Publications by authors named "Maged Henary"

72 Publications

Developments of small molecules as inhibitors for carbonic anhydrase isoforms.

Bioorg Med Chem 2021 Apr 16;39:116140. Epub 2021 Apr 16.

Department of Chemistry, 100 Piedmont Avenue SE, Georgia State University, Atlanta, GA 30303, USA; Center for Diagnostics and Therapeutics, 100 Piedmont Avenue SE, Georgia State University, Atlanta, GA 30303, USA. Electronic address:

Carbonic anhydrases are ubiquitous, and their role in the hydration of carbon dioxide is essential for the survival of many tissues and organs. However, their association with many pathological diseases, especially in glaucoma, Alzheimer's, obesity, epilepsy, and tumorigenesis, has prompted the design and synthesis of novel carbonic anhydrase inhibitors (CAIs). Herein we describe (1) approaches used in the design of CAIs and (2) synthesis of small molecules as CAIs within the last five years. Despite the active research in this area, there are still more avenues to explore, especially selective inhibition of CA I, CA IX, and XII. These isoforms would continue to open up a diversity of carbonic anhydrase inhibitors containing 1,2,3-triazoles, imidazolone, pyrrolidone, thiadiazole, isatin, and glycoconjugates as part of their molecular frameworks.
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http://dx.doi.org/10.1016/j.bmc.2021.116140DOI Listing
April 2021

Synthesis and Applications of Selected Fluorine-Containing Fluorophores.

Molecules 2021 Feb 22;26(4). Epub 2021 Feb 22.

Department of Chemistry, Petit Science Center, Georgia State University, 100 Piedmont Avenue SE, Atlanta, GA 30303, USA.

The synthesis of fluorine-containing small molecules has had numerous benefits of improving the quality and efficiency of many applications of these compounds. For example, fluorine adds promising functionalities in various areas of imaging (MRI, PET, and NIR); gives cell-targeting properties; and has demonstrated improvements in cell permeability, solubility, and other pharmacologic properties. For these and other numerous reasons, fluorination of molecules has grown in popularity in various fields of chemistry. Many reports show the effects observed from increasing the number of fluorine atoms on a fluorophore scaffold. This report will cover the most significant applications and improvements that fluorine has contributed to in various dye scaffolds such as BODIPY, rhodamine, phthalocyanine, and cyanine in the recent decade.
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http://dx.doi.org/10.3390/molecules26041160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927054PMC
February 2021

Improved pentamethine cyanine nanosensors for optoacoustic imaging of pancreatic cancer.

Sci Rep 2021 Feb 23;11(1):4366. Epub 2021 Feb 23.

Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA.

Optoacoustic imaging is a new biomedical imaging technology with clear benefits over traditional optical imaging and ultrasound. While the imaging technology has improved since its initial development, the creation of dedicated contrast agents for optoacoustic imaging has been stagnant. Current exploration of contrast agents has been limited to standard commercial dyes that have already been established in optical imaging applications. While some of these compounds have demonstrated utility in optoacoustic imaging, they are far from optimal and there is a need for contrast agents with tailored optoacoustic properties. The synthesis, encapsulation within tumor targeting silica nanoparticles and applications in in vivo tumor imaging of optoacoustic contrast agents are reported.
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http://dx.doi.org/10.1038/s41598-021-83658-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902650PMC
February 2021

Donor acceptor fluorophores: synthesis, optical properties, TD-DFT and cytotoxicity studies.

Org Biomol Chem 2021 03;19(8):1835-1846

Department of Chemistry, Petit Science Center, Georgia State University, 100 Piedmont Avenue SE, Atlanta, Georgia 30303, USA. and Center of Diagnostics and Therapeutics, Petit Science Center, Georgia State University, 100 Piedmont Avenue SE, Atlanta, Georgia 30303, USA.

Donor-π-acceptor (D-π-A) fluorophores consisting of a donor unit, a π linker, and an acceptor moiety have attracted attention in the last decade. In this study, we report the synthesis, characterization, optical properties, TD-DFT, and cytotoxicity studies of 17 near infrared (NIR) D-π-A analogs which have not been reported so far to the best of our knowledge. These fluorophores have chloroacrylic acid as the acceptor unit and various donor units such as indole, benzothiazole, benzo[e]indole, and quinoline. The fluorophores showed strong absorption in the NIR (700-970 nm) region due to their enhanced intramolecular charge transfer (ICT) between chloroacrylic acid and the donor moieties connected with the Vilsmeier-Haack linker. The emission wavelength maxima of the fluorophores were in between 798 and 870 nm. Compound 20 with a 4-quinoline donor moiety showed an emission wavelength above 1000 nm in the NIR II window. The synthesized fluorophores were characterized by 1H NMR and 13C NMR, and their optical properties were studied. Time dependent density functional theory (TD-DFT) calculations showed that the charge transfer occurs from the donor groups (indole, benzothiazole, benzo[e]indole, and quinoline) to the acceptor chloroacrylic acid moiety. Fluorophores with [HOMO] to [LUMO+1] transitions were shown to possess a charge separation character. The cytotoxicity of selected fluorophores, 4, 7, 10 and 12 was investigated against breast cancer cell lines and they showed better activity than the anti-cancer agent docetaxel.
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http://dx.doi.org/10.1039/d0ob02313bDOI Listing
March 2021

