Browsing by Author "Chen, Chiao-Yun"

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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.
A water soluble and fast response fluorescent turn-on copper complex probe for H2S detection in zebra fish
(2016-01-15)
Palanisamy, Sathyadevi
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Lee, Lu-Ying
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Wang, Yu-Liang
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Chen, Yu-Jen
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Chen, Chiao-Yun
According to the displacement method, herein we reported a water soluble copper complex [Cu(MaT-cyclen)(2)] as a fluorescent probe for the detection of H2S. For this, 1((1-(10-methylanthracen-9-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-1,4,7,10-tetraazacyclododecane (MaT-cyclen) was synthesized first To improve its solubility in aqueous media, sodium acetate group was introduced into 8-hydroxy-2-quinoline successfully. MaT-cyclen was chelated with Cu(II) to form [Cu(MaT-cyclen)2] complex, which displayed high sensitivity and selectivity for H2S over the other possible competitive substances on the basis of forming CuS. Meanwhile, [Cu(MaT-cyclen)(2)] displayed rapid response (< 1 min), well reversibility, lowest detection limit (205 nM), and high sensitivity for recognizing H2S in aqueous solution. Furthermore, its potential utility for biological applications was confirmed by fluorescence imaging of H2S in live cells as well as in zebra fish. (C) 2015 Elsevier B.V. All rights reserved.
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 novel thermal-sensitive multifunctional liposome with antibody conjugation to target EGFR-expressing tumors
(2019-01-01)
Liu, Kuan-Chieh
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Arivajiagane, Arundhathi
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Wu, Shang-Jung
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Tzou, Shey-Cherng
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Chen, Chiao-Yun
A novel EGFR-targeting, thermal-sensitive multifunctional liposome (TSML) was developed based on manganese-doped magnetismengineered iron oxide nanoparticles (MnMEIOs) and gold nanorods (AuNRs) for efficient photothermal therapy and magnetic resonance (MR) imaging. An Erbitux-conjugated TSML (Erb-TSML) was encapsulated with doxorubicin and gold nanorods conjugated with manganese-doped magnetism-engineered iron oxide nanoparticles, for theranostic applications of EGFR-positive tumors. The Erb-TSML selectively targeted EGFRpositive tumors and promoted tumor destruction by laser activation. Using confocal microscopy, MR and optical imaging, we demonstrated that Erb-TSML specifically bound to A431 tumor cells. No signs of major morphological damages to the normal tissues were observed in mice treated with Erb-TSMLand laser, indicating this theranostic platform protected heart against doxorubicin-induced toxicity to normal tissues. These results indicate that the Erb-TSML may be a promising diagnostic and therapeutic platform for EGFR-overexpressing tumors. (C) 2018 Elsevier Inc. All rights reserved.
Development of Bifunctional Gadolinium-Labeled Superparamagnetic Nanoparticles (Gd-MnMEIO) for In Vivo MR Imaging of the Liver in an Animal Model
(2016-02-17)
Kuo, Yu-Ting
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Chen, Chiao-Yun
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Liu, Gin-Chung
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Wang, Yun-Ming
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生物科技學系
Liver tumors are common and imaging methods, particularly magnetic resonance imaging (MRI), play an important role in their non-invasive diagnosis. Previous studies have shown that detection of liver tumors can be improved by injection of two different MR contrast agents. Here, we developed a new contrast agent, Gd-manganese-doped magnetism-engineered iron oxide (Gd-MnMEIO), with enhancement effects on both T1-and T2-weighted MR images of the liver. A 3.0T clinical MR scanner equipped with transmit/receiver coil for mouse was used to obtain both T1-weighted spoiled gradient-echo and T2-weighted fast spin-echo axial images of the liver before and after intravenous contrast agent injection into Balb/c mice with and without tumors. After pre-contrast scanning, six mice per group were intravenously injected with 0.1 mmol/kg Gd-MnMEIO, or the control agents, i.e., Gd-DTPA or SPIO. The scanning time points for T1-weighted images were 0.5, 5, 10, 15, 20, 25, and 30 min after contrast administration. The post-enhanced T2-weighted images were then acquired immediately after T1-weighted acquisition. We found that T1-weighted images were positively enhanced by both Gd-DTPA and Gd-MnMEIO and negatively enhanced by SPIO. The enhancement by both Gd-DTPA and Gd-MnMEIO peaked at 0.5 min and gradually declined thereafter. Gd-MnMEIO (like Gd-DTPA) enhanced T1-weighted images and (like SPIO) T2-weighted images. Marked vascular enhancement was clearly visible on dynamic T1-weighted images with Gd-MnMEIO. In addition, the T2 signal was significantly decreased at 30 min after administration of Gd-MnMEIO. Whereas the effects of Gd-MnMEIO and SPIO on T2-weighted images were similar (p = 0.5824), those of Gd-MnMEIO and Gd-DTPA differed, with Gd-MnMEIO having a significant T2 contrast effect (p = 0.0086). Our study confirms the feasibility of synthesizing an MR contrast agent with both T1 and T2 shortening effects and using such an agent in vivo. This agent enables tumor detection and characterization in single liver MRI sections.
