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Small Molecule Near Infrared Contrast Agents: Synthesis and Applications

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

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 51743

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Prof. Dr. Maged Henary

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Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Interests: organic synthesis; heterocyclic chemistry; fluorescent probes; NIR contrast agents; metal sensors; microwave synthesis; biomedical applications; bioanalytical applications
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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

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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)

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Published Papers (10 papers)

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Research

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17 pages, 4165 KiB

Open AccessFeature PaperArticle

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

by Effibe O. Ahoulou, Kaitlyn K. Drinkard, Kanchan Basnet, Anna St. Lorenz, Oleh Taratula, Maged Henary and Kathryn B. Grant

Molecules 2020, 25(12), 2926; https://doi.org/10.3390/molecules25122926 - 25 Jun 2020

Cited by 10 | Viewed by 4091

Abstract

Here, we report the syntheses of two pentamethine cyanine dyes containing quinolinium rings and substituted with either hydrogen (3) or bromine (4) at the meso carbon. The electron withdrawing bromine atom stabilizes dye 4 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 4 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 4 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 4 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. Full article

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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13 pages, 18009 KiB

Open AccessArticle

Comprehensive Effects of Near-Infrared Multifunctional Liposomes on Cancer Cells

by Yiqing Deng, Huaying Huang, Mengxiao Chen, Gang Chen, Wangcai Zou, Yanqing Zhao and Qiang Zhao

Molecules 2020, 25(5), 1098; https://doi.org/10.3390/molecules25051098 - 1 Mar 2020

Cited by 8 | Viewed by 2998

Abstract

Multifunctional theranostic systems are a recent important development of medical research. We combined the characteristics of near-infrared luminescent quantum dots and thermosensitive magnetoliposomes to develop a multifunctional nano-diagnostic material. This system is based on near-infrared magnetic thermosensitive liposomes, which encapsulate drugs and can control drug localization and release. After incubating cancer cells with the liposomes, the state of the cells was analyzed in real time by near-infrared imaging. Cell viability was significantly inhibited by heat treatment or alternating magnetic field treatment, which thus improved the anti-cancer properties of the liposomes. In the future, by combining near-infrared imaging technology and an external high-frequency alternating magnetic field, we could not only detect cancer cells noninvasively but also conduct image-guided treatments for cancer. Full article

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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13 pages, 3466 KiB

Open AccessArticle

A Fast-Response Red Shifted Fluorescent Probe for Detection of H₂S in Living Cells

by Ismail Ismail, Zhuoyue Chen, Xiuru Ji, Lu Sun, Long Yi and Zhen Xi

Molecules 2020, 25(3), 437; https://doi.org/10.3390/molecules25030437 - 21 Jan 2020

Cited by 21 | Viewed by 4936

Abstract

Near-infrared (NIR) fluorescent probes are attractive tools for bioimaging applications because of their low auto-fluorescence interference, minimal damage to living samples, and deep tissue penetration. H₂S is a gaseous signaling molecule that is involved in redox homeostasis and numerous biological processes in vivo. To this end, we have developed a new red shifted fluorescent probe 1 to detect physiological H₂S in live cells. The probe 1 is based on a rhodamine derivative as the red shifted fluorophore and the thiolysis of 7-nitro 1,2,3-benzoxadiazole (NBD) amine as the H₂S receptor. The probe 1 displays fast fluorescent enhancement at 660 nm (about 10-fold turn-ons, k₂ = 29.8 M⁻¹s⁻¹) after reacting with H₂S in buffer (pH 7.4), and the fluorescence quantum yield of the activated red shifted product can reach 0.29. The probe 1 also exhibits high selectivity and sensitivity towards H₂S. Moreover, 1 is cell-membrane-permeable and mitochondria-targeting, and can be used for imaging of endogenous H₂S in living cells. We believe that this red shifted fluorescent probe can be a useful tool for studies of H₂S biology. Full article

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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13 pages, 2325 KiB

Open AccessArticle

Use of Indocyanine Green (ICG), a Medical Near Infrared Dye, for Enhanced Fluorescent Imaging—Comparison of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) and Sodium-Taurocholate Cotransporting Polypeptide (NTCP) Reporter Genes

by Menq-Rong Wu, Yi-You Huang and Jong-Kai Hsiao

Molecules 2019, 24(12), 2295; https://doi.org/10.3390/molecules24122295 - 21 Jun 2019