Small Molecules for Multi-Wavelength Near-Infrared Fluorescent Mapping of Regional and Sentinel Lymph Nodes in Colorectal Cancer Staging.

Front Oncol 2020 17;10:586112. Epub 2020 Dec 17.

Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.

Assessing lymph node (LN) status during tumor resection is fundamental for the staging of colorectal cancer. Current guidelines require a minimum of 12 LNs to be harvested during resection and ultra-staging regional lymph nodes by sentinel lymph node (SLN) assessment is being extensively investigated. The current study presents novel near-infrared (NIR) fluorescent dyes for simultaneous pan lymph node (PanLN; regional) and SLN mapping. PanLN-Forte was intravenously injected in mice and assessed for accumulation in regional LNs. SLN800 was injected intradermally in mice, after which the collection and retention of fluorescence in SLNs were measured using indocyanine green (ICG) and its precursor, SLN700, as references. LNs in the cervical, inguinal, jejunal, iliac, and thoracic basins could clearly be distinguished after a low dose intravenous injection of PanLN-Forte. Background fluorescence was significantly lower compared to the parent compound ZW800-3A (p < 0.001). SLN700 and SLN800 specifically targeted SLNs with fluorescence being retained over 40-fold longer than the current clinically used agent ICG. Using SLN700 and SLN800, absolute fluorescence in SLN was at least 10 times higher than ICG in second-tier nodes, even at 1 hour post-injection. Histologically, the fluorescent signal localized in the LN medulla (PanLN-Forte) or sinus entry (SLN700/SLN800). PanLN-Forte and SLN800 appear to be optimal for real-time NIR fluorescence imaging of regional and SLNs, respectively.
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http://dx.doi.org/10.3389/fonc.2020.586112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774022PMC
December 2020

Cyanine Dyes Containing Quinoline Moieties: History, Synthesis, Optical Properties, and Applications.

Chemistry 2021 Mar 29;27(13):4230-4248. Epub 2020 Dec 29.

Department of Chemistry, Petit Science Center, Georgia State University, 100 Piedmont Avenue SE, Atlanta, GA, 30303, USA.

Cyanine dyes carrying quinoline moieties are an important class of organic molecules that are of great interest for applications in many fields like medicine, pharmacology, and engineering. Despite their exceptional properties, such as stability, high molar extinction coefficients, and high pH-sensitivity, this class of dyes has been less analyzed and reviewed in the last few decades. Therefore, this review article focuses on discussing the history of quinoline compounds, various synthetic routes to prepare quinolinium salts and symmetrical and asymmetrical mono-, di-, tri-, penta- and heptamethine cyanine dyes, containing quinoline moieties, together with their optical properties and applications as photosensitizers in photodynamic therapy, probes in biomolecules for labeling of nucleic acids, as well as imaging agents.
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http://dx.doi.org/10.1002/chem.202003697DOI Listing
March 2021

Ultrabright and Serum-Stable Squaraine Dyes.

J Med Chem 2020 09 19;63(17):9436-9445. Epub 2020 Aug 19.

Department of Chemistry, Georgia State University, 145 Piedmont Avenue SE, Atlanta, Georgia 30303, United States.

Highly stable symmetric and asymmetric squaraine fluorophores have been synthesized featuring an internal salt bridge between a quaternary ammonium cation and the central oxycyclobutenolate ring of the chromophore. Some of our newly synthesized symmetric and asymmetric compounds display increased molar absorptivity, quantum yield in serum, and thermal/photochemical stability over previously reported squaraine-based dyes. Consequently, both classes show great promise in resurfacing the normal environment-labile squaraine dyes as novel imaging agents and scaffolds for fluorescence sensing. Furthermore, incorporating a covalent attachment point away from the conjugated system allows for biological tagging applications without disturbing the optimum optical characteristics of the newly designed fluorophore.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00617DOI Listing
September 2020

DNA Photocleavage in the Near-Infrared Wavelength Range by 2-Quinolinium Dicarbocyanine Dyes.

Molecules 2020 Jun 25;25(12). Epub 2020 Jun 25.

Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.

