A Platinum(II) Complex of Heptamethine Cyanine for Photoenhanced Cytotoxicity and Cellular Imaging in Near-IR Light

Article abstract of DOI:10.1002/anie.201806911

Controlled generation of cytotoxic agents with near-IR light is a current focus of photoactivated cancer therapy, including that involving cytotoxic platinum species. A heptamethine cyanine scaffolded Pt^II complex, IR797-Platin exhibits unprecedented Pt?O bond scission and enhancement in DNA platination in near-IR light. This complex also displayed significant singlet oxygen quantum yield thereby qualifying as a near-IR photodynamic therapeutic agent. The complex showed 30–60 fold enhancement of cytotoxicity in near-IR light in various cancer cell lines. The cellular imaging properties were also leveraged to observe its significant co-localization in cytoplasmic organelles. This is the first demonstration of a near-IR light-initiated therapy involving the cytotoxic effects of both active cisplatin and singlet oxygen.

Full text of DOI:10.1002/anie.201806911

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Angewandte
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Accepted Article
Title: A Novel Platinum(II) Complex of Heptamethine Cyanine for
Photo-Enhanced Cytotoxicity and Cellular Imaging in Near-IR
Light
Authors: Koushambi Mitra, Chrales Lyons, and Matthew Charles
Tomandl Hartman
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806911
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10.1002/anie.201806911
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COMMUNICATION
A Novel Platinum(II) Complex of Heptamethine Cyanine for Photo
Enhanced Cytotoxicity and Cellular Imaging in Near-IR Light
Koushambi Mitra,[a,b] Charles E. Lyons, [b] and Matthew C. T. Hartman*[a,b]
Abstract: Controlled generation of cytotoxic agents with near-IR light
is a current focus of photoactivated cancer therapy, including that
involving cytotoxic platinum species. Herein, we present a novel
heptamethine cyanine scaffolded Pt(II) complex, IR797-Platin (1),
which exhibits unprecedented Pt-O bond scission and enhancement
in DNA platination in near-IR light. Complex 1 also displayed
significant singlet oxygen quantum yield thereby qualifying as a near-
IR photodynamic therapeutic agent. Complex 1 showed 30-60 fold
enhancements of cytotoxicity in near-IR light in various cancer cell
lines. The cellular imaging properties of 1 were also leveraged to
observe its significant co-localization in cytoplasmic organelles. This
is the first demonstration of a near-IR light-initiated therapy involving
the cytotoxic effects of both active cisplatin and singlet oxygen.
over clinically established photodynamic therapy (PDT), which
relies on generation of cytotoxic singlet oxygen and therefore fails
in the treatment of deep-seated hypoxic tumors.[10]
Recently, there have been a few successful efforts to photo-
release bioactive Pt(II) species.[11a] Carboplatin and its 7-
azaindole based analogues were shown to form bifunctional Pt-
DNA adducts on UVA light exposure.[11b,c] Another similar
example constitutes the novel Pt(II) complexes of curcumin which
demonstrated visible light enhanced formation of Pt-DNA
crosslinks.[11d,e] However, these approaches are limited by i)
collateral tissue damage caused by UVA light and ii) the poor
tissue penetration of light at these wavelengths.[8e] Thus, an ideal
Pt(II) based photo-initiated chemotherapeutic agent should be
activated in the “biological window” of 650-850 nm which has
improved tissue compatibility and penetrating properties.[7, 8e]
From these observations, we reasoned that it might be
possible to release a bioactive Pt(II) species from its complex with
a ligand that absorbs strongly in the near-IR region. Among
potential organic chromophores, the heptamethine cyanine dyes
have strong near-IR absorption, are easy to access synthetically,
and are widely used as imaging and PDT agents.[12, 13] Moreover,
these cyanine dyes accumulate preferentially in the mitochondria
and lysosomes. Targeting these cytoplasmic organelles is known
to overcome drug-resistance and afford improved cytotoxicity of
traditionally used anticancer agents.[14, 15]
Based on the precedent of existing platinum(II)
photoactivatable complexes,[11a] we posited that a diammine
bound Pt(II) system having a photodetachable O^O bidentate
donor in direct conjugation with the heptamethine cyanine
framework would release an active cisplatin on near-IR light
exposure. To realize our hypothesis, we successfully designed a
Pt(II) conjugate of heptamethine cyanine, which we call IR797-
Platin, 1 (Figure 1a). Herein, we describe the synthesis and
evaluation of photo-enhanced DNA binding properties and
cellular cytotoxicity of 1.