Cited by 16 | Viewed by 4163

Abstract

Molecular and cellular imaging in living organisms have ushered in an era of comprehensive understanding of intracellular and intercellular events. Currently, more efforts have been focused on the infrared fluorescent dyes that facilitate deeper tissue visualization. Both sodium taurocholate cotransporting polypeptide (NTCP) and organic-anion-transporting polypeptide 1B3 (OATP1B3) are capable of carrying indocyanine green (ICG) into the cytoplasm. We compared the feasibility of NTCP and OATP1B3 as reporter genes in combination with ICG. NTCP and OATP1B3 were transduced into HT-29 cells. Genetically modified HT-29 cells were inoculated into nude mice. ICG was administered in vitro and in vivo and the signals were observed under confocal microscopy, flow cytometry, multimode microplate reader, and an in vivo imaging system. Both NTCP- and OATP1B3-expressing cells and xenografts had higher ICG intensities. The OATP1B3-expressing xenograft has a higher ICG uptake than the NTCP-expressing xenograft. NTCP or OATP1B3 combined with ICG could serve as a noninvasive imaging modality for molecular and cellular imaging. OATP1B3 outperforms NTCP in terms of in vivo imaging. Full article

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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12 pages, 1670 KiB

Open AccessArticle

Counter Anion Effect on the Photophysical Properties of Emissive Indolizine-Cyanine Dyes in Solution and Solid State

by Jacqueline N. Gayton, Shane Autry, Ryan C. Fortenberry, Nathan I. Hammer and Jared H. Delcamp

Molecules 2018, 23(12), 3051; https://doi.org/10.3390/molecules23123051 - 22 Nov 2018

Cited by 38 | Viewed by 5845

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 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

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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11 pages, 2748 KiB

Open AccessFeature PaperArticle

Site-Specific Labeling of Proteins with Near-IR Heptamethine Cyanine Dyes

by Chen-Ming Lin, Syed Muhammad Usama and Kevin Burgess

Molecules 2018, 23(11), 2900; https://doi.org/10.3390/molecules23112900 - 7 Nov 2018

Cited by 27 | Viewed by 6701

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 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

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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15 pages, 4370 KiB

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

by Yibin Zhang, Jianheng Bi, Shuai Xia, Wafa Mazi, Shulin Wan, Logan Mikesell, Rudy L. Luck and Haiying Liu

Molecules 2018, 23(10), 2679; https://doi.org/10.3390/molecules23102679 - 18 Oct 2018

Cited by 28 | Viewed by 5357

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 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 pK_a values of 5.15 and 7.80, respectively. Full article

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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13 pages, 2518 KiB

Open AccessArticle

Near Infrared Fluorophore-Tagged Chloroquine in Plasmodium falciparum Diagnostic Imaging

by Li Yan Chan, Joshua Ding Wei Teo, Kevin Shyong-Wei Tan, Keitaro Sou, Wei Lek Kwan and Chi-Lik Ken Lee

Molecules 2018, 23(10), 2635; https://doi.org/10.3390/molecules23102635 - 14 Oct 2018

Cited by 4 | Viewed by 4771

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 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

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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14 pages, 7980 KiB

Open AccessFeature PaperArticle

Fluorescent Thienothiophene-Containing Squaraine Dyes and Threaded Supramolecular Complexes with Tunable Wavelengths between 600–800 nm

by Wenqi Liu, Hannah H. McGarraugh and Bradley D. Smith

Molecules 2018, 23(9), 2229; https://doi.org/10.3390/molecules23092229 - 1 Sep 2018

Cited by 15 | Viewed by 5795

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 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

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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Review

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24 pages, 9660 KiB

Open AccessFeature PaperReview

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

by Matt D. Laramie, Mary K. Smith, Fahad Marmarchi, Lacey R. McNally and Maged Henary

Molecules 2018, 23(11), 2766; https://doi.org/10.3390/molecules23112766 - 25 Oct 2018

Cited by 35 | Viewed by 6008

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 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

(This article belongs to the Special Issue Small Molecule Near Infrared Contrast Agents: Synthesis and Applications)

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