality imaging using these probes was performed on live cells or tumor models on living mice.

8.
ACS Appl Mater Interfaces ; 11(50): 46637-46644, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31747242

RESUMO

Metallofullerenes have attracted considerable attention as potential novel noninvasive high-relaxivity magnetic resonance contrast agents. However, the applications of metallofullerenes as stimuli-responsive biosensors to monitor biological processes are still scarce. Herein, manganese-fullerenes core-shell nanocomposites are prepared via a facile one-pot approach to achieve GSH-activatable magnetic resonance/fluorescence bimodal imaging functions. The nanocomposites initially have a FRET-induced quenched fluorescence, and water-resisting stimulated low T1-MRI contrast. Upon exposure to GSH, collapse of the outer MnO2 shell led to reconstruction of the nanoprobes and subsequently resulted in multicolor fluorescence recovery and longitudinal (T1) relaxivity enhancement (r1 value up to 29.8 mM-1 s-1 at 0.5 T based on Mn ion). Our work demonstrates feasibility of using fullerenes to fabricate activatable probes for molecular imaging of GSH, which may promote the development of new fullerene-based stimuli-responsive multimodal probes for the detection and regulation of particular biological processes in vivo.


Assuntos
Técnicas Biossensoriais , Fulerenos/química , Glutationa/isolamento & purificação , Imagem Molecular/métodos , Animais , Meios de Contraste/química , Meios de Contraste/farmacologia , Fluorescência , Glutationa/química , Humanos , Íons/química , Imagem por Ressonância Magnética , Manganês/química , Compostos de Manganês/química , Metais/química , Camundongos , Microscopia Eletrônica de Transmissão/métodos , Nanocompostos/química
9.
Anal Chem ; 91(21): 13639-13646, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31560193

RESUMO

Activatable chemiluminescent probes that show enhanced chemiluminescence upon interaction with a molecular target of interest have offered promising tools for sensing and bioimaging in terms of low background, high sensitivity, and improved penetration depth in biological tissues. Here, we reported a γ-glutamyl transpeptidase (GGT) activatable chemiluminescent probe for real-time detection of GGT activity in vitro and in living mice. The probe was designed by caging an electron-withdrawing acrylic group-substituted Schaap's phenoxy-dioxetane with a GGT-recognitive substrate (γ-Glu) and a self-immolative linker (p-aminobenzyl alcohol), which was initially chemiluminescence off. Upon interaction with GGT, strong chemiluminescence with a more than 800-fold turn-on ratio could be achieved in aqueous solution, allowing to specifically detect GGT activity with ultrahigh signal-to-background ratio and sensitivity in vitro and in live cells. We demonstrated that the probe was reliable to quantify the GGT in serum, permitting to accurately report the elevated levels of GGT in lipopolysaccharide-treated mouse serum. Moreover, through real-time chemiluminescence imaging of GGT activity, the designed probe was feasible to detect GGT-positive tumors in living mice after intravenous systemic administration. This study demonstrates the high potential of GGT-activatable chemiluminescent probe for serum assays and molecular imaging, which might find wide applications in diagnosis of GGT-related diseases.


Assuntos
Luminescência , Sondas Moleculares/química , gama-Glutamiltransferase/sangue , Animais , Linhagem Celular , Humanos , Limite de Detecção , Camundongos , Especificidade por Substrato
10.
Theranostics ; 9(14): 4168-4181, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281539

RESUMO

Our exploiting versatile multimodal theranostic agent aims to integrate the complementary superiorities of photoacoustic imaging (PAI), second near-infrared (NIR-II, 1000-1700) fluorescence and T1-weighted magnetic resonance imaging (MRI) with an ultimate objective of perfecting cancer diagnosis, thus improving cancer therapy efficacy. Herein, we engineered and prepared a water-soluble gadolinium-chelated conjugated polymer-based theranostic nanomedicine (PFTQ-PEG-Gd NPs) for in vivo tri-mode PA/MR/NIR-II imaging-guided tumor photothermal therapy (PTT). Methods: We firstly constructed a semiconducting polymer composed of low-bandgap donor-acceptor (D-A) which afforded the strong NIR absorption for PAI/PTT and long fluorescence emission to NIR-II region for in vivo imaging. Then, the remaining carboxyl groups of the polymeric NPs could effectively chelate with Gd3+ ions for MRI. The in vitro characteristics of the PFTQ-PEG-Gd NPs were studied and the in vivo multimode imaging as well as anti-tumor efficacy of the NPs was evaluated using 4T1 tumor-bearing mice. Results: The obtained theranostic agent showed excellent chemical and optical stability as well as low biotoxicity. After 24 h of systemic administration using PQTF-PEG-Gd NPs, the tumor sites of living mice exhibited obvious enhancement in PA, NIR-II fluorescence and positive MR signal intensities. Better still, a conspicuous tumor growth restraint was detected under NIR light irradiation after administration of PQTF-PEG-Gd NPs, indicating the efficient photothermal potency of the nano-agent. Conclusion: we triumphantly designed and synthesized a novel and omnipotent semiconducting polymer nanoparticles-based theranostic platform for PAI, NIR-II fluorescence imaging as well as positive MRI-guided tumor PTT in living mice. We expect that such a novel organic nano-platform manifests a great promise for high spatial resolution and deep penetration cancer theranostics.


