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Special Issue "Small Molecule Near Infrared Contrast Agents: Synthesis and Applications"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: 15 January 2019

Special Issue Editor

Guest Editor
Prof. Maged Henary

Chemistry department, Georgia State University, Atlanta, GA 30303, USA
Website | E-Mail
Interests: organic synthesis; heterocyclic chemistry; fluorescent probes; NIR contrast agents; metal sensors; microwave synthesis; biomedical applications; bioanalytical applications

Special Issue Information

Dear Colleagues,

Near-Infrared (NIR) absorbing fluorophores have become important as diagnostic and therapeutic agents in the field of tumor research, with the number of related publications having skyrocketed throughout the last few years. The utilization of the NIR spectral region (650–900 nm) is advantageous due to the inherently lower background interference, which makes it well suited for techniques analyzing high complexity samples and for many applications.

This Special Issue is focusing on “Small Molecule NIR Contrast Agents” within topic-related chapters, dealing with all aspects, such as synthesis, structure, complexity, optical properties, reactivity, stability and applications in material science, imaging, biomedical, and bioanalytical applications. Review articles by experts in the field will also be welcome.

Prof. Maged Henary
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • synthesis of NIR contrast agents
  • optical properties, reactivity, and stability of NIR fluorophores
  • NIR fluorophores interaction with Biomolecules
  • NIR Fluorescent sensors (metals, enzymatic, etc.)
  • biomedical applications
  • bioanalytical applications
  • biomolecular imaging (NIR for image-guided surgery)

Published Papers (6 papers)