[Gd(Try-TTDA)(H(2)O)](2-): A new MRI contrast agent for copper ion sensing
(2011-01-01)
Kasala, Dayananda
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Lin, Tsung-Sheng
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Chen, Chiao-Yun
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Liu, Gin-Chung
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Kao, Chai-Lin
In this study, we have developed two new L-tryptophan based contrast agents [Gd(Try-TTDA)(H(2)O)](2-) and [Gd(Try-ac-DOTA)(H(2)O)](-). Upon addition of Cu(II) to [Gd(Try-TTDA)(H(2)O)](2-), significant increases in the relaxivity (r(1)) and hydration number of [Gd(Try-TTDA)(H(2)O)](2-) were observed. However, it only induced a minute increase in the relaxivity (r(1)) in the case of [Gd(Try-ac-DOTA)(H(2)O)](-). Furthermore, the interaction of Cu(II) with the indole ring of Gd(III) complexes was explored by measuring the intrinsic fluorescence of the tryptophan of the Gd(III) complex. With the addition of one equivalent of Cu(II) to [Gd(Try-TTDA)(H(2)O)](2) the indole fluorescence was completely quenched. Moreover, the [Gd(Try-TTDA)(H(2)O)](2-) complex shows excellent selectivity towards Cu(II) over other metal ions (Cu(II) > La(III) > Mg(II)). Importantly, the significant signal intensity (2073 +/- 67) for in vitro MR imaging using [Gd(Try-TTDA)(H(2)O)](2-) in the presence of Cu(II) implicates that this new smart contrast agent ([Gd(Try-TTDA)(H(2)O)](2-)) can serve as a Cu(II) sensor for MR imaging.
[Gd(Try-TTDA)(H2O)](2-): A new MRI contrast agent for copper ion sensing
(2011-01-01)
Kasala, Dayananda
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Lin, Tsung-Sheng
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Chen, Chiao-Yun
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Liu, Gin-Chung
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Kao, Chai-Lin
In this study, we have developed two new L-tryptophan based contrast agents [Gd(Try-TTDA)(H2O)](2-) and [Gd(Try-ac-DOTA)(H2O)](-). Upon addition of Cu(II) to [Gd(Try-TTDA)(H2O)](2-), significant increases in the relaxivity (r(1)) and hydration number of [Gd(Try-TTDA)(H2O)](2-) were observed. However, it only induced a minute increase in the relaxivity (r(1)) in the case of [Gd(Try-ac-DOTA)(H2O)](-). Furthermore, the interaction of Cu(II) with the indole ring of Gd(III) complexes was explored by measuring the intrinsic fluorescence of the tryptophan of the Gd(III) complex. With the addition of one equivalent of Cu(II) to [Gd(Try-TTDA)(H2O)](2) the indole fluorescence was completely quenched. Moreover, the [Gd(Try-TTDA)(H2O)](2-) complex shows excellent selectivity towards Cu(II) over other metal ions (Cu(II) > La(III) > Mg(II)). Importantly, the significant signal intensity (2073 +/- 67) for in vitro MR imaging using [Gd(Try-TTDA)(H2O)](2-) in the presence of Cu(II) implicates that this new smart contrast agent ([Gd(Try-TTDA)(H2O)](2-)) can serve as a Cu(II) sensor for MR imaging.