Assuntos
Gadolínio/química , Imagem por Ressonância Magnética/métodos , Técnicas Fotoacústicas/métodos , Polímeros/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Linhagem Celular Tumoral , Espectroscopia de Ressonância Magnética , Camundongos , Fototerapia , Semicondutores , Nanomedicina Teranóstica/métodos
11.
J Am Chem Soc ; 141(26): 10331-10341, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31244188

RESUMO

Stimuli-responsive in situ self-assembly of small molecules to form nanostructures in living subjects has produced promising tools for molecular imaging and tissue engineering. However, controlling the self-assembly process to simultaneously activate multimodality imaging signals in a small-molecule probe is challenging. In this paper, we rationally integrate a fluorogenic reaction into enzyme-responsive in situ self-assembly to design small-molecule-based activatable near-infrared (NIR) fluorescence and magnetic resonance (MR) bimodal probes for molecular imaging. Using alkaline phosphatase (ALP) as a model target, we demonstrate that probe (P-CyFF-Gd) can be activated by endogenous ALP overexpressed on cell membranes, producing membrane-localized assembled nanoparticles (NPs) that can be directly visualized by cryo-SEM. Simultaneous enhancements in NIR fluorescence (>70-fold at 710 nm) and r1 relaxivity (∼2.3-fold) enable real-time, high-sensitivity, high-spatial-resolution imaging and localization of the ALP activity in live tumor cells and mice. P-CyFF-Gd can also delineate orthotopic liver tumor foci, facilitating efficient real-time, image-guided surgical resection of tumor tissues in intraoperative mice. This strategy combines activatable NIR fluorescence via a fluorogenic reaction and activatable MRI via in situ self-assembly to promote ALP activity imaging, which could be applicable to design other activatable bimodal probes for in vivo imaging of enzyme activity and locations in real time.


Assuntos
Fosfatase Alcalina/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Fosfatase Alcalina/análise , Animais , Células Cultivadas , Fluorescência , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/síntese química , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Raios Infravermelhos , Imagem por Ressonância Magnética , Camundongos , Estrutura Molecular , Imagem Óptica , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/síntese química
12.
Anal Chem ; 91(6): 3795-3799, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30789708

RESUMO

Liposomal photoelectrochemical (PEC) bioanalysis has recently emerged and exhibited great potential in sensitive biomolecular detection. Exploration of the facile and efficient route for advanced liposomal PEC bioanalysis is highly appealing. In this work, we report the split-type liposomal PEC immunoassay system consisting of sandwich immunorecognition, CdS quantum dots (QDs)-loaded liposomes (QDLL), and the release and subsequent capture of the QDs by a separated TiO2 nanotubes (NTs) electrode. The system elegantly operated upon the protein binding and lysis treatment of CdS QDLL labels within the 96-well plate, and then the CdS QDs-enabled sensitization of TiO2 NTs electrode. Exemplified by cardiac markers troponin I (cTnI) as target, the proposed system achieved efficient activation of TiO2 NTs electrode and thus the signal generation toward the split-type PEC immunoassay. This work features the first use of QDs for liposomal PEC bioanalysis and is expected to inspire more interests in the design and implementation of numerous QDs-involved liposomal PEC bioanalysis.