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Research

Jump to: Review

Open AccessArticle Counter Anion Effect on the Photophysical Properties of Emissive Indolizine-Cyanine Dyes in Solution and Solid State
Molecules 2018, 23(12), 3051; https://doi.org/10.3390/molecules23123051
Received: 1 October 2018 / Revised: 13 November 2018 / Accepted: 15 November 2018 / Published: 22 November 2018
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Abstract
Near-infrared emissive materials with tunable Stokes shifts and solid-state emissions are needed for several active research areas and applications. To aid in addressing this need, a series of indolizine-cyanine compounds varying only the anions based on size, dipole, and hydrophilicity were prepared. The
[...] Read more.
Near-infrared emissive materials with tunable Stokes shifts and solid-state emissions are needed for several active research areas and applications. To aid in addressing this need, a series of indolizine-cyanine compounds varying only the anions based on size, dipole, and hydrophilicity were prepared. The effect of the non-covalently bound anions on the absorption and emission properties of identical π-system indolizine-cyanine compounds were measured in solution and as thin films. Interestingly, the anion choice has a significant influence on the Stokes shift and molar absorptivities of the dyes in solution. In the solid-state, the anion choice was found to have an effect on the formation of aggregate states with higher energy absorptions than the parent monomer compound. The dyes were found to be emissive in the NIR region, with emissions peaking at near 900 nm for specific solvent and anion selections. Full article
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Open AccessFeature PaperArticle Site-Specific Labeling of Proteins with Near-IR Heptamethine Cyanine Dyes
Molecules 2018, 23(11), 2900; https://doi.org/10.3390/molecules23112900
Received: 19 October 2018 / Revised: 5 November 2018 / Accepted: 6 November 2018 / Published: 7 November 2018
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Abstract
Convenient labeling of proteins is important for observing its function under physiological conditions. In tissues particularly, heptamethine cyanine dyes (Cy-7) are valuable because they absorb in the near-infrared (NIR) region (750–900 nm) where light penetration is maximal. In this work, we found Cy-7
[...] Read more.
Convenient labeling of proteins is important for observing its function under physiological conditions. In tissues particularly, heptamethine cyanine dyes (Cy-7) are valuable because they absorb in the near-infrared (NIR) region (750–900 nm) where light penetration is maximal. In this work, we found Cy-7 dyes with a meso-Cl functionality covalently binding to proteins with free Cys residues under physiological conditions (aqueous environments, at near neutral pH, and 37 °C). It transpired that the meso-Cl of the dye was displaced by free thiols in protein, while nucleophilic side-chains from amino acids like Tyr, Lys, and Ser did not react. This finding shows a new possibility for convenient and selective labeling of proteins with NIR fluorescent probes. Full article
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Open AccessArticle A Near-Infrared Fluorescent Probe Based on a FRET Rhodamine Donor Linked to a Cyanine Acceptor for Sensitive Detection of Intracellular pH Alternations
Molecules 2018, 23(10), 2679; https://doi.org/10.3390/molecules23102679
Received: 18 September 2018 / Revised: 11 October 2018 / Accepted: 15 October 2018 / Published: 18 October 2018
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Abstract
A fluorescence resonance energy transfer (FRET)-based near-infrared fluorescent probe (B+) for double-checked sensitive detection of intracellular pH changes has been synthesized by binding a near-infrared rhodamine donor to a near-infrared cyanine acceptor through robust C-N bonds via a nucleophilic substitution
[...] Read more.
A fluorescence resonance energy transfer (FRET)-based near-infrared fluorescent probe (B+) for double-checked sensitive detection of intracellular pH changes has been synthesized by binding a near-infrared rhodamine donor to a near-infrared cyanine acceptor through robust C-N bonds via a nucleophilic substitution reaction. To demonstrate the double-checked advantages of probe B+, a near-infrared probe (A) was also prepared by modification of a near-infrared rhodamine dye with ethylenediamine to produce a closed spirolactam residue. Under basic conditions, probe B+ shows only weak fluorescence from the cyanine acceptor while probe A displays nonfluorescence due to retention of the closed spirolactam form of the rhodamine moiety. Upon decrease in solution pH level, probe B+ exhibits a gradual fluorescence increase from rhodamine and cyanine constituents at 623 nm and 743 nm respectively, whereas probe A displays fluorescence increase at 623 nm on the rhodamine moiety as acidic conditions leads to the rupture of the probe spirolactam rings. Probes A and B+ have successfully been used to monitor intracellular pH alternations and possess pKa values of 5.15 and 7.80, respectively. Full article
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Open AccessArticle Near Infrared Fluorophore-Tagged Chloroquine in Plasmodium falciparum Diagnostic Imaging
Molecules 2018, 23(10), 2635; https://doi.org/10.3390/molecules23102635
Received: 29 September 2018 / Revised: 11 October 2018 / Accepted: 12 October 2018 / Published: 14 October 2018
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Abstract
Chloroquine was among the first of several effective drug treatments against malaria until the onset of chloroquine resistance. In light of diminished clinical efficacy of chloroquine as an antimalarial therapeutic, there is potential in efforts to adapt chloroquine for other clinical applications, such
[...] Read more.
Chloroquine was among the first of several effective drug treatments against malaria until the onset of chloroquine resistance. In light of diminished clinical efficacy of chloroquine as an antimalarial therapeutic, there is potential in efforts to adapt chloroquine for other clinical applications, such as in combination therapies and in diagnostics. In this context, we designed and synthesized a novel asymmetrical squaraine dye coupled with chloroquine (SQR1-CQ). In this study, SQR1-CQ was used to label live Plasmodium falciparum (P. falciparum) parasite cultures of varying sensitivities towards chloroquine. SQR1-CQ positively stained ring, mature trophozoite and schizont stages of both chloroquine–sensitive and chloroquine–resistant P. falciparum strains. In addition, SQR1-CQ exhibited significantly higher fluorescence, when compared to the commercial chloroquine-BODIPY (borondipyrromethene) conjugate CQ-BODIPY. We also achieved successful SQR1-CQ labelling of P. falciparum directly on thin blood smear preparations. Drug efficacy experiments measuring half-maximal inhibitory concentration (IC50) showed lower concentration of effective inhibition against resistant strain K1 by SQR1-CQ compared to conventional chloroquine. Taken together, the versatile and highly fluorescent labelling capability of SQR1-CQ and promising preliminary IC50 findings makes it a great candidate for further development as diagnostic tool with drug efficacy against chloroquine-resistant P. falciparum. Full article
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Open AccessFeature PaperArticle Fluorescent Thienothiophene-Containing Squaraine Dyes and Threaded Supramolecular Complexes with Tunable Wavelengths between 600–800 nm
Molecules 2018, 23(9), 2229; https://doi.org/10.3390/molecules23092229
Received: 15 August 2018 / Revised: 28 August 2018 / Accepted: 31 August 2018 / Published: 1 September 2018
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Abstract
A new family of fluorescent thiophene and thienothiophene-containing squaraine dyes is described with tunable wavelengths that cover the absorption/emission range of 600–800 nm. The deep-red and near-infrared fluorescent compounds were easily prepared by simple synthesis and purification methods. Spectral studies showed that each
[...] Read more.
A new family of fluorescent thiophene and thienothiophene-containing squaraine dyes is described with tunable wavelengths that cover the absorption/emission range of 600–800 nm. The deep-red and near-infrared fluorescent compounds were easily prepared by simple synthesis and purification methods. Spectral studies showed that each squaraine was rapidly encapsulated by a tetralactam macrocycle, with nanomolar affinity in water, to produce a threaded supramolecular complex with high chemical stability, increased fluorescence quantum yield, and decreased fluorescence quenching upon dye self-aggregation. Energy transfer within the supramolecular complex permitted multiplex emission. That is, two separate dyes with fluorescence emission bands that match the popular Cy5 and Cy7 channels, could be simultaneously excited with a beam of 375 nm light. A broad range of practical applications is envisioned in healthcare diagnostics, microscopy, molecular imaging, and fluorescence-guided surgery. Full article
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Review