Humanized bispecific antibody (mPEG x HER2) rapidly confers PEGylated nanoparticles tumor specificity for multimodality imaging in breast cancer
(2020-08-27)
Cheng, Yi-An
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Wu, Tung-Ho
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Wang, Yun-Ming
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Cheng, Tian-Lu
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Chen, I-Ju
Background: Developing a universal strategy to improve the specificity and sensitivity of PEGylated nanoaparticles (PEG-NPs) for assisting in the diagnosis of tumors is important in multimodality imaging. Here, we developed the anti-methoxypolyethylene glycol (mPEG) bispecific antibody (BsAb; mPEG x HER2), which has dual specificity for mPEG and human epidermal growth factor receptor 2 (HER2), with a diverse array of PEG-NPs to confer nanoparticles with HER2 specificity and stronger intensity. Result: We used a one-step formulation to rapidly modify the nanoprobes with mPEG x HER2 and optimized the modified ratio of BsAbs on several PEG-NPs (Lipo-DiR, SPIO, Qdot and AuNP). The alpha HER2/PEG-NPs could specifically target MCF7/HER2 cells (HER2(++)) but not MCF7/neo1 cells (HER2(+/-)). The alpha HER2/Lipo-DiR and alpha HER2/SPIO could enhance the sensitivity of untargeted PEG-NPs on MCF7/HER2 (HER2(++)). In in vivo imaging, alpha HER2/Lipo-DiR and alpha HER2/SPIO increased the specific targeting and enhanced PEG-NPs accumulation at 175% and 187% on 24 h, respectively, in HER2-overexpressing tumors. Conclusion: mPEG x HER2, therefore, provided a simple one-step formulation to confer HER2-specific targeting and enhanced sensitivity and contrast intensity on HER2 positive tumors for multimodality imaging.
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 Nitroxyl with Copper Fluorescent Probe in Living Cells and Zebrafish
(2018-10-01)
Palanisamy, Sathyadevi
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Wang, Yu-Liang
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Chen, Yu-Jen
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Chen, Chiao-Yun
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Tsai, Fu-Te
Nitroxyl (HNO) plays a critical role in many physiological processes which includes vasorelaxation in heart failure, neuroregulation, and myocardial contractility. Powerful imaging tools are required to obtain information for understanding the mechanisms involved in these in vivo processes. In order to develop a rapid and high sensitive probe for HNO detection in living cells and the zebrafish model organism, 2-((2-(benzothiazole-2yl)benzylidene) amino)benzoic acid (AbTCA) as a ligand, and its corresponding copper(II) complex Cu(II)-AbTCA were synthesized. The reaction results of Cu(II)-AbTCA with Angeli's salt showed that Cu(II)-AbTCA could detect HNO quantitatively in a range of 40-360 mu M with a detection limit of 9.05 mu M. Furthermore, Cu(II)-AbTCA is more selective towards HNO over other biological species including thiols, reactive nitrogen, and reactive oxygen species. Importantly, Cu(II)-AbTCA was successfully applied to detect HNO in living cells and zebrafish. The collective data reveals that Cu(II)-AbTCA could be used as a potential probe for HNO detection in living systems.
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.
In vivo magnetic resonance imaging of mice liver tumors using a new gadolinium-based contrast agent
(2013-05-01)
Chen, Shih-Hsien
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Kuo, Yu-Ting
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Cheng, Tian-Lu
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Chen, Chiao-Yun
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Chiu, Yen-Yu
