- Synthetic probes for in vitro purification and in vivo tracking of hepatocytes derived from human pluripotent stem cells
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Hepatocytes derived from human pluripotent stem cells (hPSCs) are promising candidates for cell therapy and drug discovery. However, it remains challenging to efficiently purify hepatocytes from undesired cell types after differentiation and to accurately monitor grafted cells after transplantation. Indocyanine Green (ICG), an FDA-approved, near-infrared (NIR) dye, has been used for various clinical purposes and is exclusively taken up by hepatocytes. However, ICG has a long emission wavelength (λem > 800 nm) that is beyond the detection range of fluorescence-activated cell sorting (FACS) systems. Moreover, it is easily eliminated from hepatocytes, hindering its application for NIR imaging. Here, we designed and synthesized two different probes based on the properties of ICG; 1) hepatocyte purifying agent (HPA, λem = 562 nm) for in vitro sorting and 2) hepatocyte imaging agent (HIA, λem = 817 nm) for efficient in vivo NIR imaging. We obtained highly enriched populations of hPSC-derived hepatocytes (hPSC-Heps) from various hPSC lines using HPA probe-based FACS purification. In addition, HIA labelling and NIR imaging allowed the direct visualization and tracking of grafted hPSC-Heps in animals with liver injuries. These results demonstrated that these two probes could be used as powerful tools with hPSC-Heps in both cell replacement therapy and drug screening.
- Park, Ji Young,Han, Jiyou,Jung, Hyo Sung,Lee, Gyunggyu,Kim, Hyo Jin,Cho, Gun-Sik,Park, Han-Jin,Han, Choongseong,Kim, Jong Seung,Kim, Jong-Hoon
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- Synthesis, fluorescence and biodistribution of a bone-targeted near-infrared conjugate
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Enhanced imaging of early-stage bone abnormalities, such as primary tumors or metastases is highly required as the widely-used bone scan frequently lacks the desired sensitivity. Near IR (NIR) fluorescence imaging affords high contrast and enhanced sensitivity, as body tissue expresses minimal autofluorescence at NIR range (600-1200 nm). Indocyanine green (ICG), a biocompatible NIR dye, is widely used in the imaging of various organs, such as liver, heart and blood circulation. We report the preparation and in-vivo testing of a bone-targeting ICG derivative, in comparison to the parent molecule(s). Since ICG itself is chemically unreactive, and could not form conjugates, we prepared two novel ICG conjugatable derivatives. The overall ICG structure was maintained while only a replacement of one or two sulfonate groups with carboxylic acids resulted in new linkers for covalent binding to biomolecules. These derivatives were evaluated for their fluorescence and biodistribution in comparison to ICG and were found to be comparable. One of the novel ICG-derivatives was conjugated to a bone-targeting moiety and this new compound was found to bind to growing regions of the skeleton, and emit fluorescence for as long as two weeks in young mice.
- Mizrahi, Dana M.,Ziv-Polat, Ofra,Perlstein, Benny,Gluz, Eran,Margel, Shlomo
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- Design, synthesis, and evaluation of monoamine oxidase A inhibitors–indocyanine dyes conjugates as targeted antitumor agents
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Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates combining the MAOA inhibitor isoniazid (INH) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds G1–G13 were evaluated in vitro for their cytotoxicity against PC-3 cells using the MTT assay, and molecular docking studies were performed. Results showed that most tested compounds exhibited improved antitumor efficacy compared with INH. Moreover, conjugates G10 and G11 showed potent anticancer activity with IC50 values (0.85 and 0.4 μM respectively) comparable to that of doxorubicin (DOX). This may be attributable to the preferential accumulation of these conjugates in tumor cells. G10, G11, and G12 also demonstrated moderate MAOA inhibitory activities. This result and the results of molecular docking studies were consistent with their cytotoxicity activities. Taken together, these data suggest that a combination of the MAOA inhibitor INH with tumor-targeting heptamethine cyanine dyes may prove to be a highly promising tool for the treatment of advanced prostate cancer.
