- Protein triggered fluorescence switching of near-infrared emitting nanoparticles for contrast-enhanced imaging
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Sub-100 nm colloidal particles which are surface-functionalized with multiple environmentally-sensitive moieties have the potential to combine imaging, early detection, and the treatment of cancer with a single type of long-circulating nanodevice . Deep tissue imaging is achievable through the development of particles which are surface-modified with fluorophores that operate in the near-infrared (NIR) spectrum and where the fluorophore's signal can be maximized by turning-on the fluorescence only in the targeted tissue. We present a general approach for the synthesis of NIR emitting nanoparticles that exhibit a protein triggered activation/deactivation of the emission. Dispersing the particles into an aqueous solution, such as phosphate buffered saline (PBS), resulted in an aggregation of the hydrophobic fluorophores and a cessation of emission. The emission can be reinstated, or activated, by the conversion of the surface-attached fluorophores from an aggregate to a monomeric species with the addition of an albumin. This activated probe can be deactivated and returned to a quenched state by a simple tryptic digestion of the albumin. The methodology for emission switching offers a path to maximize the signal from the typically weak quantum yield inherent in NIR fluorophores.
- Jetty, Ragini,Bandera, Yuriy P.,Daniele, Michael A.,Hanor, David,Hung, Hsin-I.,Ramshesh, Venkat,Duperreault, Megan F.,Nieminen, Anna-Liisa,Lemasters, John J.,Foulger, Stephen H.
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Read Online
- Visible diode laser-induced fluorescence detection in liquid chromatography after precolumn derivatization of amines
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To fully exploit the attractive visible diode laser-induced fluorescence (LIF) detection technique in column liquid chromatography (LC), covalent labeling procedures need to be developed which are compatible with near-infrared fluorescence. For this purpose, several red-absorbing labels containing a single succinimidyl ester functionality were synthesized and used for the derivatization of primary and secondary amines. Oxazines/thiazines, squaraines, and dicarbocyanines were examined as redabsorbing fluorophores. The quality of the LC-diode LIF system for the analytes concerned is illustrated by the concentration detection limit of the labeled n-octylamine (a test compound), which was as low as 2 x 10-12 M. As expected in view of the limited reactivity of the succinimidyl ester group, the analyte concentrations required to obtain quantitative reaction with the label were equal to or higher than 2 x 10-8 M. To show the applicability of the method to biological samples, urine was spiked with 5 x 10-7 M 1-adamantanamine, extracted, derivatized with a dicarbocyanine-based label, and analyzed by LC-diode LIF.
- Mank,Van Der Laan,Lingeman,Goojjer,Brinkman,Velthorst
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Read Online
- Preparation and characterization of phospholipid-conjugated indocyanine green as a near-infrared probe
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We have rationally designed and synthesized a novel near-infrared (NIR) photoactivating probe, designated by iDOPE, in which an indocyanine green (ICG) fluorophore is covalently conjugated with a phospholipid moiety, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), to incorporate into liposome bilayers. NIR irradiation showed that iDOPE retained the optical and fluorescence properties of ICG and demonstrated photoactivator characteristics: fluorescence emission at around 820 nm in a solvent, singlet oxygen production, and concentration-dependent heat generation. Additionally, iDOPE was incorporated into liposome bilayers and maintained stable liposomally formulated iDOPE (LP-iDOPE) over 1 week under physiological conditions. We also observed the tumor-specific biodistribution of LP-iDOPE of in vivo xenografts. These findings suggest that LP-iDOPE might be a promising tool for NIR optical imaging, photodynamic therapy, and photothermal therapy.
- Suganami, Akiko,Toyota, Taro,Okazaki, Shigetoshi,Saito, Kengo,Miyamoto, Katsuhiko,Akutsu, Yasunori,Kawahira, Hiroshi,Aoki, Akira,Muraki, Yutaka,Madono, Tomoyuki,Hayashi, Hideki,Matsubara, Hisahiro,Omatsu, Takashige,Shirasawa, Hiroshi,Tamura, Yutaka
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Read Online
- Deuterated Indocyanine Green (ICG) with Extended Aqueous Storage Shelf-Life: Chemical and Clinical Implications
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Indocyanine Green (ICG) is a clinically approved near-infrared fluorescent dye that is used extensively for various imaging and diagnostic procedures. One drawback with ICG is its instability in water, which means that reconstituted clinical doses have to be used very shortly after preparation. Two deuterated versions of ICG were prepared with deuterium atoms on the heptamethine chain, and the spectral, physiochemical, and photostability properties were quantified. A notable mechanistic finding is that self-aggregation of ICG in water strongly favors dye degradation by a photochemical oxidative dimerization reaction that gives a nonfluorescent product. Storage stability studies showed that replacement of C?H with C?D decreased the dimerization rate constant by a factor of 3.1, and it is likely that many medical and preclinical procedures will benefit from the longer shelf-lives of these two deuterated ICG dyes. The discovery that ICG self-aggregation promotes photoinduced electron transfer can be exploited as a new paradigm for next-generation photodynamic therapies.
