Single photon DNA photocleavage at 830 nm by quinoline dicarbocyanine dyes

Article abstract of DOI:10.1039/c9cc04751d

We have synthesized symmetrical carbocyanine dyes in which two 4-quinolinium rings are joined by a pentamethine bridge that is meso-substituted with H or Cl. Irradiation of the halogenated dye at 830 nm produces hydroxyl radicals that generate DNA direct

Full text of DOI:10.1039/c9cc04751d

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Single photon DNA photocleavage at 830 nm
by quinoline dicarbocyanine dyes†
Cite this: Chem. Commun., 2019,
5, 12667
5
a
a
b
b
Kanchan Basnet, Tayebeh Fatemipouya, Anna St. Lorenz, Mindy Nguyen,
b
ac
a
Received 20th June 2019,
Accepted 23rd September 2019
Oleh Taratula, Maged Henary
*
and Kathryn B. Grant
*
DOI: 10.1039/c9cc04751d
rsc.li/chemcomm
We have synthesized symmetrical carbocyanine dyes in which two enhanced penetration of incident irradiation afforded by minimal
-quinolinium rings are joined by a pentamethine bridge that is light absorption in this range by molecules in the body. Thus, the
4
meso-substituted with H or Cl. Irradiation of the halogenated dye light depth attained at 835 nm through biological tissue is
at 830 nm produces hydroxyl radicals that generate DNA direct approximately twice that at B630 nm, the wavelength used to
1
strand breaks. This represents the first reported example of DNA activate porfimer sodium.
photocleavage upon single photon excitation of a chromophore at
wavelengths above 800 nm.
Although infrared light passes through tissues more effi-
ciently, the result of red-shifting the lmax of a chromophore is
9
to reduce triplet state energy. This places limits on near-IR
5
Photodynamic therapy (PDT) is an emerging cancer treatment ROS production. For example, Type 2 singlet oxygen is gene-
aimed at minimizing the side effects associated with traditional rated only when a PS has a triplet state energy equivalent
chemotherapeutic agents. In PDT, excitation of a photosensitizer to or higher than the excitation energy of O2 (95 kJ mol
1
ꢁ1
,
4
(PS) with low energy light triggers the production of highly B1270 nm). When taking into consideration the minimal
ꢁ1
1
localized reactive oxygen species (ROS) in diseased tissues with energy gap (r63 kJ mol ) between the first excited PS* and
1–3
3
minimal involvement of surrounding cells. In the most com-
PS* states of PDT agents, this translates into an B810 nm
1
1
10
mon PDT mechanism, singlet oxygen ( O
2 2
) is generated by Type 2 upper absorption limit for O production. In order for a photo-
3
energy transfer between the triplet excited state ( PS*) of the PS sensitizer to form Type 1 superoxide, the oxidation potential of the
3
4
and ground state triplet oxygen ( O ). The triplet state can also PS triplet state should be higher than the oxidation potential of
2
3
3
ꢀ
ꢁ
11
react with O2 by Type 1 electron transfer to yield superoxide ground state triplet oxygen (E1( O /O ) = 0.16 V at pH 7.0), but
anion radicals (O2 ). Spontaneous dismutation of O generates lowering triplet state energy inopportunely decreases excited state
H O , which gives rise to hydroxyl radicals ( OH) via Fenton oxidation potentials. For the above reasons, there are relatively
chemistry. With respective diffusion distances of 50–100 nm
and 0.8–6.0 nm, the short-lived and highly reactive O
formed upon dye excitation cause extensive oxidative damage to the longest wavelengths to trigger DNA strand scission upon
DNA and other cellular macromolecules in their vicinity.
The clinical PDT agents porfimer sodium (Photofrin ), 800 nm. In a seminal study, Chakravarty et al. cleaved plasmid
talaporfin (Aptocinet), and verteporfin (Visudyne ) directly DNA in high yield by employing an anthracenyl-bis(pyridyl)Fe(III)
2
2
ꢀ
ꢁ
ꢀ
ꢁ
2
ꢀ
12
2 2
4,5
6
few examples of DNA photocleaving agents that are effective ROS
7
1
ꢀ
2
2
and OH generators in the near-infrared range. Until the present report,
8
direct, single photon chromophore activation were all under
s
s
sensitize genomic DNA cleavage when irradiated in tissue catecholate complex to photosensitize hydroxyl radical production
2
13
culture and/or in circulating cells. While their absorption bands under single photon 785 nm illumination.