Jump to: Research

Open AccessFeature PaperReview Small Molecule Optoacoustic Contrast Agents: An Unexplored Avenue for Enhancing In Vivo Imaging
Molecules 2018, 23(11), 2766; https://doi.org/10.3390/molecules23112766
Received: 18 September 2018 / Revised: 19 October 2018 / Accepted: 22 October 2018 / Published: 25 October 2018
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Abstract
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
[...] Read more.
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. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Determination of total carotenoid and phenolic content in blackberries (/Rubus fructicosus/L. ) combining near infrared spectroscopy (NIRS) and multivariate analysis
Author: Mercedes del Río Celestino
Abstract: A quick method to determine the content of phenolic compounds (TPC) and total carotenoid content (TCC) in blackberries based on near infrared spectroscopy (NIRS) was studied aiming to provide reductions of cost and analysis time for the food industry. A total of 106 samples were analyzed by the Folin-Ciocalteu method for TPC analysis and the method based in UV-Vis Spectrometer for TCC analysis. The average contents of TPC and TCC found were 24.27 mg g^-1 dwand 8.30 µg g^-1 dwrespectively. Modified partial least squares (MPLS) regression was used for obtaining the calibration models of the compounds. The RPD values from external validation (ratio of the standard deviation of the reference data to the standard error of prediction) for both TPC and TCC was between 1.5<RPD_p <2.5 and RER values (ratio of the range in the reference data to SEP) was 5.92 for TPC and 8.63 for TCC. These values showed that both equations to predictive ability were suitable for screening purposes. MPLS loading plots corresponding to the first terms of the equations showed the influence of sugars, chlorophyll, lipids and cellulose in the modelling of prediction equations.

Title: Ultra-bright and Stable Near-infrared Fluorescent Squaraine  Dyes
Author: Maged Henary
Abstract
: 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.  The newly synthesized symmetric and asymmetric compounds display increased molar absorptivity (DMSO: symmetric average 447,325 M-1cm-1 and asymmetric average 333,725 M-1cm-1; Fetal Bovine Serum: 398,050 M-1cm-1 and 375,100 M-1 cm-1, respectively), quantum yield in serum (symmetric average ε = 45%, asymmetric average  ε = 79%), and thermal/photochemical stability over previously reported squaraine based dyes.  Consequently, both classes show great promise in re-surfacing the normally 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.

Title: Counter Ion Effect on NIR Emission from Indolizine-based Cyanine Dyes
Author: Jared Delcamp
Abstract: A series of 6 NIR absorbing indolizine-based cyanine dyes with varying counter ions based on size, dipole and hydrophilicity have been analyzed in solution and as solid state films. While the absorption of these materials remained consistent in wavelength and molar absorptivity, the emission quantum yields and wavelengths were found to vary in solution. Since many NIR cyanine dyes have been found to aggregate heavily in aqueous environments, we also evaluated films of these materials to analyze the effect of counter ion on aggregation state and emission intensity from the condensed state. 

 

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