Here, we report the syntheses of two pentamethine cyanine dyes containing quinolinium rings and substituted with either hydrogen () or bromine () at the carbon. The electron withdrawing bromine atom stabilizes dye in aqueous buffer, allowing complex formation to occur between the dye and double-helical DNA. UV-visible, CD, and fluorescence spectra recorded at low DNA concentrations suggest that dye initially binds to the DNA as a high-order aggregate. As the ratio of DNA to dye is increased, the aggregate is converted to monomeric and other low-order dye forms that interact with DNA in a non-intercalative fashion. The brominated dye is relatively unreactive in the dark, but, under 707-759 nm illumination, generates hydroxyl radicals that cleave DNA in high yield (pH 7.0, 22 °C). Dye is also taken up by ES2 ovarian carcinoma cells, where it is non-toxic under dark conditions. Upon irradiation of the ES2 cells at 694 nm, the brominated cyanine reduces cell viability from 100 ± 10% to 14 ± 1%. Our results suggest that 2-quinolinium-based carbocyanine dyes equipped with stabilizing electron withdrawing groups may have the potential to serve as sensitizing agents in long-wavelength phototherapeutic applications.
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http://dx.doi.org/10.3390/molecules25122926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355653PMC
June 2020

Chemical Modulation of Bioengineered Exosomes for Tissue-Specific Biodistribution.

Adv Ther (Weinh) 2019 Nov 13;2(11). Epub 2019 Sep 13.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

The physicochemical properties of nanomaterials play a key role in tissue-specific targeting by reducing nonspecific background uptake as well as controlling biodistribution and clearance. Due to the strong influence of surface chemistry, chemical modulation of bioinert exosomes with chargeable and traceable small molecule fluorophores has a significant effect on the targeting, stability, and toxicity of the final conjugates. In this study, charge-variable exosomes are designed by conjugating their surface proteins with near-infrared fluorophores to control the in vivo fate of exosomes. Interestingly, zwitterionic fluorophore-labeled exosomes show rapid renal clearance with minimum to none nonspecific tissue uptake, whereas anionic exosomes are excreted through the hepatobiliary route with high uptake in the liver. The biodistribution and pharmacokinetics of exosome conjugates are comparable to their corresponding free fluorophores, demonstrating that the surface characteristics govern the fate of final conjugates in the living organism. Such unique surface properties of chemically modulated exosomes are confirmed in the lymphatic system after intradermal administration, which results in distinctive kinetic profiles in the secondary lymphoid tissues. This finding can subsequently serve as the foundation for developing tissue-specific exosome-based therapeutics.
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http://dx.doi.org/10.1002/adtp.201900111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172497PMC
November 2019

Rapid and Selective Targeting of Heterogeneous Pancreatic Neuroendocrine Tumors.

iScience 2020 Apr 25;23(4):101006. Epub 2020 Mar 25.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Design of tissue-specific contrast agents to delineate tumors from background tissues is a major unmet clinical need for ultimate surgical interventions. Bioconjugation of fluorophore(s) to a ligand has been mainly used to target overexpressed receptors on tumors. However, the size of the final targeted ligand can be large, >20 kDa, and cannot readily cross the microvasculature to meet the specific tissue, resulting in low targetability with a high background. Here, we report a small and hydrophilic phenoxazine with high targetability and retention to pancreatic neuroendocrine tumor. This bioengineered fluorophore permits sensitive detection of ultrasmall (<0.5 mm) ectopic tumors within a few seconds after a single bolus injection, highlighting every tumor in the pancreas from the surrounding healthy tissues with reasonable half-life. The knowledge-based approach and validation used to develop structure-inherent tumor-targeted fluorophores have a tremendous potential to improve treatment outcome by providing definite tumor margins for image-guided surgery.
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http://dx.doi.org/10.1016/j.isci.2020.101006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139119PMC
April 2020

Single photon DNA photocleavage at 830 nm by quinoline dicarbocyanine dyes.

Chem Commun (Camb) 2019 Oct;55(84):12667-12670

Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.

We have synthesized symmetrical carbocyanine dyes in which two 4-quinolinium rings are joined by a pentamethine bridge that is meso-substituted with H or Cl. Irradiation of the halogenated dye at 830 nm produces hydroxyl radicals that generate DNA direct strand breaks. This represents the first reported example of DNA photocleavage upon single photon excitation of a chromophore at wavelengths above 800 nm.
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http://dx.doi.org/10.1039/c9cc04751dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953408PMC
October 2019

Second Generation G-Quadruplex Stabilizing Trimethine Cyanines.

Bioconjug Chem 2019 10 26;30(10):2647-2663. Epub 2019 Sep 26.