The FDA validated platinum based anticancer drugs cisplatin,
oxaliplatin and carboplatin form the centerpiece of metal-based
anticancer drug therapy.[1] The putative mechanism of cytotoxicity
relies on an initial Pt-X (X = Cl, O) bond scission to form aquated
Pt(II) species. These activated Pt(II) species can then react with
nuclear DNA and form cyto-lethal Pt-DNA crosslinks ultimately
leading to apoptotic cell death.[2] However, the anarchic hydrolytic
behavior of these drugs leads to undesired systemic toxicity and
limits the administration of higher drug-dosage levels. Controlled
generation of the bioactive (aquated) form of platinum(II) drugs
specifically within the targeted tumor is, therefore, an ideal way to
prevent the off-target toxicity.[3] To gain control over the kinetics
of metal-ligand bond rupture, Pt(IV) complexes were introduced
as inert prodrugs which produce DNA damaging platinum(II)
species only upon reduction by cell-abundant glutathione.[4,5]
These Pt(IV) complexes showed promising tumor-targeted
anticancer activities and oftentimes resulted in delivery of multiple
drugs and adjuvants. Though efficacious, this strategy relies on
endogenous entities for drug activation and thus the regulation of
cytotoxicity is lost once the drug is administered. In another
approach, platinum(II) cytotoxins were generated from
photosensitive Pt(IV) diazido molecules with light.[6] The
exploitation of exogenous light for uncaging “active”
chemotherapeutics offers a spatio-temporal control over drug
activation.[7-9] Such photo-initiated chemotherapy has advantages
The new acetylacetone (Hacac) derivative of heptamethine
cyanine, IR797-acac was successfully synthesized in one step
from
a chloro cyanine precursor (Figure S1a, Supporting
information). IR797-Platin, 1 was prepared by reacting this ligand
with cisplatin after pre-activation with AgNO3. To understand the
role of the organic chromophore and light, we also prepared a
cyanine-lacking analog, [Pt(NH3)2(acac)](NO3)], 2 and used it as
a control in our experiments (Figure S1b, Supporting information).
The newly synthesized compounds were characterized by
analytical and spectroscopic techniques (Figures S2-S8,
[a]
Department of Chemistry,
Virginia Commonwealth University
1001 West Main Street, P. O. Box 842006, Richmond,
VA 23284, USA.
E-mail: mchartman@vcu.edu
1
Supporting information). H NMR spectra of 1 displayed signals
[b]
Massey Cancer Center,
assignable to the cyanine scaffold (Figure S5, Supporting
information). A notable upfield shift of 0.3 ppm observed for the
methyl protons of acac in 1 supported coordination of the oxygen
atoms to Pt(II) center. A single mass spectra signal at m/z value
of 380.6 with a Pt isotopic distribution pattern and a bi-positive
Virginia Commonwealth University,
401 College Street, Richmond, VA 23298, USA.
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201806911
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COMMUNICATION
charge of the fragment implicated the successful formation of 1
(Figure S7, Supporting information). The purity of 1 was also
verified using analytical HPLC (Figure S8, Supporting
information).