Assuntos
Imunoensaio/instrumentação , Limite de Detecção , Lipossomos/química , Nanoporos , Processos Fotoquímicos , Pontos Quânticos/química , Semicondutores , Calibragem , Eletroquímica , Eletrodos
13.
ACS Nano ; 13(2): 2544-2557, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30730695

RESUMO

Combination therapy, especially photodynamic/photothermal therapy (PDT/PTT), has shown promising applications in cancer therapy. However, sequential irradiation by two different laser sources and even the utilization of single high-power laser to induce either combined PDT/PTT or individual PTT will be subjected to prolonged treatment time, complicated treatment process, and potential skin burns. Thus, low power single laser activatable combined PDT/PTT is still a formidable challenge. Herein, we propose an effective strategy to achieve synergistic cancer phototherapy under low power single laser irradiation for short duration. By taking advantage of dual plasmonic PTT nanoagents (AuNRs/MoS2), a significant increase in temperature up to 60 °C with an overall photothermal conversion efficiency (PCE) of 68.8% was achieved within 5 min under very low power (0.2 W/cm2) NIR laser irradiation. The enhanced PCE and PTT performance is attributed to the synergistic plasmonic PTT effect (PPTT) of dual plasmonic nanoagents, promoting simultaneous release (85%) of electrostatically bonded indocyanine green (ICG) to induce PDT effects, offering simultaneous PDT/synergistic PPTT. Both in vitro and in vivo investigations reveal complete cell/tumor eradication, implying that simultaneous PDT/synergistic PPTT effects induced by AuNRs/MoS2-ICG are much superior over individual PDT or synergistic PPTT. Notably, synergistic PPTT induced by dual plasmonic nanoagents also demonstrates higher in vivo antitumor efficacy than either individual PDT or PTT agents. Taken together, under single laser activation with low power density, the proposed strategy of simultaneous PDT/synergistic PPTT effectively reduces the treatment time, achieves high therapeutic index, and offers safe treatment option, which may serve as a platform to develop safer and clinically translatable approaches for accelerating cancer therapeutics.


Assuntos
Lasers , Nanopartículas/química , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Proliferação de Células/efeitos dos fármacos , Dissulfetos/química , Dissulfetos/farmacologia , Relação Dose-Resposta a Droga , Ouro/química , Ouro/farmacologia , Células HeLa , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Verde de Indocianina/química , Verde de Indocianina/farmacologia , Molibdênio/química , Molibdênio/farmacologia , Imagem Óptica , Fármacos Fotossensibilizantes/química
14.
Angew Chem Int Ed Engl ; 58(15): 4886-4890, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30688393

RESUMO

Photoacoustic (PA) imaging shows promise in the sensitive detection of caspase-3 activated in early tumor apoptosis in response to chemotherapy; smart PA probes are thus in high demand. Herein, we report the first smart PA probe (1-RGD) responsive to caspase-3, enabling real-time and high-resolution imaging of tumor apoptosis. 1-RGD is designed to leverage the synergetic effect of active delivery and caspase-3 activation. It is selectively recognized by active caspase-3 to trigger peptide substrate cleavage and biocompatible macrocyclization-mediated self-assembly, leading to an amplified PA imaging signal and prolonged retention in apoptotic tumor cells. Strong, high-resolution PA images are obtained in chemotherapy-induced apoptotic tumors in living mice after intravenous administration with 1-RGD, facilitating sensitive reporting of caspase-3 activity and distribution within tumor tissues.


Assuntos
Apoptose , Caspases/metabolismo , Glioblastoma/diagnóstico por imagem , Compostos Macrocíclicos/química , Sondas Moleculares/química , Imagem Óptica , Técnicas Fotoacústicas , Caspases/química , Ciclização , Humanos , Compostos Macrocíclicos/metabolismo , Imagem Molecular , Sondas Moleculares/biossíntese , Estrutura Molecular
15.
Nano Lett ; 19(2): 937-947, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30688465

RESUMO

Targeted delivery of enzyme-activatable probes into cancer cells to facilitate accurate imaging and on-demand photothermal therapy (PTT) of cancers with high spatiotemporal precision promises to advance cancer diagnosis and therapy. Here, we report a tumor-targeted and matrix metalloprotease-2 (MMP-2)-activatable nanoprobe (T-MAN) formed by covalent modification of Gd-doping CuS micellar nanoparticles with cRGD and an MMP-2-cleavable fluorescent substrate. T-MAN displays a high r1 relaxivity (∼60.0 mM-1 s-1 per Gd3+ at 1 T) and a large near-infrared (NIR) fluorescence turn-on ratio (∼185-fold) in response to MMP-2, allowing high-spatial-resolution magnetic resonance imaging (MRI) and low-background fluorescence imaging of gastric tumors as well as lymph node (LN) metastasis in living mice. Moreover, T-MAN has a high photothermal conversion efficiency (PCE, ∼70.1%) under 808 nm laser irradiation, endowing it with the ability to efficiently generate heat to kill tumor cells. We demonstrate that T-MAN can accumulate preferentially in gastric tumors (∼23.4% ID%/g at 12 h) after intravenous injection into mice, creating opportunities for fluorescence/MR bimodal imaging-guided PTT of subcutaneous and metastatic gastric tumors. For the first time, accurate detection and laser irradiation-initiated photothermal ablation of orthotopic gastric tumors in intraoperative mice was also achieved. This study highlights the versatility of using a combination of dual biomarker recognition (i.e., αvß3 and MMP-2) and dual modality imaging (i.e., MRI and NIR fluorescence) to design tumor-targeting and activatable nanoprobes with improved selectivity for cancer theranostics in vivo.