Department of Chemistry , Georgia State University , Petit Science Center, 100 Piedmont Ave SE. Atlanta Georgia 30303 , United States.

G-Quadruplex DNA has been recognized as a highly appealing target for the development of new selective chemotherapeutics, which could result in markedly reduced toxicity toward normal cells. In particular, the cyanine dyes that bind selectively to G-quadruplex structures without targeting duplex DNA have attracted attention due to their high amenability to structural modifications that allows fine-tuning of their biomolecular interactions. We have previously reported pentamethine and symmetric trimethine cyanines designed to effectively bind G-quadruplexes through end stacking interactions. Herein, we are reporting a second generation of drug candidates, the asymmetric trimethine cyanines. These have been synthesized and evaluated for their quadruplex binding properties. Incorporating a benz[,]indolenine heterocyclic unit increased overall quadruplex binding, and elongating the alkyl length increases the quadruplex-to-duplex binding specificity.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032661PMC
October 2019

Squaraine Dyes: Molecular Design for Different Applications and Remaining Challenges.

Bioconjug Chem 2020 02 12;31(2):194-213. Epub 2019 Aug 12.

Department of Chemistry, Petit Science Center , Georgia State University , 100 Piedmont Avenue SE , Atlanta , Georgia 30303 , United States.

Squaraine dyes are a class of organic dyes with strong and narrow absorption bands in the near-infrared. Despite high molar absorptivities and fluorescence quantum yields, these dyes have been less explored than other dye scaffolds due to their susceptibility to nucleophilic attack. Recent strategies in probe design including encapsulation, conjugation to biomolecules, and new synthetic modifications have seen squaraine dyes emerging into the forefront of biomedical imaging and other applications. Herein, we provide a concise overview of (1) the synthesis of symmetrical and unsymmetrical squaraine dyes, (2) the relationship between structure and photophysical properties of squaraine dyes, and (3) current applications of squaraine dyes in the literature. Given the recent successes at overcoming the limitations of squaraine dyes, they show high potential in biological imaging, in photodynamic and photothermal therapies, and as molecular sensors.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845514PMC
February 2020

Calculated vibrational properties of semiquinones in the A binding site in photosystem I.

Biochim Biophys Acta Bioenerg 2019 09 12;1860(9):699-707. Epub 2019 Jul 12.

Department of Physics and Astronomy, Georgia State University, Atlanta, GA, United States of America. Electronic address:

Time-resolved (P700A - P700A) FTIR difference spectra have been obtained using photosystem I (PSI) particles with several different quinones incorporated into the A protein binding site. Difference spectra were obtained for PSI with unlabeled and O labeled phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone) and 2-methyl-1,4-naphthaquinone (2MNQ) incorporated, and for PSI with unlabeled 2,3-dimethyl-1,4-naphthoquinone (DMNQ) incorporated. (O - O), (2MNQ - PhQ) and (DMNQ - PhQ) FTIR double difference spectra were constructed from the difference spectra. These double difference spectra allow one to more easily distinguish protein and pigment bands in convoluted difference spectra. To further aid in the interpretation of the difference spectra, particularly the spectra associated with the semiquinones, we have used two-layer ONIOM methods to calculate corresponding difference and double difference spectra. In all cases, the experimental and calculated double difference spectra are in excellent agreement. In previous two and three-layer ONIOM calculations it was not possible to adequately simulate multiple difference and double difference spectra. So, the computational approach outlined here is an improvement over previous calculations. It is shown that the calculated spectra can vary depending on the details of the molecular model that is used. Specifically, a molecular model that includes several water molecules that are near the incorporated semiquinones is required.
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http://dx.doi.org/10.1016/j.bbabio.2019.07.003DOI Listing
September 2019

Lysosome-Targeted Bioprobes for Sequential Cell Tracking from Macroscopic to Microscopic Scales.

Adv Mater 2019 Apr 10;31(14):e1806216. Epub 2019 Feb 10.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

Longitudinal tracking of living cells is crucial to understanding the mechanism of action and toxicity of cell-based therapeutics. To quantify the presence of administered cells in the host tissue without sacrifice of animals, labeling of the target cells with a nontoxic and stable contrast agent is a prerequisite. However, such long-term live cell tracking is currently limited by the lack of fluorophores with steady optical and physicochemical properties in the near-infrared (NIR) window. Herein, for the first time, the design of fixable cell-tracking NIR fluorophores (CTNFs) with high optical properties, excellent cell permeation and retention, and high stability against chemical treatments is reported. Efficient cellular labeling and tracking of CTNFs using intraoperative optical fluorescence imaging by following the fate of NIR-labeled cells from the time of injection into animals to ex vivo cellular analysis after resection of the target tissue is demonstrated. Due to the lipophilic cationicity and primary amine docking group, CTNF126 outperforms the other tested fluorophores with rapid diffusion into the cytoplasmic membrane and sequestration inside the lysosomes, which prevents cellular efflux and improves cellular retention. Thus, CTNF126 will be useful to track cells in living organisms for the mechanism of action at the single cell level.
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http://dx.doi.org/10.1002/adma.201806216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6574216PMC
April 2019

Defining the epigenetic status of blood cells using a cyanine-based fluorescent probe for PRMT1.