- Li, Dong-Hao,Smith, Bradley D.
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supporting information
p. 14535 - 14542
(2021/09/28)
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- Cyanine Nanocage Activated by Near-IR Light for the Targeted Delivery of Cyclosporine A to Traumatic Brain Injury Sites
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More than 2.8 million annually in the United States are afflicted with some form of traumatic brain injury (TBI), where 75% of victims have a mild form of TBI (MTBI). TBI risk is higher for individuals engaging in physical activities or involved in accidents. Although MTBI may not be initially life-threatening, a large number of these victims can develop cognitive and physical dysfunctions. These late clinical sequelae have been attributed to the development of secondary injuries that can occur minutes to days after the initial impact. To minimize brain damage from TBI, it is critical to diagnose and treat patients within the first or "golden" hour after TBI. Although it would be very helpful to quickly determine the TBI locations in the brain and direct the treatment selectively to the affected sites, this remains a challenge. Herein, we disclose our novel strategy to target cyclosporine A (CsA) into TBI sites, without the need to locate the exact location of the TBI lesion. Our approach is based on TBI treatment with a cyanine dye nanocage attached to CsA, a known therapeutic agent for TBI that is associated with unacceptable toxicities. In its caged form, CsA remains inactive, while after near-IR light photoactivation, the resulting fragmentation of the cyanine nanocage leads to the selective release of CsA at the TBI sites.
- Black, Caroline E.,Zhou, Eugene,Deangelo, Caitlin,Asante, Isaac,Yang, Rong,Petasis, Nicos A.,Louie, Stan G.,Humayun, Mark
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p. 4499 - 4509
(2021/01/01)
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- N-alkylated linear heptamethine polyenes as potent non-azole leads against Candida albicans fungal infections
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In this study, eighteen heptamethine dyes were synthesised and their antifungal activities were evaluated against three clinically relevant yeast species. The eighteen dyes were placed within classes based on their core subunit i.e. 2,3,3-trimethylindolenine (5a-f), 1,1,2-trimethyl-1H-benzo[e]indole (6a-f), or 2-methylbenzothiazole (7a-f). The results presented herein imply that the three families of cyanine dyes, in particular compounds 5a-f, show high potential as selective scaffolds to treat C. albicans infections. This opens up the opportunity for further optimisation and investigation of this class compounds for potential antifungal treatment.
- Critchley, Megan E.,Lawrence, Clare L.,McKenna, Sean T.,Okoh, Adeyi Okoh,Smith, Robert B.,Vishwapathi, Vinod
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supporting information
(2020/07/21)
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- Preparation method and application of heptamethine benzo indole cyanine dye
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The invention discloses a preparation method and application of a heptamethine benzo indole cyanine dye, and belongs to the field of polymethine indole cyanine dyes and preparation thereof. The methodcomprises the following steps: 1) carrying out a heating reaction on raw materials containing a 2,3,3-trimethyl-4,5-benzoindole derivative and a nucleophilic substituted compound under a vacuum condition to obtain an organic ammonium salt; and 2) carrying out a heating reaction on a solution containing the organic ammonium salt obtained in the step 1) and a cycloalkene derivative under a closed condition, wherein the structural formula of the heptamethine benzo indole cyanine dye is represented by a formula (I). According to the invention, the dye has near-infrared light absorption and fluorescence development performances and can be used as a probe auxiliary agent; and the method has the advantages of short synthesis route, environment-friendly solvent, simple process, avoidance of noblemetal catalysis, high yield, high product purity and the like, is high in applicability, and can be used for synthesizing products of various structure types.
