Angewandte
Chemie
Photodynamic Therapy
Hot Paper
Intracellular Modulation of Excited-State Dynamics in a Chromophore
Dyad: Differential Enhancement of Photocytotoxicity Targeting
Cancer Cells**
Safacan Kolemen, Murat Is¸ık, Gyoung Mi Kim, Dabin Kim, Hao Geng,
Muhammed Buyuktemiz, Tugce Karatas, Xian-Fu Zhang, Yavuz Dede, Juyoung Yoon,* and
Engin U. Akkaya*
Abstract: The photosensitized generation of reactive oxygen
species, and particularly of singlet oxygen [O2(a1Dg)], is the
essence of photodynamic action exploited in photodynamic
therapy. The ability to switch singlet oxygen generation on/off
would be highly valuable, especially when it is linked to
a cancer-related cellular parameter. Building on recent findings
related to intersystem crossing efficiency, we designed a dimeric
BODIPY dye with reduced symmetry, which is ineffective as
a photosensitizer unless it is activated by a reaction with
intracellular glutathione (GSH). The reaction alters the
properties of both the ground and excited states, consequently
enabling the efficient generation of singlet oxygen. Remark-
ably, the designed photosensitizer can discriminate between
different concentrations of GSH in normal and cancer cells
and thus remains inefficient as a photosensitizer inside
a normal cell while being transformed into a lethal singlet
oxygen source in cancer cells. This is the first demonstration of
such a difference in the intracellular activity of a photosensi-
tizer.
selectivity, but painful edemas are very common side-effects
that are due to photosensitization in an unrelated part of the
body. This fact prompted many in the field to propose the use
of “activatable photosensitizers”,[3] which are to be turned on
only when cancerous tissue or cells are encountered; other-
wise they are to remain in a passive state in which they are not
capable of photosensitization even when the molecule
happens to absorb a photon of stray light.
Earlier examples[4] made use of pH differences between
the extracellular medium of the tumors and normal tissues.
The difference (1–1.5 pH units) is actually found in the
extracellular environment, not in the cytoplasm of the cells,[5]
although the distinction is somewhat blurred in the current
literature. The intracellular glutathione (GSH) concentration,
which is reportedly higher in cancer cells,[6] was also exploited
as a modulator;[7] however, no differences in the photo-
sensitization activity in cancer cells have been shown explic-
itly thus far.
Furthermore, the two-module approach renders the
activatable photosensitizer too large, in some cases making
it cell-impermeable, thus limiting their potential. Also,
extracellular GSH/biothiol activation reactions are non-
specific and do not improve the selectivity of photosensitiza-
tion.
P
hotodynamic therapy, which is based on the photosensi-
tized generation of singlet oxygen by irradiation in the visible/
near-IR region of the spectrum, has been recognized as a non-
invasive cancer treatment modality of great potential for
some time;[1] however, its potential has not been fully realized
owing to a number of limitations, both practical and
fundamental.[2] In principle, it should be possible to localize
irradiation to the area of the tumor, thus increasing spatial
To incorporate GSH responsiveness into a photosensitizer,
we made use of a recent finding in our laboratories,[8] dimeric
BODIPY dyes with unexpectedly high intersystem crossing
(ISC) efficiencies[9] and low dark toxicity. The latter charac-
[*] Dr. S. Kolemen, Dr. M. Is¸ık, Prof. E. U. Akkaya
UNAM-Institute of Material Science and Nanotechnology
Bilkent University
M. Buyuktemiz, Prof. Y. Dede
Department of Chemistry, Gazi University
Ankara 06500 (Turkey)
Ankara 06800 (Turkey)
E-mail: eua@fen.bilkent.edu.tr
T. Karatas, Prof. E. U. Akkaya
Department of Chemistry, Bilkent University
Ankara 06800 (Turkey)
Dr. M. I¸sık
Department of Metallurgical and Materials Engineering
Bingol University
Bingol 12400 (Turkey)
[**] E.U.A. gratefully acknowledges support from TUBITAK (112T480).
J.Y. acknowledges a grant from the National Research Foundation of
Korea (NRF) funded by the Korean government (MSIP,
G. M. Kim, D. Kim, Prof. J. Yoon
Department of Chemistry and NanoScience
Ewha Womans University
2012R1A3A2048814). Y.D. thanks TUBITAK for funding through
project 110T647, and M.B. thanks TUBITAK for a scholarship.
ULAKBIM TR-GRID is acknowledged for computing resources. We
are also grateful to Bora BilgiÅ for designing the cover art.
Seoul 120-750 (Korea)
E-mail: jyoon@ewha.ac.kr
Supporting information for this article is available on the WWW
H. Geng, Prof. X.-F. Zhang
Department of Chemistry & Center of Instrumental Analysis
Hebei Normal University of Science and Technology
Qinhuangdao, Hebei Province 066004 (China)
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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