Blood Adv 2018 11;2(21):2829-2836

Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL.

Dynamic regulation of histone modification enzymes such as PRMT1 (protein arginine methyltransferase 1) determines the ordered epigenetic transitions in hematopoiesis. Sorting cells according to the expression levels of histone modification enzymes may further define subpopulations in hematopoietic lineages with unique differentiation potentials that are presently defined by surface markers. We discovered a vital near infrared dye, E84, that fluoresces brightly following binding to PRMT1 and excitation with a red laser. The staining intensity as measured by flow cytometry is correlated with the PRMT1 expression level. Importantly, E84 staining has no apparent negative effect on the proliferation of the labeled cells. Given that long-term hematopoietic stem cells (LT-HSCs) produce low levels of PRMT1, we used E84 to sort LT-HSCs from mouse bone marrow. We found that SLAM (the signalling lymphocyte activation molecule family) marker-positive LT-HSCs were enriched in the E84 cell fraction. We then performed bone marrow transplantations with E84 or E84 LinSca1Kit (LSK) cells and showed that whole blood cell lineages were successfully reconstituted 16 weeks after transplanting 200 E84 LSK cells. Thus, E84 is a useful new tool to probe the role of PRMT1 in hematopoiesis and leukemogenesis. Developing E84 and other small molecules to label histone modification enzymes provides a convenient approach without modifying gene loci to study the interaction between hematopoietic stem/progenitor cell epigenetic status and differentiation state.
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http://dx.doi.org/10.1182/bloodadvances.2018020727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234380PMC
November 2018

Small Molecule Optoacoustic Contrast Agents: An Unexplored Avenue for Enhancing In Vivo Imaging.

Molecules 2018 Oct 25;23(11). Epub 2018 Oct 25.

Department of Chemistry, 100 Piedmont Avenue SE, Georgia State University, Atlanta, GA 30303, USA.

Almost every variety of medical imaging technique relies heavily on exogenous contrast agents to generate high-resolution images of biological structures. Organic small molecule contrast agents, in particular, are well suited for biomedical imaging applications due to their favorable biocompatibility and amenability to structural modification. PET/SPECT, MRI, and fluorescence imaging all have a large host of small molecule contrast agents developed for them, and there exists an academic understanding of how these compounds can be developed. Optoacoustic imaging is a relatively newer imaging technique and, as such, lacks well-established small molecule contrast agents; many of the contrast agents used are the same ones which have found use in fluorescence imaging applications. Many commonly-used fluorescent dyes have found successful application in optoacoustic imaging, but others generate no detectable signal. Moreover, the structural features that either enable a molecule to generate a detectable optoacoustic signal or prevent it from doing so are poorly understood, so design of new contrast agents lacks direction. This review aims to compile the small molecule optoacoustic contrast agents that have been successfully employed in the literature to bridge the information gap between molecular design and optoacoustic signal generation. The information contained within will help to provide direction for the future synthesis of optoacoustic contrast agents.
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http://dx.doi.org/10.3390/molecules23112766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278390PMC
October 2018

Introduction of various substitutions to the methine bridge of heptamethine cyanine dyes Via substituted dianil linkers.

Photochem Photobiol Sci 2018 Oct;17(10):1409-1416

Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.

The unique optical properties of cyanine dyes have prompted their use in numerous applications. Heptamethine cyanines are commonly modified on the methine bridge after synthesis of a meso-chlorine containing cyanine. Herein, a series of heptamethine cyanines containing modified methine bridges were synthesized using substituted dianil linkers. Their optical properties including, molar absorptivity, fluorescence, and quantum yield were measured as well as their hydrophobic effects in polar buffer solution. It was shown that dyes containing cyclopentene in the methine bridge or a phenyl ring in the meso position display increased molar absorptivity while the increased flexibility of the dye containing a cycloheptene in the methine bridge prevented fluorescence.
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http://dx.doi.org/10.1039/c8pp00218eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193477PMC
October 2018

Synthesis and Optical Properties of Near-Infrared meso-Phenyl-Substituted Symmetric Heptamethine Cyanine Dyes.

Molecules 2018 Jan 24;23(2). Epub 2018 Jan 24.

Department of Chemistry, Georgia State University, 50 Decatur St., Atlanta, GA 30303, USA.

