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Visualization of Anti-cancer Targeted Drug Delivery using NIR fluorescent switchable reporters.


Project Description

What is the Technology Developed in the Laboratory?

A chemotherapeutic drug, by means of a biodegradable linker, is bound to a switchable fluorescent dye that allows it tracing in body. Upon the environment-mediated cleavage of the linker, the absorption and/or emission spectra of the dye undergo a noticeable shift signaling the drug release event. A ratio between these two fluorescence signals, originated from the bound and unbound dye, is proportional to the drug release ratio. A modification of this method consists in the replacement of the switchable dye with two dyes, one of which is not sensitive to drug release while another one is sensitive: it is non-fluorescent when bound to the drug but becomes fluorescent upon the drug release or vice versa.The drug-dye system are linked to a target-specific carrier such as peptide, antibody or nanoparticle to facilitate selective targeted drug delivery. Furthermore, the carrier can be bound to an activatable PDT sensitizer via a biodegradable linker. The activatable sensitizer has a low photodynamic activity in the bound state and an increased activity upon cleavage of the linker. The proposed method enables fluorescence drug delivery monitoring and PDT reducing side-effects of chemotherapeutic and photodynamic treatment. Novel theranostic systems comprising a chemotherapeutic drug or a PDT sensitizer conjugated with one or two fluorescent reporter dyes and a target-specific carrier are especially suitable for anticancer chemotherapy and anticancer PDT. The developed method is advantageous to a state-of-the-art in vitro and in vivo fluorescence imaging applications.

What has been Achieved in the Laboratory?

1) Theoretical principles have been developed and tested on model systems.
2) Switchable and activatable fluorescent reporter dyes were synthesized.
3) Several model theranostic systems comprising anticancer drug, switchable dye, targeting peptide and antibody have been synthesized and tested on cancer cells and animal models using spectrofluorimetrical, fluorescence microscopy and in vivo imaging techniques.

Funding Notes

We now have several fully funded openings for graduate students with our multinational team at Ariel University

References

1. “Water-soluble 4-hydroxystyryl and 4-hydroxyphenyl-butadienyls dyes with switchable fluorescence” K. Bondar, M. Bokan, G.
Gellerman, L. D. Patsenker. Dyes and Pigments, 2020, 107801. https://doi.org/10.1016/j.dyepig.2019.107801
2. “Fluorescent Reporters for Drug Delivery Monitoring” L. Patsenker, G. Gellerman, Isr. J. Chem. 2020, 60, 1 – 16. DOI:
10.1002/ijch.201900137
3. '' Bifunctional reactive pentamethine cyanine dyes for biomedical applications'' A. Rozovsky, L. Patsenker, G. Gellerman, Dyes &
Pigments (2019), 162, 18-25
4. “Drug delivery platform comprising long-wavelength fluorogenic phenolo-cyanine dye for real-time monitoring of drug release” M.
Bokan, G. Gellerman, L. Patsenker, Dyes and Pigments, 2019, 107703.
5. “Peptide-Driven Targeted Drug Delivery System Comprising Turn-On NIR Fluorescent Xanthene-Cyanine Reporter for Real Time
Monitoring of Drug Release” T. M. Ebaston, A. Rozovsky, A. Zaporozhets, A. Bazylevich, H. Tuchinsky, G. Gellerman, L. D.
Patsenker. ChemMedChem 2019, 14, 1727 – 1734
6. ''Theranostic system for ratiometric fluorescence monitoring of peptide-guided targeted drug deivery'' A. Rozovsky, T. M. Ebaston, A.
Zaporozhets, A. Bazylevich, H. Tuchinsky, L. Patsenker, G. Gellerman. RCS Advances, 2019,9, 32656-32664.
7. ''New somatostatin-drug conjugates for effective targeting pancreatic cancer'' E. Ragozina, A. Hesin, A. Bazylevich, H. Tuchinsky, A.
Bovina, M.A. Firer, M.Y. Sherman, G. Gellerman, Bioorganic & Medicinal Chemistry 26 (2018) 3825–3836
8. "Toward the development of a novel non-RGD cyclic peptide drug conjugate for treatment of human metastatic melanoma" Redko B.,
Tuchinsky L., Segal T., Tobi D., Luboshits G., Ashur-Fabian O., Pinhasov A., Gerlitz G., Gellerman G., Oncotarget, 2017(8), 757-768

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