Assuntos
Cobre/uso terapêutico , Gadolínio/uso terapêutico , Pontos Quânticos/uso terapêutico , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/terapia , Nanomedicina Teranóstica/métodos , Animais , Cobre/química , Gadolínio/química , Hipertermia Induzida/métodos , Imagem por Ressonância Magnética/métodos , Imãs/química , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Imagem Óptica/métodos , Fototerapia/métodos , Pontos Quânticos/química , Pontos Quânticos/ultraestrutura , Neoplasias Gástricas/metabolismo
16.
Chembiochem ; 20(4): 474-487, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30062708

RESUMO

γ-Glutamyltranspeptidase (GGT) is a cell-membrane-bound protease that participates in cellular glutathione and cysteine homeostasis, which are closely related to many physiological and pathological processes. The accurate measurement of GGT activity is useful for the early diagnosis of diseases. In the past few years, many efforts have been made to build optical imaging probes for the detection of GGT activity both in vitro and in vivo. In this Minireview, recent advances in the development of various optical imaging probes for GGT, including activatable fluorescence probes, ratiometric fluorescence probes, and activatable bioluminescence probes, are summarized. This review starts from the instruction of the GGT enzyme and its biological functions, followed by a discussion of activatable fluorescence probes that show off-on fluorescence in response to GGT. GGT-activatable two-photon fluorescence imaging probes with improved imaging depth and spatial resolution are also discussed. Ratiometric fluorescence probes capable of accurately reporting on GGT levels through a self-calibration mechanism are discussed, followed by describing GGT-activatable bioluminescence probes that can offer a high signal-to-background ratio to detect GGT in living mice. Finally, current challenges and further perspectives for the development of molecular imaging probes for GGT are addressed.


Assuntos
Corantes Fluorescentes/química , Imagem Óptica/métodos , gama-Glutamiltransferase/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico por imagem , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Luciferina de Vaga-Lumes/química , Humanos , Microscopia de Fluorescência , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , gama-Glutamiltransferase/química
17.
J Am Chem Soc ; 140(47): 16340-16352, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30384600

RESUMO

Electrochromic materials (EMs) are widely used color-switchable materials, but their applications as stimuli-responsive biomaterials to monitor and control biological processes remain unexplored. This study reports the engineering of an organic π-electron structure-based EM (dicationic 1,1,4,4-tetraarylbutadiene, 12+) as a unique hydrogen sulfide (H2S)-responsive chromophore amenable to build H2S-activatable fluorescent probes (12+-semiconducting polymer nanoparticles, 12+-SNPs) for in vivo H2S detection. We demonstrate that EM 12+, with a strong absorption (500-850 nm), efficiently quenches the fluorescence (580, 700, or 830 nm) of different fluorophores within 12+-SNPs, while the selective conversion into colorless diene 2 via H2S-mediated two-electron reduction significantly recovers fluorescence, allowing for non-invasive imaging of hepatic and tumor H2S in mice in real time. Strikingly, EM 12+ is further applied to design a near-infrared photosensitizer with tumor-targeting and H2S-activatable ability for effective photodynamic therapy (PDT) of H2S-related tumors in mice. This study demonstrates promise for applying EMs to build activatable probes for molecular imaging of H2S and selective PDT of tumors, which may lead to the development of new EMs capable of detecting and regulating essential biological processes in vivo.