are compatible with visible light sources that emit at wavelengths Near-infrared cyanine dyes are currently being developed as
14,15
r689 nm, alternative photosensitizers with near-infrared maxima PDT agents
extending from B700 nm to 900 nm are desired. This is due to probes in the diagnosis and imaging of cancer. DNA interactions
and are used in clinical settings as fluorescent
16
are facilitated by the cyanines’ two flanking heteroaromatic nitrogen
rings, which share a positive charge that is delocalized through a
a
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
1
7
18
E-mail: kbgrant@gsu.edu, mhenary1@gsu.edu; Tel: +1-404-413-5522,
central polymethine bridge. DNA cleavage by hydroxyl radicals
+
1-404-413-5566
18–20
and singlet oxygen
lengths in the visible range
dyes, particularly those with 2-quinolinium rings, avidly interact
has been reported, with excitation wave-
b
Department of Pharmaceutical Sciences, College of Pharmacy,
Oregon State University, Portland, OR 97201, USA
1
9,20
18
up to 700 nm. Certain cyanine
c
Center for Diagnostics and Therapeutics, Atlanta, GA 30303, USA
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc04751d with the DNA minor groove as monomers, dimers, and higher order
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The DNA-induced absorption changes shown in Fig. 1 indicated
that it should be possible to employ the 4-quinolinium dyes to
sensitize photocleavage at near-infrared wavelengths Z 800 nm.
Towards this end, cyanines 4 and 5 were equilibrated with pUC19
plasmid and irradiated with 808 nm and 830 nm LED lasers (pH =
Scheme 1 Chemical structures of the 4-quinolinium pentamethine carbo-
cyanine dyes under study.
7.0). Duplicate sets of reactions were maintained at 10 1C (Fig. 2)
and at 22 1C (Fig. S8, ESI†) during irradiation. Additional samples
were kept in the dark at 10 1C, 22 1C, and 37 1C (Fig. S9, ESI†). DNA
17
aggregates. In the design and syntheses of cyanine dyes 4 and 5 products resolved on agarose gels showed that 808 nm and 830 nm
Scheme 1 and Scheme S1, Fig. S1–S5, ESI†), a 4-quinolinium motif near-infrared light caused the dyes to convert uncut supercoiled
(
in combination with a highly conjugated central pentamethine plasmid to nicked DNA through the formation of direct strand
bridge was selected to maximize near-infrared light absorption breaks (Fig. 2 and Fig. S8, ESI†). Dye 4, which rapidly degrades in
(4700 nm). Cyanines possessing extended polymethine chains aqueous buffer (Fig. 1 and Fig. S7A, C, ESI†), generated lower levels
can lose color in aqueous solutions due to spontaneous dye auto- of cleavage. Considerably more strand breakage was sensitized by
21
oxidation (no hn). Substituting the H atom at the meso position of the stable halogenated dye (5). Increasing the reaction temperature
the pentamethine bridge of 4-quinolinium dye 4 with electron from 10 1C to 22 1C had no effect on cleavage yields (Fig. S8, ESI†).
withdrawing Cl (5) was intended to reduce the dye oxidation Moreover, minimal levels of strand breakage were observed in all of
22
process and, through a heavy atom effect, accelerate intersystem the dark control reactions containing dye, even after the tempera-
23
crossing rates from the singlet to the triplet excited PS state.
ture was increased from 10 1C to 37 1C (Fig. S9, ESI†). Taken
In UV-visible absorption spectra recorded over time, together, the above results appear to rule against a thermal process
4-quinolinium carbocyanines 4 and 5 appeared to be stable in and instead suggest that the DNA direct strand breaks produced
DMSO, with absorption maxima of 823 nm (4, X = H) and by exposing cyanine dyes 4 and 5 to 808 nm and 830 nm LED lasers
95 nm (5, X = Cl) (Fig. S6, ESI†; red lines in Fig. 1). In aqueous are photochemical in nature. In our next experiment, plasmid
7
buffer however, the dyes exhibited markedly different signatures. samples containing 5 mM up to 50 mM of 4-quinolinium cyanine 5
The peak heights of the 823 nm and 795 nm absorption bands (X = Cl) were irradiated at 830 nm for 30 min. DNA cleavage was
seen in DMSO were less prominent and new blue-shifted absorp- observed at the lowest dye concentrations tested (5 mM) and
tion maxima at 644 nm (4) and 547 nm (5) appeared (black gradually increased until approaching a plateau at B30 mM of
24
lines in Fig. 1). In contrast to DMSO, the major bands of dye (Fig. S10, ESI†). When 20 mM reactions were irradiated as a
both cyanines lost intensity in the aqueous medium, although function of time, DNA cleavage occurred up until the 120 min
substitution of the meso hydrogen for electron withdrawing Cl experimental endpoint (830 nm hn; Fig. S11, ESI†). To the best of
considerably slowed down absorption loss over time (Fig. S7A and our knowledge, the plasmid experiments described in this paper
B, ESI†). Interestingly, the addition of calf thymus (CT) DNA to the constitute the first reported examples of DNA strand breakage
aqueous buffer stabilized the dyes, especially in the case of 5 upon single photon dye excitation at wavelengths above 800 nm.