Heptamethine cyanine dyes are a class of near infrared fluorescence (NIRF) probes of great interest in bioanalytical and imaging applications due to their modifiability, allowing them to be tailored for particular applications. Generally, modifications at the -position of these dyes are achieved through Suzuki-Miyaura C-C coupling and S1 nucleophilic substitution of the chlorine atom at the -position of the dye. Herein, a series of 15 phenyl-substituted heptamethine cyanines was synthesized utilizing a modified dianil linker. Their optical properties, including molar absorptivity, fluorescence, Stokes shift, and quantum yield were measured. The HSA binding affinities of two representative compounds were measured and compared to that of a series of trimethine cyanines previously synthesized by our lab. The results indicate that the binding of these compounds to HSA is not only dependent on hydrophobicity, but may also be dependent on steric interferences in the binding site and structural dynamics of the NIRF compounds.
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http://dx.doi.org/10.3390/molecules23020226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017188PMC
January 2018

Synthesis, optical properties and cytotoxicity of meso-heteroatom substituted IR-786 analogs.

Bioorg Med Chem Lett 2018 02 6;28(3):509-514. Epub 2017 Dec 6.

Department of Chemistry, Georgia State University, United States; Center for Diagnostics and Therapeutics, Petit Science Center, 100 Piedmont Ave SE, Atlanta, GA 30303, United States. Electronic address:

Eight near-infrared heptamethine cyanines have been successfully synthesized based on IR 786 with oxygen, sulfur and amine moieties at the central position. These dyes show diverse optical properties resulting from different substitutions. Particularly, the heptamethine dyes with amine moieties have larger Stokes shifts and higher quantum yields of fluorescence. We also investigated these dyes for tumor cell cytotoxicity using cell viability and in vitro proliferation assays. Two of the compounds showed high cytotoxicity against PC-3 cancer cells.
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http://dx.doi.org/10.1016/j.bmcl.2017.12.001DOI Listing
February 2018

Synthesis and Optical Properties of Pentamethine Cyanine Dyes With Carboxylic Acid Moieties.

Anal Chem Insights 2017 30;12:1177390117711938. Epub 2017 May 30.

Department of Chemistry, Georgia State University, Atlanta, GA, USA.

Cyanine dyes possessing carboxylic acid groups have been used in many different fields of study. The acid groups can act as handles for bioconjugation or as metal chelators. Several pentamethine cyanine dyes with propionic acid handles were synthesized and their optical properties were studied to determine their usefulness as fluorescent probes. The optical properties studies performed include the absorbance and emission maxima values as well as the calculation of quantum yield and molecular brightness levels. Molecular models were also calculated to help analyze the dyes' behavior and were compared with similar dyes with varying alkyl chain lengths replacing the acid moieties.
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http://dx.doi.org/10.1177/1177390117711938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457140PMC
May 2017

Intraoperative Near-Infrared Fluorescence Imaging of Thymus in Preclinical Models.

Ann Thorac Surg 2017 Apr 10;103(4):1132-1141. Epub 2016 Dec 10.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Curadel, LLC, Marlborough, Massachusetts; Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Electronic address:

Background: There are currently no thymus-specific contrast agents for biomedical imaging. Thus, finding ectopic thymic tissue during certain operations is extremely difficult. The purpose of the present study was to determine if near-infrared (NIR) fluorescence imaging could provide high sensitivity, real-time identification of thymic tissue during the operation.

Methods: After initial in vivo screening of a 315-compound NIR fluorophore library for thymic uptake, methylene blue and five different 700-nm emitting candidate molecules were injected into CD-1 mice for quantitation of the signal-to-background ratio as a function of kinetics and dosing. Results were confirmed in 35-kg Yorkshire pigs. Dual-channel NIR imaging was also performed using a variety of 800-nm emitting NIR fluorophores targeted to various tissues in the mediastinum and neck.

Results: The compound Oxazine 170 demonstrated the highest signal-to-background ratio (≥3) for thymic tissue relative to mediastinal fat, heart, lung, muscle, thyroid gland, and parathyroid gland, with peak signal-to-background ratio occurring 4 h after 1 intravenous injection of a human equivalent dose of approximately 7 mg. Simultaneous dual-channel NIR imaging permitted unambiguous identification of the thymus from surrounding tissues, such as endocrine glands and lymph nodes.

Conclusions: In mouse and pig, NIR fluorescence imaging using Oxazine 170 permits high sensitivity, real-time identification of thymic tissue for surgical procedures requiring its resection or avoidance. The performance of Oxazine 170 for imaging human thymic tissue is currently not known.
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http://dx.doi.org/10.1016/j.athoracsur.2016.09.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376245PMC
April 2017

Site-Specific In Vivo Bioorthogonal Ligation via Chemical Modulation.