Assuntos
Compostos de Anilina/uso terapêutico , Corantes Fluorescentes/uso terapêutico , Sulfeto de Hidrogênio/análise , Fármacos Fotossensibilizantes/uso terapêutico , Estilbenos/uso terapêutico , Compostos de Anilina/síntese química , Compostos de Anilina/farmacologia , Compostos de Anilina/toxicidade , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Corantes Fluorescentes/toxicidade , Células HEK293 , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/metabolismo , Raios Infravermelhos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Imagem Molecular/métodos , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/toxicidade , Polímeros/química , Células RAW 264.7 , Oxigênio Singlete/metabolismo , Estilbenos/síntese química , Estilbenos/farmacologia , Estilbenos/toxicidade , Tiadiazóis/química , Compostos de Vinila/química , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Chemistry ; 24(39): 9812-9819, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29766578

RESUMO

Selective imaging and inducing mitochondrial dysfunction in tumor cells using mitochondria-targeting probes has become as a promising approach for cancer diagnosis and therapy. Here, we report the design of a fluorescent berberine analog, dehydroberberine (DH-BBR), as a new mitochondria-targeting probe capable of self-assembling into monodisperse organic nanoparticles (DTNPs) upon integration with a lipophilic counter anion, allowing for enhanced fluorescence imaging and treatment of tumors in living mice. X-ray crystallography revealed that the self-assembly process was attributed to a synergy of different molecular interactions, including π-π stacking, O⋅⋅⋅π interaction and electrostatic interaction between DH-BBR and counter anions. We demonstrated that DTNPs could efficiently enter tumor tissue following intravenous injection and enhance mitochondrial delivery of DH-BBR via an electrostatic interaction driven anion exchange process. Selective accumulation in the mitochondria capable of emitting strong fluorescence and causing mitochondrial dysfunction was achieved, enabling efficient inhibition of tumor growth in living mice. This study demonstrates promise for applying lipophilic anions to control molecular self-assembly and tune antitumor activity of mitochondria-targeting probes, which can facilitate to improve cancer treatment in vivo.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Berberina/química , Corantes Fluorescentes/química , Mitocôndrias/efeitos dos fármacos , Animais , Camundongos , Mitocôndrias/química
19.
J Chromatogr Sci ; 56(8): 724-730, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29762651

RESUMO

A rapid and sensitive high-performance liquid chromatography-mass spectrometry method was developed and validated to determine 4-fluoroaniline concentration in ezetimibe. Chromatographic separation was achieved on a Phenomenex Gemini-NX C18 column (150 × 4.6 mm, 3 µm) maintained at 30°C. The liquid chromatography system was operated in gradient mode with an injection volume of 20 µL at a flow rate of 1 mL/min. Mobile phase A was water and mobile phase B consisted of acetonitrile with 0.05% acetic acid. The detection was performed using a single quadrupole mass spectrometer in single ion monitoring mode by using positive ionization. An m/z value of 112 was selected for monitoring 4-fluoroaniline. The method showed good linearity over the concentration range of 0.94-30.26 ng/mL. The limit of quantification and limit of detection were 0.19 and 0.94 ng/mL, respectively. The precision relative standard deviations were less than 8.7% (n = 12), and the accuracy values were within 92-99%. A standard solution of 4-fluoroaniline was stable for at least 24 h at 25°C. Small changes in the organic phase acidity of the mobile phase, flow rate, column temperature, and the instrument parameters had no significant effect on the results for 4-fluoroaniline.


Assuntos
Compostos de Anilina/análise , Anticolesterolemiantes/química , Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Medicamentos , Ezetimiba/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Cromatografia Líquida de Alta Pressão/economia , Limite de Detecção , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/economia
20.
Inorg Chem ; 57(8): 4310-4316, 2018 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-29608289

RESUMO

Aggregation-induced emission has been extensively found in organic compounds and metal complexes. In contrast, aggregation-induced electrochemiluminescence (AI-ECL) is rarely observed. Here, we employ two tridentate ligands [2,2':6',2″-terpyridine (tpy) and 1,3-bis(1 H-benzimidazol-2-yl)benzene (bbbiH3)] to construct a cyclometalated iridium(III) complex, [Ir(tpy)(bbbi)] (1), showing strong AI-ECL. Its crystal structure indicates that neighboring [Ir(tpy)(bbbi)] molecules are connected through both π-π-stacking interactions and hydrogen bonds. These supramolecular interactions can facilitate the self-assembly of complex 1 into nanoparticles in an aqueous solution. The efficient restriction of molecular vibration in these nanoparticles leads to strong AI-ECL emission of complex 1. In a dimethyl sulfoxide-water (H2O) mixture with a gradual increase in the H2O fraction from 20% to 98%, complex 1 showed a ∼39-fold increase in the electrochemiluminescence (ECL) intensity, which was ∼4.04 times as high as that of [Ru(bpy)3]2+ under the same experimental conditions. Moreover, the binding of bovine serum albumin to the nanoparticles of complex 1 can improve the ECL emission of this complex, facilitating the understanding of the mechanism of AI-ECL for future applications.

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