(X = Cl), which, in contrast to 4, was extremely stable when the
The superior DNA photo-cleaving abilities of 5 led us to
DNA was present (Fig. 1 and Fig. S7C, D, ESI†). A second effect of investigate its DNA binding mode(s). In circular dichroism (CD)
DNA addition was to red-shift the long wavelength cyanine dye spectra of calf thymus (CT) DNA, the achiral cyanine generated an
absorption maxima, e.g., from 801 nm to 826.5 nm (4, X = H); intense, bisignate induced CD (ICD) band indicative of exciton
777 nm to 805 nm (5, X = Cl).
coupling (Fig. 3, black line). The band passes through zero – at
the 547 nm absorption maximum of the DNA-bound form of the
chlorinated cyanine (Fig. 3, green line) and has an overall appear-
ance consistent with the formation of a right-handed helical H
Fig. 2 Agarose gels showing cyanine dye-sensitized photocleavage of
pUC19 plasmid DNA irradiated with 808 nm (A) and 830 nm (B) LED lamps
ꢁ2
(
2.8 W cm , 30 min hn at 10 1C). Reactions contained 10 mM sodium
Fig. 1 UV-visible spectra of 10 mM of dyes 4 and 5: in DMSO (red line, t = 0 min);
0 mM sodium phosphate pH 7.0 buffer, without DNA (black line, t = 0 min) and
with 150 mM bp CT DNA (blue line, t = 0 to purple line, t = 25 min).
phosphate buffer pH 7.0 and 38 mM bp DNA in the absence and presence
of 20 mM of dye. Yields and standard deviation were obtained over 3 trials.
Abbreviations: L = linear; N = nicked; S = supercoiled.
1
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aggregate in which cofacial cyanine dimers assemble in an end-to- may be interacting with DNA in a conformationally flexible fashion
25,26
end fashion in the DNA minor groove.
UV-visible absorption distinct from classical minor groove binding and intercalation.
titrations were then conducted in which small volumes of calf While exciting the non-fluorescent dye monomer of 5 with
thymus (CT) DNA titrant were sequentially added to a solution 808 and 830 nm LED lasers sensitized plasmid DNA cleavage in
containing a fixed amount of 5 (Fig. S12, ESI†). A known effect of good yields (Fig. 2), less strand breakage occurred under a 532 nm
raising DNA concentration is to disrupt cyanine aggregation in favor laser, possibly due to a depletion of excited state populations caused
25,27
of monomeric dye.
Adding DNA to 5 increased the intensity of by the fluorescence of the corresponding putative DNA-bound H
the dye’s 805 nm absorption maximum while decreasing the height aggregate (Fig. S15, ESI†).
of its 547 band. A similar absorption change was observed when 5
Mechanisms contributing to DNA photocleavage were evaluated
was moved from buffered aqueous solvent expected to promote dye by using chemical agents to modulate direct strand break for-
aggregation (black line in Fig. 1B, no DNA) to DMSO, a polar organic mation. Irradiating reactions in an argon-purged glove box reduced
24
solvent that stabilizes dye monomers (red line in Fig. 1B, no DNA).
strand scission by 5 up to 75%, strongly implicating the involve-
Taken together, the CD and UV-visible data suggest that the 547 nm ment of ground state triplet oxygen (Table S1 and Fig. S16, ESI†).