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Paragraph 0170-0174
(2020/09/23)
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- Preparation method of heptamethine benzoindocyanine dye
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The invention discloses a preparation method of a heptamethine benzoindocyanine dye. The method at least comprises the following steps that a 2,3,3-trimethyl-4,5-benzindole derivative reacts with a nucleophilic substitution compound and re-crystallized to obtain organic ammonium salt; the organic ammonium salt, a cyclohexene derivative and a sodium acetate solution react with one another, the product is mixed with alcohol and ether, the mixture is extracted many times, and the heptamethine benzoindocyanine dye is obtained. The method is short in synthetic route, simple in process, free of catalysis of precious metal and high in yield, the extraction method is simple, chromatographic column separation is not needed, the solvent consumption is low, the preparation efficiency of the dye is greatly improved, and low-cost batch production can be achieved. The method has great significance in the aspects of production and application research of heptamethine benzoindocyanine. The prepared heptamethine benzoindocyanine dye contains an aliphatic chain substituted N structure, and has or independently has near-infrared light absorption and fluorescent development functions.
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Paragraph 0099-0103
(2019/06/27)
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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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Paragraph 0069-0070
(2019/11/19)
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- Heptamethine benzoindocyanine dye and preparation method and application thereof
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The invention discloses a heptamethine benzoindocyanine dye and a preparation method and application thereof. The heptamethine benzoindocyanine dye contains an aliphatic chain substituted N structure,and has or independently has near-infrared light absorption and fluorescent development functions. The preparation method is short in synthetic route, simple in process, free of catalysis of preciousmetal, high in yield and large in single reaction amount, the preparation efficiency of the dye is greatly improved, and low-cost batch production can be realized. The dye and the preparation methodhave great significance in the aspects of production and application research of heptamethine benzoindocyanine.
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Paragraph 0091-0095
(2019/06/27)
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- 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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- Monoamine oxidase A inhibitor indocyanine coupling compounds and preparation method and use thereof
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The invention belongs to the technical field of medicines and relates to monoamine oxidase A inhibitor indocyanine coupling compounds and a preparation method and use thereof. The preparation method comprises that an MAO-A inhibitor isoniazid and heptamethine indocyanine dye with excellent in-vivo fluorescence imaging characters and a tumor targeting function are bonded through an amide covalent bond according to the splicing principle so that the novel monoamine oxidase A inhibitor-indocyanine coupling compounds targeting tumors are obtained. The monoamine oxidase A inhibitor indocyanine coupling compounds have structural formulas (I) to (III). The in-vitro tumor cell growth inhibition test result shows that the compounds have good inhibitory effects on prostate tumor cells.
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Paragraph 0108; 0110; 0160; 0162; 0163; 0164
(2018/11/22)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF INDOCYANINE GREEN
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The present invention involves an improved process for the preparation of Indocyanine green of Formula (I) having high purity of about 99%, wherein the process comprises steps of reacting 1,1,2-trimethyl-1H-benzo[e]indole with 1,4-butane sulfone in boiling solvent to give 4-(1,1,2-trimethyl-1H-benzo[e]indolium-3-yl)butane-1-sulfonate. Followed by reacting 4-(1,1,2-trimethyl-1H-benzo[e]indolium-3-yl)butane-1-sulfonate of Formula (IV) and N-phenyl-N-((1E,3E,5E)-5-(phenylimino)penta-1,3-dienyl)acetamide of formula (V) in presence of sodium acetate and alcohol; and extracting the title compound formula (I) with an ester solvent.
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Page/Page column 9
(2017/09/02)
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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; 0033; 0034
(2017/07/01)
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- Fluorescent Probe for Imaging Lymph Nodes
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Disclosed is a near-infrared fluorescent imaging agent comprising an indocyanine-based fluorescent dye and a liposome. The near-infrared fluorescent imaging agent of the present invention demonstrates high fluorescence intensity and a long anchoring time in sentinel lymph nodes, thereby making it useful for detecting sentinel lymph nodes in sentinel lymph node navigation surgery. Also disclosed is an indocyanine green derivative that is particularly suitable for use in the near-infrared fluorescent imaging agent of the present invention.