We compared the enhancement effect between a newly synthesized tissue-specific contrast agent, [Gd-DOTA-FP beta G], and a commercially available agent, [Gd(DOTA)](-), in a murine model of liver tumor using a clinical magnetic resonance imaging scanner. The colon cancer cell lines with and without beta-glucuronidase (beta G) expression were implanted into the liver of mice. Self-synthesized gadolinium-based magnetic resonance contrast agent, [Gd(DOTA-FP beta G)], was administered to measure enhancement on magnetic resonance images using a commercially available agent, [Gd(DOTA)](-), as control in a clinical 3.0 tesla (T) magnetic resonance scanner. In vivo fluorescence imaging and histopathology of the liver were also performed to compare and correlate with the magnetic resonance studies. The in vivo fluorescence imaging failed to depict a sufficiently intense signal for liver or liver tumor of mice without exposure of the liver following an incision on the abdominal wall. The tissue-specific magnetic resonance agent, [Gd(DOTA-FP beta G)], caused significantly stronger enhancement in tumors expressing beta G (CT26/m beta G-eB7) than in tumors not expressing beta G (CT26) (p < 0.05). In the magnetic resonance imaging studies using control agent [Gd(DOTA)](-), the tumors with and without beta G expression depicted no significant difference in enhancement on the T1-weighted images. The [Gd(DOTA-FP beta G)] also provided significantly more contrast uptake in the CT26/m beta G-eB7 tumor than in the normal liver parenchyma, whereas the [Gd(DOTA)](-) did not. This study confirms that better contrast enhancement can be readily detected in vivo by the use of a tissue-specific magnetic resonance contrast agent to target tumor cells with specific biomarkers in a clinical magnetic resonance imaging scanner. Copyright (c) 2012, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
In vivo MR/optical imaging for gastrin releasing peptide receptor of prostate cancer tumor using Gd-TTDA-NP-BN-Cy5.5
(2011-02-01)
Lin, Ying-Hsiu
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Dayananda, Kasala
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Chen, Chiao-Yun
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Liu, Gin-Chung
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Luo, Tsai-Yueh
Magnetic resonance imaging (MRI) has become the leading imaging tool for providing fine anatomical and physiology details. Optical imaging is offering a sensitive and specific method for in vivo molecular imaging of targeting molecules. The goal of this study is to design, synthesize, and characterize a new target-specific dual contrast agent for MR and optical imaging. Hence, [Gd(TTDA-NP)(H(2)O)](2-) was prepared and characterized. In addition, an 8-amino acid Bombesin analogue (BN) peptide substrate, which can target prostate, breast, and colon cancer, was synthesized by solid-phase peptide synthesis and subsequently conjugated with [Gd(TTDA-NP)(H(2)O)](2-) to form BN conjugated Gd-TTDA-NP-BN. The water-exchange rate (ke(ex)(298)) for [Gd(TTDA-NP)(H(2)O)](2-) (110 x 10(6) s(-1)) is significantly higher than that of [Gd(DTPA) (H(2)O)](2-) complex and the rotational correlation time (tau(R)) for [Gd(TTDA-NP)(H(2)O)](2-) (145 ps) is also higher than those of [Gd(TTDA)(H(2)O)](2-) (104 ps) and [Gd(DTPA)(H(2)O)](2-) (103 ps). The Gd-TTDA-NP-BN shows remarkable high relaxivity (7.12 mM(-1) s(-1)) comparing to that of [Gd(TTDA-NP)(H(2)O)](2-). The fluorescence studies showed that the Gd-TTDA-NP-BN could efficiently enter PC-3 cells. Additionally, the human cancer cells xenografts using Gd-TTDA-NP-BN-Cy5.5 as an optical imaging probe clearly visualized subcutaneous PC-3 tumor and demonstrated its targeting ability to the gastrin releasing peptide (GRP) receptor overexpression. Furthermore, the biodistribution studies demonstrated significantly high tumor uptake (25.97 +/- 1.07% ID/g) and high tumor-to-normal tissue ratios at one hour post-injection of Gd-TTDA-NP-BN-Cy5.5 in the animal model. These results suggest that the Gd-1TDA-NP-BN-Cy5.5 is a superior probe for in vivo optical imaging. Importantly, the MR imaging studies showed notable signal enhancement (44.9 +/- 4.2%) on the tumor, indicating a high level accumulation of the contrast agent within the PC-3 tumor sites. Hence, targeting of prostate cancer cells was observed under in vitro and in vivo MR imaging studies using Gd-TTDA-NP-BN contrast agent. We conclude that Gd-TTDA-NP-BN and Gd-TTDA-NP-BN-Cy5.5 can be potentially used as the contrast agents for targeting GRP receptor oyerexpressing cells and tumors. (C) 2010 Elsevier Ltd. All rights reserved.
Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H(2)O)](2-) Derivatives
(2011-02-21)
Chang, Ya-Hui
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Chen, Chiao-Yun
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Singh, Gyan
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Chen, Hsing-Yin
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Liu, Gin-Chung
The present study was designed to exploit optimum lipophilicity and high water-exchange rate (k(ex)) on low molecular weight Gd(III) complexs to generate high bound relaxivity (r(1)(b)), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-) both display high stability constant (log K(GdL) = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K((Gd/Zn)) = 4.22) and Bz-CB-TTDA (log K((Gd/Zn)) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K((Gd/Zn)) = 2.93), EPTPA-bz-NO(2) (log K((Gd/Zn)) = 3.19), and DTPA (log K((Gd/Zn)) = 3.76). However, the stability constant values of [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-) are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature (17)O NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 x 10(6) s(-1) for [Gd(CB-TTDA)(H(2)O)](2-) and 271 x 10(6) s(-1) for [Gd(Bz-CB-TTDA)(H(2)O)](2-). They are higher than those of [Gd(TTDA)(H(2)O)](2-) (146 x 10(6) s(-1)), [Gd(DTPA)(H(2)O)](2-) (4.1 x 10(6) s(-1)), and MS-325 (6.1 x 10(6) s(-1)). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-). In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of [Gd(Bz-CB-TTDA)(H(2)O)](2-). The binding affinity of [Gd(Bz-CB-TTDA)(H(2)O)](2-) to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K(A)) for [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-) are 1.1 x 10(2) and 1.5 x 10(3), respectively. Although the K(A) value for [Gd(Bz-CB-TTDA)(H(2)O)](2-) is lower than that of MS-325 (K(A) = 3.0 x 10(4)), the r(1)(b) value, r(1)(b) = 66.7 mM(-1) s(-1) for [Gd(Bz-CB-TTDA)(H(2)O)](2-), is significantly higher than that of MS-325 (r(1)(b) = 47.0 mM(-1) s(-1)). As measured by the Zn(II) transmetalation process, the kinetic stabilities of [Gd(CB-TTDA)(H(2)O)](2-), [Gd(Bz-CB-TTDA)(H(2)O)](2-), and [Gd(DTPA)(H(2)O)](2-) are similar and are significantly higher than that of [Gd(DTPA-BMA)(H(2)O)](2-) High thermodynamic and kinetic stability and optimized lipophilicity of [Gd(CB-TTDA)(H(2)O)](2-) make it a favorable blood pool contrast agent for MRI.
Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H2O)](2-) Derivatives
(2011-02-21)
Chang, Ya-Hui
;
Chen, Chiao-Yun
;
Singh, Gyan
;
Chen, Hsing-Yin
;
Liu, Gin-Chung
The present study was designed to exploit optimum lipophilicity and high water-exchange rate (k(ex)) on low molecular weight Gd(III) complexs to generate high bound relaxivity (r(1)(b)), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) both display high stability constant (log K-GdL = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K-(Gd/Zn) = 4.22) and Bz-CB-TTDA (log K-(Gd/Zn) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K-(Gd/Zn) = 2.93), EPTPA-bz-NO2 (log K-(Gd/Zn) = 3.19), and DTPA (log K-(Gd/Zn) = 3.76). However, the stability constant values of [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature O-17 NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 x 10(6) s(-1) for [Gd(CB-TTDA)(H2O)](2-) and 271 x 10(6) s(-1) for [Gd(Bz-CB-TTDA)(H2O)](2-). They are higher than those of [Gd(TTDA)(H2O)](2-) (146 x 10(6) s(-1)), [Gd(DTPA)(H2O)](2-) (4.1 x 10(6) s(-1)), and MS-325 (6.1 x 10(6) s(-1)). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-). In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of [Gd(Bz-CB-TTDA)(H2O)](2-). The binding affinity of [Gd(Bz-CB-TTDA)(H2O)](2-) to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K-A) for [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) are 1.1 x 10(2) and 1.5 x 10(3), respectively. Although the K-A value for [Gd(Bz-CB-TTDA)(H2O)](2-) is lower than that of MS-325 (K-A = 3.0 x 10(4)), the r(1)(b) value, r(1)(b) = 66.7 mM(-1) s(-1) for [Gd(Bz-CB-TTDA)(H2O)](2-), is significantly higher than that of MS-325 (r(1)(b) = 47.0 mM(-1) s(-1)). As measured by the Zn(II) transmetalation process, the kinetic stabilities of [Gd(CB-TTDA)(H2O)](2-), [Gd(Bz-CB-TTDA)(H2O)](2-), and [Gd(DTPA)(H2O)](2-) are similar and are significantly higher than that of [Gd(DTPA-BMA)(H2O)](2-) High thermodynamic and kinetic stability and optimized lipophilicity of [Gd(CB-TTDA)(H2O)](2-) make it a favorable blood pool contrast agent for MRI.
Targeted Herceptin-dextran iron oxide nanoparticles for noninvasive imaging of HER2/neu receptors using MRI
(2009-02-01)
Chen, Ting-Jung
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Cheng, Tsan-Hwang
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Chen, Chiao-Yun
;
Hsu, Sodio C. N.
