2019 Fiscal Year Annual Research Report
Design and synthesis of functional cyanine dyes for imaging and therapeutic application
| Project/Area Number |
18F18767
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| Research Institution | Keio University |
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Principal Investigator |
チッテリオ ダニエル 慶應義塾大学, 理工学部(矢上), 教授 (00458952)
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| Co-Investigator(Kenkyū-buntansha) |
KURUTOS ATANAS 慶應義塾大学, 理工学部, 外国人特別研究員
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| Project Period (FY) |
2018-11-09 – 2021-03-31
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| Keywords | cyanine dyes / polymethine dyes / NIR probes / fluorescent probes / pH response / DFT calculations |
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| Outline of Annual Research Achievements |
During the period 01/04/2019-31/3/2020, the main achievements of Dr. Atanas Kurutos under the project “Design and synthesis of functional cyanine dyes for imaging and therapeutical applications” cover the study of photophysical properties, and computational investigation of a series of novel NIR-heptamethine cyanine dyes conjugated with pH sensitive amino moieties. The optical characteristics (λmax, λfl., Stokes shifts, molar extinction coefficients and fluorescence quantum yield) were evaluated in organic and/or buffer solutions. The possibility for solvatochromism and intramolecular charge transfer (ICT) was investigated in organic solvents with a wide polarity range. Furthermore, the resistance of the dyes against photooxidative degradation was studied upon continuous irradiation at the corresponding absorption maxima. Quantum chemical calculations were employed using Density Functional Theory, aiming to clarify the origin of the enhanced Stokes shift of the amino-substituted cyanines. The DFT calculations of both the ground and the excited states were performed in gas phase and water using Gaussian 09 software package. NMR and computational approaches were used in order to explain the protonation and spectral behavior of the pH responsive cyanines. In the view of practical application of the NIR dyes as an efficient proton sensing platform, we performed cellular imaging with HeLa cells and cytotoxicity by MTT assay. Last but not least, the series of NIR compound were expanded targeting to fine-tune heptamethines absorbing > 1000 nm.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
The implementation of the current project relies on a combination of several and hence essential overlapping steps. The original proposal with a total duration of 24 months covers the following: i) Theoretical studies - Design and quantum chemical calculations via DFT method aiming to optimize the new cyanine fluorophores and select the most appropriate chemical structures containing the various molecular modifications, ii) Synthesis of the target cyanines and intermediate products. Structural characterization of all planned compounds by NMR spectroscopy, mass spectrometry, and IR spectroscopy, and iii) Photophysical studies - Measurements of UV-Vis and emission spectra of all newly synthesized compounds. Up to date, the majority of the proposal’s targets are accomplished. The finely-tuned pH response of NIR probes were found to be good potential candidates for further quantitative bioanalysis. Currently, the series of promising sensing compounds is further expanded in the same direction, aiming to optimize their performance for biologically related applications.
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| Strategy for Future Research Activity |
Future plans leading to the successful accomplishment of the current project, include the implementation of further in-depth photophysical investigation as well as the synthesis of further series pointing towards the same direction, and in particular on the design of novel pH responsive sensors. The preparation of organic molecules bearing alternations to both the fluorogenic dye, as well as the introduction an even wider selection of pKa sensitive moieties is planned. A more detailed computational studies in both the ground and the excited state is planned, which is expected to serve as supporting material to the findings from the experimental part. Finally, applying the same strategy, efforts would be directed to apply these model compounds as a proof of concept via implementation of those chemical structures showing the most promising photophysical properties into bio-imaging, and potentially to be tested as anti-cancer PTT agents, or even be encapsulated into functionalized stimuli-responsive polymeric micelles (prone to undergo disruption at locally acidic pH) for the selective in-target delivery to tumor cells.
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