Browsing by Author "Wu, Shou-Cheng"

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A N-(2-Aminophenyl)-5-(dimethylamino)-1-naphthalenesulfonic Amide (Ds-DAB) Based Fluorescent Chemosensor for Peroxynitrite
(2013-08-16)
Lin, Ku-Kuei
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Wu, Shou-Cheng
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Hsu, Kuang-Mei
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Hung, Chen-Hsiung
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Liaw, Wen-Feng
A dansyl derivative (Ds-DAB) was prepared and used as a fluorescent probe for peroxynitrite (ONOO-) detection. The results showed that the addition of peroxynitrite to the aqueous solution of Ds-DAB would result in obvious fluorescence enhancement. This probe is highly specific for peroxynitrite in aqueous solution, avoiding interference from other reactive oxygen species (ROS) and nitrogen species (RNS). The advantages of high selectivity, fast reaction rate, and peroxynitrite bioimaging render Ds-DAB suitable for peroxynitrite detection.
A switch-on MRI contrast agent for noninvasive visualization of methylmercury
(2015-01-01)
Singh, Gyan
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Hsu, Kuang-Mei
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Chen, Yu-Jen
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Wu, Shou-Cheng
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Chen, Chiao-Yun
This communication presents the first Gd(III)-based T-1 MRI contrast agent, o-MeHgGad, for noninvasive visualization of CH3Hg+. o-MeHgGad showed a relaxivity enhancement of 62% in the presence of 1 equiv. of CH3Hg+. Moreover, a noticeable contrast enhancement was recorded in the liver, kidney, and intestine of mice exposed to CH3Hg+. Thus, the newly designed contrast agent has the potential to be used for in vivo bio-imaging of CH3Hg+ and could be useful for biomedical applications.
Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes
(2019-10-01)
Chen, Yu-Jen
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Wu, Shou-Cheng
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Wang, Hsiang-Ching
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Wu, Tung-Ho
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Yuan, Shyng-Shiou F.
In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe-2(mu-SCH2CH2OH)(2)(NO)(4)] (DNIC-1) with a sustainable NO-release reactivity (t(1/2) = 27.4 +/- 0.5 h at 25 degrees C and 16.8 +/- 1.8 h at 37 degrees C) activates the NO-sGC-cGMP pathway and displays the best proangiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable (NO)-N-center dot-release reactivity on the activation of angiogenesis and wound healing.
Bispecific Antibody Conjugated Manganese-Based Magnetic Engineered Iron Oxide for Imaging of HER2/neu- and EGFR-Expressing Tumors
(2016-01-01)
Wu, Shou-Cheng
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Chen, Jen
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Wang, Hsiang-Ching
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Chou, Min-Yuan
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Chang, Teng-Yuan
The overexpression of HER2/neu and EGFR receptors plays important roles in tumorigenesis and tumor progression. Targeting these two receptors simultaneously can have a more widespread application in early diagnosis of cancers. In this study, a new multifunctional nanoparticles (MnMEIO-CyTE777-(Bis)-mPEG NPs) comprising a manganese-doped iron oxide nanoparticle core (MnMEIO), a silane-amino functionalized poly(ethylene glycol) copolymer shell, a near infrared fluorescence dye (CyTE777), and a covalently conjugated anti-HER2/neu and anti-EGFR receptors bispecific antibody (Bis) were successfully developed. In vitro T-2-weighted MR imaging studies in SKBR-3 and A431 tumor cells incubated with MnMEIO-CyTE777-(Bis)-mPEG NPs showed -94.8 +/- 3.8 and -84.1 +/- 2.8% negative contrast enhancement, respectively. Pharmacokinetics study showed that MnMEIO-CyTE777-(Bis)-mPEG NPs were eliminated from serum with the half-life of 21.3 mins. In vivo MR imaging showed that MnMEIO-CyTE777-(Bis)-mPEG NPs could specifically and effectively target to HER2/neu-and EGFR-expressing tumors in mice; the relative contrast enhancements were 11.8 (at 2 hrs post-injection) and 61.5 (at 24 hrs post-injection) fold higher in SKBR-3 tumors as compared to Colo-205 tumors. T2-weighted MR and optical imaging studies revealed that the new contrast agent (MnMEIO-CyTE777-(Bis)-mPEG NPs) could specifically and effectively target to HER2/neu-and/or EGFR-expressing tumors. Our results demonstrate that MnMEIO-CyTE777-(Bis)-mPEG NPs are able to recognize the tumors expressing both HER2/neu and/or EGFR, and may provide a novel molecular imaging tool for early diagnosis of cancers expressing HER2/neu and/or EGFR.