;
Cheng, Tian-Lu
A novel magnetic resonance imaging (MRI) contrast agent containing Herceptin is reported. The surfaces of superparamagnetic iron oxide nanoparticles were modified with dextran and conjugated with Herceptin (Herceptin-nanoparticles) to improve their dispersion, magnetization, and targeting of the specific receptors on cells. From analytical results, we found that Herceptin nanoparticles were well dispersed in solutions of various pH range, and had no hysteresis, high saturation magnetization ( 80 emu/g), and low cytotoxicity to a variety of cells. Notably, the magnetic resonance enhancements for the different breast cancer cell lines (BT-474, SKBR-3, MDA-MB-231, and MCF-7) are proportional to the HER2/neu expression level in vitro. When Herceptin-nanoparticles were administered to mice bearing breast tumor allograft by intravenous injection, the tumor site was detected in T(2)-weighted magnetic resonance images as a 45% enhancement drop, indicating a high level of accumulation of the contrast agent within the tumor sites. Therefore, targeting of cancer cells was observed by in vitro and in vivo MRI studies using Herceptin-nanoparticles contrast agent. In addition, Herceptin-nanoparticles enhancing the magnetic resonance signal intensity were sufficient to detect the cell lines with a low level of HER2/neu expression.
Targeted RGD nanoparticles for highly sensitive in vivo integrin receptor imaging
(2012-01-01)
Lin, Ren-Yen
;
Dayananda, Kasala
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Chen, Ting-Jung
;
Chen, Chiao-Yun
;
Liu, Gin-Chung
A new magnetic resonance imaging (MRI) contrast bearing RGD peptide is reported. In this study, ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles with various sizes were prepared. Particles sizes between 6 and 13?nm were tuned by varying the stirring rate. Remarkable negative contrast was observed because USPIO nanoparticles (13.1?+/-?2.1?nm) generated high transversal relaxivity r2 (188?+/-?3?m m-1?s-1) and saturation magnetization (94?emu?g-1 Fe). The USPIO nanoparticles were coated with PDA [2-(pyridyldithio)-ethylamine; PDA nanoparticles] containing functional polymer, which can be readily synthesized by Michael addition. The PDA nanoparticles were conjugated with RGD peptide (RGD nanoparticles) for targeting the specific site. The target specificity and high relaxivity allowed RGD nanoparticles to differentiate the expression level of integrin receptor on several cell lines and tumors (MCF-7, A-549, HT-29 and HT-1080) by in vitro and in vivo MR imaging. Importantly, a remarkable negative contrast (-51.3?+/-?6.7%) was observed for in vivo MR imaging of MCF-7 tumor. This result implies that the RGD nanoparticles that greatly enhance the MR imaging are highly sensitive for early stage tumor detection. Copyright (c) 2012 John Wiley & Sons, Ltd.
Ultrasensitive Electrical Detection of Follicle-Stimulating Hormone Using a Functionalized Silicon Nanowire Transistor Chemosensor
(2018-10-24)
Lee, Mucian
;
Palanisamy, Sathyadevi
;
Zhou, Bin-Hou
;
Wang, Li-Yu
;
Chen, Chiao-Yun
The follicle-stimulating hormone (FSH) is a hormone that belongs to a family of glycoprotein hormones. Determination of FSH can help in interpreting various factors that include physiology of the reproductive system, fertility maintenance, and identification or treatment of reproductive disorders. Sialic acids are derivatives of neuraminic acids with negative charges, present at the end of the sugar chains and further linked to the cell surfaces and glycoproteins. The direct measurement of FSH in a human body can be recorded by developing a sensor probe that responds particularly to sialic acids over the other hormones. However, existing diagnostic methods still suffer from many difficulties in terms of complicated handling techniques, expensive instrumentation, etc. Development of accurate, rapid, and low-cost FSH detection chemosensors is important to meet these demands. Herein, we utilized a novel sensing method for accurate and fast FSH detection using a metal-oxide semiconductor silicon nanowire field effect transistor (SiNW-FET) device. This is the first report to demonstrate the boronic acid-functionalized SiNW-FET device in FSH detection. FSH detection has been successfully determined using an assay buffer solution with 0.72 fM detection limit as well as using 20% serum with 1.1. fM detection limit. We also investigated the specificity with other gonadotropins/glycosylated serum proteins. The current measurements on FSH concentrations at different time intervals were also studied. The sensitive, cheap, and miniaturized SiNW-FET device can serve as an effective sensing approach for rapid screening of FSH and menopause diagnosis.