- Yang, Xiao-Guang,Mou, Yan-Hua,Wang, Yong-Jun,Wang, Jian,Li, Yan-Yu,Kong, Rui-Heng,Ding, Meng,Wang, Dun,Guo, Chun
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- Near-infrared-fluorescence imaging of lymph nodes by using liposomally formulated indocyanine green derivatives
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Liposomally formulated indocyanine green (LP-ICG) has drawn much attention as a highly sensitive near-infrared (NIR)-fluorescence probe for tumors or lymph nodes in vivo. We synthesized ICG derivatives tagged with alkyl chains (ICG-Cn), and we examined NIR-fluorescence imaging for lymph nodes in the lower extremities of mice by using liposomally formulated ICG-Cn (LP-ICG-Cn) as well as conventional liposomally formulated ICG (LP-ICG) and ICG. Analysis with a noninvasive preclinical NIR-fluorescence imaging system revealed that LP-ICG-Cn accumulates in only the popliteal lymph node 1 h after injection into the footpad, whereas LP-ICG and ICG accumulate in the popliteal lymph node and other organs like the liver. This result indicates that LP-ICG-Cn is a useful NIR-fluorescence probe for noninvasive in vivo bioimaging, especially for the sentinel lymph node.
- Toyota, Taro,Fujito, Hiromichi,Suganami, Akiko,Ouchi, Tomoki,Ooishi, Aki,Aoki, Akira,Onoue, Kazutaka,Muraki, Yutaka,Madono, Tomoyuki,Fujinami, Masanori,Tamura, Yutaka,Hayashi, Hideki
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- PROCESS FOR THE PREPARATION OF SODIUM 4-(2-((1E,3E,5E,7Z)-7-(1,1-DIMETHYL-3-(4-SULFONATOBUTYL)-1H-BENZO[e]INDOL-2(3H)-YLIDENE) HEPTA-1,3,5-TRIENYL)-1,1-DIMETHYL-1H-BENZO[e]INDOLIUM-3-YL) BUTANE-1-SULFONATE (INDOCYANINE GREEN)
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A process for the preparation of substantially pure Indocyanine green of formula with purity greater than 99.0% is provided. More particularly, the embodiments relate to the process for the preparation of Indocyanine green of formula and its intermediates thereof. It further provides crystalline form I of Indocyanine green of formula and process thereof.
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- Indocyanine green derivative and preparaiton method
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The invention discloses an indocyanine green derivative and a preparaiton method. The indocyanine green derivative has the structure shown in the formula a (the formula is shown in the description). In the formula a, R1 is C1-C10 linear or branched alkyl or cycloalkyl or substituted cycloalkyl or aryl or substituted aryl with or without heteroatoms; R2 is -NH2 or -COOH or _COOCH3 or -COOEt or -OH;R3 is a metal cation. Independent active groups exist in the indocyanine green derivative so that a biological material can easily modify indocyanine green and the indocyanine green derivative, and the application range of the ndocyanine green and the indocyanine green derivative is expanded.
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Paragraph 0035; 0045; 0053; 0054; 0055
(2018/07/30)
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- Indocyanine green, and preparation method and application thereof
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The invention provides indocyanine green, and a preparation method and application thereof. The indocyanine green is shown as formula 1. The method is performed according to a path recorded in the specification. According to the path, 2, 3, 3-trimethyl-4, 5-benzoindoles, 1, 4-butyl sultone and 2-glutarate diphenylamine hydrochloride, as raw materials, are compounded into the indocyanine green shown as the target compound formula 1. The method has a short compounding path, simple process and high yield, does not need heavy metal catalysis, and meets requirements of 'green chemical' development.
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Paragraph 0030-0032; 0035; 0036
(2017/07/01)
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- SKELETAL REMOVAL OF BISPHOSPHONATES
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Disclosed herein are methods and compositions for removing or displacing bisphosphonates in skeletal tissue.
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- Discrete PEG Based Dyes
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Disclosed are discrete PEGylated dyes, that is, dyes, generally ones that are fluorescent, but could also include chemi-luminescent or electrochemiluminescent and related dye or dye precursors, that have discrete PEG constructs chemically attached in various configurations on the dye, and in the entire range of constructs, discrete PEG compounds (polyethylene glycol oligomers that are made synthetically according to methods disclosed in U.S. Pat. No. 7,888,536 and US Pub. No. 2013/0052130). The dyes are modified in a range of ways to control or optimize the properties of water solubility, non-specific binding (in vitro), biodistribution (in vivo), cell internalization (non-cell or cell based assays in vitro, and in vivo diagnostics and therapy), as well as aggregation.
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Paragraph 0109; 0110; 0111
(2015/03/16)
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- LIPOSOME COMPOSITE BODY
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An object of the present invention is to provide a drug delivery system capable of sustainedly releasing a drug noninvasively at any given point in time. The present invention relates to a liposome complex comprising a liposome membrane-constituting substance bonded to a light-absorbing compound having an absorption wavelength in the near-infrared region, selected from the group consisting of indocyanine green dyes, phthalocyanine dyes, squarylium dyes, croconium dyes, and diimmonium dyes.
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Paragraph 0057
(2014/08/20)
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