Development of a Mucin4-Targeting SPIO Contrast Agent for Effective Detection of Pancreatic Tumor Cells in Vitro and in Vivo
(2013-11-28)
Wu, Shou-Cheng
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Chen, Yu-Jen
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Lin, Yi-Jan
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Wu, Tung-Ho
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Wang, Yun-Ming
In search of a unique and reliable contrast agent targeting pancreatic adenocarcinoma, new multifunctional nanoparticles (MnMEIO-silane-NH2-(MUC4)-mPEG NPs) were successfully developed in this study. Mucin4-expression levels were determined through different imaging studies in a panel of pancreatic tumor cells (HPAC, BxPC-3, and Panc-1) both in vitro and in vivo studies. The in vitro T-2-weighted MR imaging study in HPAC and Panc-1 tumor cells treated with NPs showed -89.1 +/- 5.7% and -0.9 +/- 0.2% contrast enhancement, whereas in in vivo study, it is found to be -81.5 +/- 4.5% versus -19.6 +/- 5.2% (24 h postinjection, 7.0 T), respectively. The T-2-weighted MR and optical imaging studies revealed that the novel agent can specifically and effectively target to mucin4-expressing tumors in nude mice. Hence, it is suggested that MnMEIO-silane-NH2-(MUC4)-mPEG NPs are able to provide an efficient and targeted delivery of MUC4 antibodies to mucin4-expressing pancreatic tumors.
Extension of C-elegans lifespan using the center dot NO-delivery dinitrosyl iron complexes
(2018-07-01)
Huang, Hsiao-Wen
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Lin, Yen-Hung
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Lin, Min-Hsuan
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Huang, Ya-Rong
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Chou, Chih-Hung
The ubiquitous and emerging physiology function of endogenous nitric oxide in vascular, myocardial, immune, and neuronal systems prompts chemists to develop a prodrug for the controlled delivery of center dot NO in vivo and for the translational biomedical application. Inspired by the discovery of natural [Fe(NO)(2)] motif, herein, we develop the synthetic dinitrosyl iron complexes (DNICs) [Fe-2(mu-SR)(2)(NO)(4)] (1) as a universal platform for the O-2-triggered release of center dot NO, for the regulation of center dot NO-release kinetics (half-life = 0.6-27.4 h), and for the activation of physiological function of center dot NO. Using C. elegans as a model organism, the center dot NO-delivery DNIC 1 regulates IIS signaling pathway, AMPK signaling pathway, and mitochondrial function pathway to extend the lifespan and to delay the aging process based on the lifespan analysis, SA-beta gal activity assay, and next-generation RNA sequencing analysis. This study unveils the anti-aging effect of center dot NO and develops DNICs as a chemical biology probe for the continued discovery of unprecedented NO physiology. [GRAPHICS] .
Identification of Id1 as a downstream effector for arsenic-promoted angiogenesis via PI3K/Akt, NF-kappa B and NOS signaling
(2016-01-01)
Tsai, Chun-Hao
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Yang, Ming-Hui
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Hung, Amos C.
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Wu, Shou-Cheng
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Chiu, Wen-Chin
Exposure to arsenic is known to be a risk factor for various types of cancer. Apart from its carcinogenic activity, arsenic also shows promoting effects on angiogenesis, a crucial process for tumor growth. Yet, the mechanism underlying arsenic-induced angiogenesis is not fully understood. In this study, we aimed at investigating the involvement of inhibitor of DNA binding 1 (Id1) and the associated signal molecules in the arsenic-mediated angiogenesis. Our initial screening revealed that treatment with low concentrations of arsenic (0.5-1 mu M) led to multiple cellular responses, including enhanced endothelial cell viability and angiogenic activity as well as increased protein expression of Id1. The arsenic-induced angiogenesis was suppressed in the Id1-knocked down cells compared to that in control cells. Furthermore, arsenic-induced Id1 expression and angiogenic activity were regulated by PI3K/Akt, NF-kappa B, and nitric oxide synthase (NOS) signaling. In summary, our current data demonstrate for the first time that Id1 mediates the arsenic-promoted angiogenesis, and Id1 may be regarded as an antiangiogenesis target for treatment of arsenic-associated cancer.