Adv Healthc Mater 2016 10 29;5(19):2510-2516. Epub 2016 Aug 29.

Gordon Center for Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

A critical limitation of bioorthogonal click chemistry for in vivo applications has been its low reaction efficiency due to the pharmacokinetic barriers, such as blood distribution, circulation, and elimination in living organisms. To identify key factors that dominate the efficiency of click chemistry, here a rational design of near-infrared fluorophores containing tetrazine as a click moiety is proposed. Using trans-cyclooctene-modified cells in live mice, it is found that the in vivo click chemistry can be improved by subtle changes in lipophilicity and surface charges of intravenously administered moieties. By controlling pharmacokinetics, biodistribution, and clearance of click moieties, it is proved that the chemical structure dominates the fate of in vivo click ligation.
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http://dx.doi.org/10.1002/adhm.201600574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541365PMC
October 2016

Tissue-Specific Near-Infrared Fluorescence Imaging.

Acc Chem Res 2016 09 26;49(9):1731-40. Epub 2016 Aug 26.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts 02114, United States.

Near-infrared (NIR) fluorescence light has been widely utilized in clinical imaging by providing surgeons highly specific images of target tissue. The "NIR window" from 650 to 900 nm is especially useful due to several special features such as minimal autofluorescence and absorption of biomolecules in tissue, as well as low light scattering. Compared with visible wavelengths, NIR fluorescence light is invisible, thus allowing highly sensitivity real-time image guidance in human surgery without changing the surgical field. The benefit of using NIR fluorescence light as a clinical imaging technology can be attributed to its molecular fluorescence as an exogenous contrast agent. Indeed, whole body preoperative imaging of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) remains important in diagnostic utility, but they lack the efficacy of innocuous and targeted NIR fluorophores to simultaneously facilitate the real-time delineation of diseased tissue while preserving vital tissues. Admittedly, NIR imaging technology has been slow to enter clinical use mostly due to the late-coming development of truly breakthrough contrast agents for use with current imaging systems. Therefore, clearly defining the physical margins of tumorous tissue remains of paramount importance in bioimaging and targeted therapy. An equally noteworthy yet less researched goal is the ability to outline healthy vital tissues that should be carefully navigated without transection during the intraoperative surgery. Both of these paths require optimizing a gauntlet of design considerations to obtain not only an effective imaging agent in the NIR window but also high molecular brightness, water solubility, biocompatibility, and tissue-specific targetability. The imaging community recognizes three strategic approaches which include (1) passive targeting via the EPR effect, (2) active targeting using the innate overall biodistribution of known molecules, and (3) activatable targeting through an internal stimulus, which turns on fluorescence from an off state. Recent advances in nanomedicine and bioimaging offer much needed promise toward fulfilling these stringent requirements as we develop a successful catalog of targeted contrast agents for illuminating both tumors and vital tissues in the same surgical space by employing spectrally distinct fluorophores in real time. These tissue-specific contrast agents can be versatile arsenals to physicians for real-time intraoperative navigation as well as image-guided targeted therapy. There is a versatile library of tissue-specific fluorophores available in the literature, with many discussed herein, which offers clinicians an array of possibilities that will undoubtedly improve intraoperative success and long-term postoperation prognosis.
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http://dx.doi.org/10.1021/acs.accounts.6b00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776714PMC
September 2016

Endocrine-specific NIR fluorophores for adrenal gland targeting.

Chem Commun (Camb) 2016 Aug;52(67):10305-8

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA and Gordon Center for Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

The adrenal glands (AGs) are relatively small yet require definitive identification during their resection, or more commonly their avoidance. To enable image-guided surgery involving the AGs, we have developed novel near-infrared (NIR) fluorophores that target the AGs after a single intravenous injection, which provided dual-NIR image-guided resection or avoidance of the AGs during both open and minimally-invasive surgery.
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http://dx.doi.org/10.1039/c6cc03845jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982771PMC
August 2016

Nile Red and Nile Blue: Applications and Syntheses of Structural Analogues.

Chemistry 2016 Sep 13;22(39):13764-13782. Epub 2016 Jul 13.

Department of Chemistry, Georgia State University, Atlanta, GA, 30302, USA.

Nile red and Nile blue are highly fluorescent and photostable organic dyes from the benzo[a]phenoxazine family. They have been used as histological stains for imaging lysosomes and lipids in vitro. The dyes' high quantum yields and solvent-dependent optical properties make them ideal scaffolds for the development of pH probes and local polarity indicators. Reviews of the literature in this area are scarce with only one review ever published in 2006. It has been 10 years since and the field has evolved. This review aims to expand upon topics covered by the previous reviewers and to report on recent advances in the literature. As authors, we hope to convey a sense of scope and to spark renewed interest in this useful niche of dye chemistry.
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http://dx.doi.org/10.1002/chem.201601570DOI Listing
September 2016

Near-Infrared Illumination of Native Tissues for Image-Guided Surgery.