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Paragraph 0058; 0059
(2016/08/29)
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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 0106; 0107; 0108
(2015/03/16)
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- Carbocyanines for G-Quadruplex DNA Stabilization and Telomerase Inhibition
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Cyanines which selectively bind to G-quadruplex DNA complexes, particularly quadruplexes expressed in cancer cells, and methods of making and using thereof are described herein. The cyanine can be a symmetrical or unsymmetrical streptocyanine, hemicyanine, closed chain cyanine, or combinations thereof. The cyanine is preferably substituted with one or more groups that minimize or prevent aggregation of the cyanine and/or inhibit binding of the cyanine to duplex DNA. One or more of the cyanines can be formulated with one or more pharmaceutical excipients and/or carrier to prepare pharmaceutical compositions suitable for administration to a patient, particular a human patient. The compounds and compositions described herein can be used to treat diseases or disorders characterized by the expression of G-quadruplex DNA, such as cancer.
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Paragraph 0314
(2014/05/25)
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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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p. 721 - 727
(2014/01/23)
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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 0056
(2014/08/20)
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- Fluorescent Probe for Imaging Lymph Nodes
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Disclosed is a near-infrared fluorescent imaging agent comprising an indocyanine-based fluorescent dye and a liposome. The near-infrared fluorescent imaging agent of the present invention demonstrates high fluorescence intensity and a long anchoring time in sentinel lymph nodes, thereby making it useful for detecting sentinel lymph nodes in sentinel lymph node navigation surgery. Also disclosed is an indocyanine green derivative that is particularly suitable for use in the near-infrared fluorescent imaging agent of the present invention.
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Paragraph 0060
(2013/06/04)
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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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supporting information; experimental part
p. 5175 - 5183
(2011/11/29)
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- Cyanine dyes as optical contrast agents for ophthalmological surgery
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Cyanine dyes were prepared as optical contrast media for supporting the surgery of the lamina limitans interna (LLI) of the retina and other structures of the human eye. Their absorption spectra were adapted both to the spectral sensitivity of the human eye and to standard illumination. The contrast could be further amplified by the application of the strong fluorescence of the dyes used. The binding of the dyes to various surfaces was studied. No toxic effects could be detected for the applied dyes.
- Langhals, Heinz,Varja, Ana,Laubichler, Peter,Kernt, Marcus,Eibl, Kirsten,Haritoglou, Christos
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experimental part
p. 3903 - 3925
(2011/07/31)
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- A New Method for the Synthesis of Heptamethine Cyanine Dyes: Synthesis of New Near-Infrared Fluorescent Labels
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A new uncatalyzed synthesis of heptamethine cyanine dyes is described.The reaction involves heating a mixture of N-alkyl-substituted quaternary salts derived from 2,3,3-trimethylindole or 2,3,3-trimethylbenzindole and 2-chloro-1-formyl-3-(hydroxymethylene)cyclohex-1-ene to reflux in a mixture of 1-butanol and benzene (7:3) as solvent.No catalyst is used, and water is removed as an azeotrope.The resulting chloro compounds possess strong absorption and fluorescence properties in the near-infrared region and are converted to dyes bearing reactive functionalities such as hydroxy and isothiocyanate groups useful as fluorescent tags for nucleic acids and proteins.Several symmetric and nonsymmetric dyes have been synthesized in high yields.
- Narayanan, Narasimhachari,Patonay, Gabor
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p. 2391 - 2395
(2007/10/02)
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- Visible diode laser induced fluorescence detection in liquid chromatography after precolumn derivatization of thiols
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New cyanine labels containing only a single active group for the chemical derivatization of thiols were synthesized in order to apply visible diode laser induced fluorescence (DIO-LIF) detection in conventional-size liquid chromatography (LC). 2-Mercaptobenzothiazole (MBT) was selected as test compound. The most appropriate label was CY5.4a-IA, a sulfonated dicarbocyanine with a iodoacetamide reactive group. The detection limit of labeled MBT in the LC-DIO-LIF system was 8 X 10-12 M. The detection limit of MBT was 1 × 10-9 M; lower concentrations are not labeled quantitatively. The injection repeatability was 1.0% (n = 6), the reaction repeatability was 3.0% (n = 6), and linearity was observed from 2.5 × 10-9 to 1.0 × 10-5 M. As an example, MBT-spiked river water and urine samples were derivatized with CY5.4a-IA and analyzed by LC-DIO-LIF. Hardly any interference was found. The method compares very favorably with existing techniques.
- Mank, Arjan J. G.,Molenaar, Ernst J.,Lingeman, Henk,Gooijer, Cees,Brinkman, Udo A. Th.,Velthorst, Nel H.
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p. 2197 - 2203
(2007/10/02)
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