Imaging specificity of MR-optical imaging agents following the masking of surface charge by poly(ethylene glycol)
(2013-05-01)
Wu, Shou-Cheng
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Lin, Kun-Liang
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Wang, Tzu-Pin
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Tzou, Shey-Cherng
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Singh, Gyan
The coupling of specific antibodies to imaging agents often improves imaging specificity. However, free amine groups designed for the coupling can cause nonspecific binding of the imaging agents. We report here development of a nanocarrier, MnMEIO-silane-NH2-mPEG nanoparticles (NPs), consisting of a manganese-doped iron oxide nanoparticle core (MnMEIO), a copolymer shell of silane and amine-functionalized poly(ethylene glycol) (silane-EA-mPEG). The key feature in MnMEIO-silane-NH2-mPEG is the flexible PEG, which masks the non-conjugated reactive amine groups (-NH2 <-> -NH3+) and reduces nonspecific binding of MnMEIO-silane-NH2-mPEG to cells. The amine groups on MnMEIO-silane-NH2-mPEG were conjugated with the fluorescent dye, Cy777 or antibodies [Erbitux (Erb)] to form a MR-optical imaging contrast agent (MnMEIO-silane-NH2-(Erb)-mPEG) for EGFR-expressing tumors. Confocal microscopic and flow cytometric analyses showed that MnMEIO-silane-NH2-(Erb)-mPEG displayed low nonspecific binding. Moreover, TEM images showed that MnMEIO-silane-NH2-(Erb)-mPEG were endocytosed by EGFR-expressing cells. In line with their EGFR expression levels, A431, PC-3, and Colo-205 tumors treated with MnMEIO-silane-NH2-(Erb)-mPEG NPs showed -97.1%, -49.7%, and -2.8% contrast enhancement, respectively, in in vitro T-2-weighted MR imaging. In vivo T-2-weighted MR imaging and optical images showed that MnMEIO-silane-NH2-(Erb)mPEG could specifically and effectively target to EGFR-expressing tumors in nude mice; the relative contrast enhancements were 7.94 (at 2 h) and 7.59 (at 24 h) fold higher in A431 tumors as compared to the EGFR-negative Colo-205 tumors. On the contrary, MnMEIO-silane-NH2-(Erb) NPs showed only 1.44 (at 2 h) and 1.52 (at 24 h) fold higher in EGFR-positive tumors as compared to the EGFR-negative tumors. Finally, antibodies can be readily changed to allow imaging of other tumors bearing different antigens. These data indicate that masking surface charges on contrast agents is a useful strategy to improve imaging efficacy. (c) 2013 Elsevier Ltd. All rights reserved.
In vitro and in vivo imaging of peroxynitrite by a ratiometric boronatebased fluorescent probe
(2017-05-15)
Palanisamy, Sathyadevi
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Wu, Pei-Yu
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Wu, Shou-Cheng
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Chen, Yu-Jen
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Tzou, Shey-Cherng
Peroxynitrite (ONOO-) is an important species involved in many physiopathological processes. Progresses have been made in developing novel fluorescent probes to detect peroxynitrite with relatively high sensitivity and specificity. Herein, we report the synthesis, characterization and biological applications of a new boronate-based fluorescent probe, 4-MB. The studies showed that 4-MB exhibits a dual ratiometric and calorimetric response toward peroxynitrite due to ONOO--triggered oxidative reaction. A possible mechanism of the oxidation reaction was proposed and the reaction product was isolated and characterized using different spectroscopic methods. We have thoroughly demonstrated the utility of 4-MB for intracellular peroxynitrite imaging. Further, we showed that 4-MB can be potentially employed to visualize exogenous and endogenous peroxynitrite in RAW264.7 macrophages, EAhy926 cells, zebrafish and in live tissues from a high-fat diet-induced obese mouse model.