J Med Chem 2016 06 19;59(11):5311-23. Epub 2016 May 19.

Center for Diagnostics and Therapeutics, Center for Biotechnology and Drug Design, Department of Chemistry, Georgia State University , Petit Science Center, 100 Piedmont Ave SE, Atlanta, Georgia 30303, United States.

Our initial efforts to prepare tissue-specific near-infrared (NIR) fluorescent compounds generated successful correlation between physicochemical properties and global uptake in major organs after systemic circulation and biodistribution. Herein, we focus on the effects on biodistribution based on modulating electronic influencing moieties from donating to withdrawing moieties at both the heterocyclic site and through meso-substitution of pentamethine cyanine fluorophores. These selected modifications harnessed innate biodistribution pathways through the structure-inherent targeting, resulting in effective imaging of the adrenal glands, pituitary gland, lymph nodes, pancreas, and thyroid and salivary glands. These native-tissue contrast agents will arm surgeons with a powerful and versatile arsenal for intraoperative NIR imaging in real time.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733074PMC
June 2016

Benz[c,d]indolium-containing Monomethine Cyanine Dyes: Synthesis and Photophysical Properties.

Molecules 2015 Dec 24;21(1):E23. Epub 2015 Dec 24.

Department of Chemistry, Georgia State University, 50 Decatur St., Atlanta, GA 30303, USA.

Asymmetric monomethine cyanines have been extensively used as probes for nucleic acids among other biological systems. Herein we report the synthesis of seven monomethine cyanine dyes that have been successfully prepared with various heterocyclic moieties such as quinoline, benzoxazole, benzothiazole, dimethyl indole, and benz[e]indole adjoining benz[c,d]indol-1-ium, which was found to directly influence their optical and energy profiles. In this study the optical properties vs. structural changes were investigated using nuclear magnetic resonance and computational approaches. The twisted conformation unique to monomethine cyanines was exploited in DNA binding studies where the newly designed sensor displayed an increase in fluorescence when bound in the DNA grooves compared to the unbound form.
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http://dx.doi.org/10.3390/molecules21010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274575PMC
December 2015

Cartilage-Specific Near-Infrared Fluorophores for Biomedical Imaging.

Angew Chem Int Ed Engl 2015 Jul 10;54(30):8648-52. Epub 2015 Jun 10.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, SL436A, Boston, MA 02215 (USA).

A novel class of near-infrared fluorescent contrast agents was developed. These agents target cartilage with high specificity and this property is inherent to the chemical structure of the fluorophore. After a single low-dose intravenous injection and a clearance time of approximately 4 h, these agents bind to all three major types of cartilage (hyaline, elastic, and fibrocartilage) and perform equally well across species. Analysis of the chemical structure similarities revealed a potential pharmacophore for cartilage targeting. Our results lay the foundation for future improvements in tissue engineering, joint surgery, and cartilage-specific drug development.
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http://dx.doi.org/10.1002/anie.201502287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504790PMC
July 2015

700-nm Zwitterionic Near-Infrared Fluorophores for Dual-Channel Image-Guided Surgery.

Mol Imaging Biol 2016 Feb;18(1):52-61

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Room SL-436A, Boston, MA, 02215, USA.

Purpose: The purpose of this study was to develop a family of 700-nm zwitterionic pentamethine indocyanine near-infrared fluorophores that would permit dual-channel image-guided surgery.

Procedures: Three complementary synthetic schemes were used to produce novel zwitterionic chemical structures. Physicochemical, optical, biodistribution, and clearance properties were compared to Cy5.5, a conventional pentamethine indocyanine now used for biomedical imaging.

Results: ZW700-1a, ZW700-1b, and ZW700-1c were synthesized, purified, and analyzed extensively in vitro and in vivo. All molecules had extinction coefficients ≥199,000 M(-1) cm(-1), emission ≥660 nm, and stability ≥99 % after 24 h in warm serum. In mice, rats, and pigs, ≥80 % of the injected dose was completely eliminated from the body via renal clearance within 4 h. Either alone or conjugated to a tumor targeting ligand, ZW700-1a permitted dual-channel, high SBR, and simultaneous imaging with 800-nm NIR fluorophores using the FLARE® imaging system.

Conclusions: Novel 700-nm zwitterionic NIR fluorophores enable dual-NIR image-guided surgery.
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http://dx.doi.org/10.1007/s11307-015-0870-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684479PMC
February 2016