ꢀ
absorption peak (Fig. 1B and 3) may arise from a DNA-bound A role for Type 1 hydroxyl radicals was then suggested by the OH
H-aggregate, while absorption at 805 nm represents DNA-bound scavenger sodium benzoate, which decreased photocleavage by
monomer. For 5, the absence of an ICD signal corresponding to B40%. Although DNA strand scission was inhibited by the popular
8
05 nm absorption sheds light on a possible mode of DNA Type 2 singlet oxygen scavenger sodium azide, cleavage was
interaction of the putative monomeric dye form (Fig. 3 and Fig. suppressed by B12% when H O was replaced with D O, a solvent
S13, ESI†). While polymethine cyanines that engage in intercalation that produces a 10-fold enhancement in the lifetime of singlet
2
2
31
1
or groove binding typically generate ICDs, induced CD signals are oxygen (Table S1 and Fig. S17, S18, ESI†). This rules against O as
2
frequently absent in the case of chromophores that bind to DNA a contributing ROS and instead points to the residual ability of
2
7–30
ꢀ
32
externally.
The fluorescence spectra of dye 5 (X = Cl) were recorded next
Fig. S14, ESI†). Excitation wavelengths of 550 nm and 800 nm 3 -(4-hydroxyphenyl)fluorescein (HPF) to detect hydroxyl radicals
sodium azide to react with Type 1 OH.
To confirm ROS involvement, we used the fluorescent probes
0
(
s
1
33
were selected to target the putative H-aggregated and monomeric and Singlet Oxygen Sensor Green
(SOSG) to trap
2
O .
dye forms, respectively. Without DNA, 550 nm excitation resulted in In preliminary controls, hydroxyl radicals generated by the Fenton
little if any emission (Fig. S14A, ESI†). When DNA was present reagent (ammonium iron(II) sulphate + H O ) and singlet oxygen
2
2
however, the dye fluoresced markedly. In contrast, no emission was photosensitized by methylene blue were detected by HPF and
observed under the 800 nm irradiation (Fig. S14B, ESI†). Upon DNA SOSG, respectively (Fig. S19, ESI†). Upon irradiating the cyanine
intercalation, the conformational mobility responsible for rapid dye at 830 nm, there was a substantial fluorescence increase when
non-radiative decay of cyanine dyes from the singlet excited state HPF was present in the reaction, vs. a small decrease in the case of
1
7,27
ꢀ
is restricted, leading to large fluorescence enhancements.
same principle has been applied to cyanine dyes that become significantly reduced HPF signal intensity. Considered together with
The SOSG (Fig. 4). Finally, adding the OH scavenger sodium benzoate
17
emissive upon interacting with the DNA minor groove. Taken the data in Table S1 (ESI†), the fluorescence experiments point to
together with the ICD spectra, the fluorescence data suggest that the hydroxyl radicals as the primary ROS responsible for the near-
putative dye monomers responsible for 805 nm cyanine absorption infrared DNA photocleavage sensitized by chlorinated cyanine dye 5.
To evaluate the cellular internalization and intracellular
localization of the synthesized dye, ES2 ovarian carcinoma
3
4
35
cells were analyzed with fluorescence microscopy following
ꢁ
1
incubation with dye 5 (10 mg mL ) for 24 h. The obtained
Fig. 3 Double y-axis plots superimposing the circular dichroism (CD) and
UV-visible absorption (Abs) spectra of dye 5 (22 1C). Samples contained
Fig. 4 Fluorescence spectra recorded in 10 mM sodium phosphate buffer
pH 7.0 without and with 20 mM of 5 and: (A) 3 mM HPF (lex = 490 nm) ꢂ 100 mM
sodium benzoate (SB); (B) 0.75 mM SOSG (lex = 480 nm). Reactions were kept in
the dark or irradiated (hn) at 830 nm for 30 min (22 1C).
1
0 mM sodium phosphate buffer pH 7.0, 10 mM of dye and/or 120 mM
bp (CD) to 150 mM bp (Abs) of CT DNA.
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Conflicts of interest
There are no conflicts to declare.
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2
9
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This work was supported by NIH grants to OT (R37CA234006)
and to MH (R01EB022230) and by grants to MH from the Brains
and Behaviour Seed Grant Program, the Atlanta Clinical & Trans-
lational Science Institute (Healthcare Innovation Program), and the
Georgia Research Alliance Ventures Phase 1 Grant Program. The
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12670 | Chem. Commun., 2019, 55, 12667--12670
This journal is ©The Royal Society of Chemistry 2019