Peptide-based MRI contrast agent and near-infrared fluorescent probe for intratumoral legumain detection
(2014-01-01)
Chen, Yu-Jen
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Wu, Shou-Cheng
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Chen, Chung-Yung
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Tzou, Shey-Cherng
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Cheng, Tian-Lu
Recent studies suggest that intratumoral legumain promotes tumorigenesis. To monitor legumain activity in tumors, we developed a new MM contrast agent ([Gd-NBCB-TTDA-Leg(L)]) and a NIR fluorescence probe (CyTE777-Leg(L)-CyTE807). The MRI contrast agent was prepared by introduction of cyclobutyl and benzyl group residues to TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triaza-dodecanedioic acid), followed by the attachment of a legumain-specific substrate peptide (Leg(L)). The NIR fluorescence probe was designed by conjugating two NIR fluorochromes (CyTE777 and CyTE807) with Leg(L). Peptide cleavage of the MM contrast agent by legumain can increase its hydrophobicity and promote rotational correlation time (tau(R)). Peptide cleavage of the NIR probes by the legumain relieves the self quench of the probe. Peptide cleavage of the MRI contrast agent and the NIR fluorescence probe by legumain were confirmed by T-1 relaxometric studies and by fluorescence studies, respectively. In vivo MR images showed that [Gd-NBCB-TTDA-Leg(L)] attained 55.3 fold (254.2% versus 4.6%, at 2.0 h post-injection) higher imaging enhancement, as compared with control contrast agent bearing a noncleaveable peptide ([Gd-NBCB-TTDA-Leg(D)], in the CT-26 (legumain(+)) tumors. Similarly, optical imaging probe CyTE777-Leg(L)-CyTE807 attained 15.2 fold (3.34 x 10(9) photons/min versus 0.22 x 10(9) photons/min, at 24.0 h post-injection) higher imaging enhancement in the CT-26 (legumain(+)) tumors, compared to a NIR control probe (CyTE777-Leg(D)-CyTE807). These data indicate that the [Gd-NBCB-TTDA-Leg(L)] and the CyTE777-Leg(L)-CyTE807 probes may be promising tools to image the legumain-expressing cancers for diagnoses and targeted treatments. (C) 2013 Elsevier Ltd. All rights reserved.
Reaction-based epoxide fluorescent probe for in vivo visualization of hydrogen sulfide
(2015-06-15)
Sathyadevi, Palanisamy
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Chen, Yu-Jen
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Wu, Shou-Cheng
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Chen, Yen-Hao
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Wang, Yun-Ming
Hydrogen sulfide (H2S) has emerged as the most important biosynthetic gasotransmitters along with nitric oxide (NO) and carbon monoxide (CO). In this study, we report the design and the synthesis of a new epoxide fluorescent probe 7-glycidyloxy-9-(2-glycidyloxycarbonylphenyl)-2-xanthone (FEPO) for use in in vivo visualization of hydrogen sulfide. The probe employs a fluorescein as a fluorophore, and is equipped with an operating epoxide unit. FEPO functions via epoxide ring opening upon nucleophilic attack of H2S. This ring opening strategy may open a new avenue for the development of various H2S fluorescent sensors. FEPO showed high selectivity and high sensitivity for H2S. FEPO\'s cytotoxicity was tested using MTT (2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide) assay. Furthermore, the use of confocal imaging of H2S and in vivo imaging in live zebra fish demonstrated FEPO\'s potential biological applications. We anticipate that, owing to their ideal properties, probes of this type will find great uses in exploring the role of H2S in biology. (C) 2015 Elsevier B.V. All rights reserved.
Water-Soluble Dinitrosyl Iron Complex (DNIC): a Nitric Oxide Vehicle Triggering Cancer Cell Death via Apoptosis
(2016-09-19)
Wu, Shou-Cheng
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Lu, Chung-Yen
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Chen, Yi-Lin
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Lo, Feng-Chun
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Wang, Ting-Yin
Nitric oxide (NO) is an important cellular signaling molecule that modulates various physiological activities. Angiogenesis-promoting activities of NO-donor drugs have been explored in both experimental and clinical studies. In this study, a structurally well characterized and water-soluble neutral {Fe-(NO)(2)}(9) DNIC [(S(CH2)(2)OH)(S(CH2)(2)NH3)Fe(NO)(2)] (DNIC 2) was synthesized to serve as a NO-donor species. The antitumor activity of DNIC 2 was determined by MTT assay, confocal imaging, and Annexin-V/PI staining. The IC50 values of DNIC 2 were 18.8, 42.9, and 38.6 mu M for PC-3, SKBR-3, and CRLS866 tumor cells, respectively. Moreover, DNIC 2 promoted apoptotic cell death via activation of apoptosis-associated proteins and inhibition of survival associated proteins. In particular, DNIC 2 treatment suppressed PC-3 tumor growth by 2.34- and 19.3-fold at 7 and 21 days, in comparison with the control group. These results indicate that water-soluble DNIC 2 may serve as a promising drug for cancer therapy.