at different time intervals. To our gratification, we observed the
appearance of a new signal (m/z of 533.3) which corresponds to
the free ligand IR797-acac within a brief irradiation time (Figure
S12, Supporting information). A portion of this photo-exposed
sample when subjected to HPLC depicted the appearance of a
peak which was collected and characterized as free IR797-acac
(inset of Figure S12, Supporting information). This clearly
indicates the Pt-O bond in 1 rapidly dissociates and liberates the
free ligand on near-IR light exposure (Figure 1c). On further
irradiation, an increase in relative counts at m/z of 565.3 was
observed (Figures S13, Supporting information). This signal is
attributed to the isomeric 1,2-dioxetanes, P1a and P1b and is
consistent with oxidative reaction of released IR797-acac and
singlet oxygen.[16b] On warming the solutions to 37 °C for 1 h, new
m/z signals at 202.2, 176.1 and 390.2 were seen which are
assignable to the smaller degraded products P2-P4 (Figures S14-
S16, Supporting information). Irradiation of 1 also lead to a peak
of m/z 396.5 which is consistent with 1,2-dioxetane (P5a/ P5b)
formation (Figure S17, Supporting Information). In the absence of
light, 1 showed no decomposition (Figure S18a, Supporting
information). The accumulation and disappearance of these
products over time, as discerned from a light-dose-dependent LC-
MS analysis, helped us to propose the sequential photolytic
scheme (Figure 1c, Figure S18b, Supporting information). 1H
NMR studies of 1 and IR797-acac further demonstrated the
formation of similar photoproducts on near-IR light exposure
(Figures S19, S20, Supporting information).[16a] The importance of
singlet oxygen for degradation was confirmed from retention of
absorption and emission intensity when irradiated under inert
atmosphere or in presence of NaN3, a singlet oxygen quencher
(Figure S21, Supporting information). When the same set of
experiments was carried out with IR797-acac, we also observed
formation of P1-P4 (Figure S22, Supporting information) in
accordance with the known photooxidative degradation of
cyanine dyes.[16b]
Complex 1 and ligand IR797-acac showed comparable
absorption profiles with a maxima at 790 nm and a high molar
extinction coefficient (ε) of 4-5 x104 M-1.cm-1 (Figure S9a, Table
S1, Supporting information). Such strong near-IR absorptions are
rare for metal complexes.[8,9] It was previously noted that the N or
O substitution in heptamethine cyanine dyes resulted in a large
absorption blue-shift of ~100 nm.[16a,b] Interestingly, the C-
substituted variants, IR797-acac and 1 retained the maximum
absorbance in the near-IR region. The free ligand showed intense
emission at 825 nm (φf = 0.53) reflecting a characteristic small
Stokes shift of 25 nm (Figure S9b, Table S1, Supporting
information). Complex 1 imitated the emissive features of IR797-
acac (λemi = 820 nm, φf = 0.32), but showed partial quenching due
to the diamagnetic Pt(II) center.
The widely perceived mechanism holds that “bioactive Pt(II)
DNA-philes” are responsible for cisplatin cytotoxicity.[1b, 2] In order
to track the fate of the released Pt(II) species upon irradiation of
1, we chose to perform the release experiments in the presence
of pyridine (py), a simple monodentate N donor which should trap
any reactive Pt(II) species. A solution containing 1 (20 μM) and
pyridine (50 μM) was exposed to near-IR light and subjected to
mass spectral analysis. Predominant peaks at m/z of 193.6 and
256.4 assignable to [Pt(NH3)2(py)2]2+, P6, and [Pt(py)4]2+, P7,
fragments were duly noted only in light exposed solutions (Figure
2a, Figure S23, Supporting information). Formation of P6 and P7
were not observed in light-unexposed controls. The formation of
these Pt-pyridine adducts therefore likely proceeded via an initial
diaqua diammine Pt(II) species. These reactive Pt(II) species also
formed covalent adducts with ctDNA which increased over time.
ICP-MS measurements revealed enhanced platination of isolated
ctDNA (2-7 ng of Pt/ μM of ctDNA) when complex 1 (50 M) was
exposed to near-IR light compared to controls in the dark (Table
S2, Supporting information). As expected, we did observe slow
incorporation of Pt(II) into DNA upon extended incubation of
ctDNA with 1 or 2 in the dark (Table S2, Supporting Information).
The DNA melting experiments and Hoechst displacement assays
revealed 1 and IR797-acac interact with the minor groove of
ctDNA in the dark (Figure S24, Supporting information).[17a]
Figure 1. (a) Chemical structure of cationic IR797-Platin, 1. (b)
Absorption spectral traces of complex 1 (3 μM in 0.1% DMSO-PBS)
exposed to light (readings at 30 sec and 1 min intervals) showing
decrease in intensity at 790 nm and increase in intensity at 430 nm. (c)
Proposed mechanism of photo-degradation of 1 when exposed to near-
IR light (panel of LEDs, 720-740 nm, 3.5 ±1.5 mW/cm2).
Near-IR light-triggered uncaging of C4’-amine-substitued
cyanine analogs was recently demonstrated by Schnermann and
co-workers.[16] This finding, coupled with the observations
suggesting that the Pt(II)-O bonds are photolabile,[11] prompted us
to examine the photo-degradation pathways of 1. We performed
the stability studies in solvents relevant to cell-culture settings i.e.
1% DMSO in PBS or DMEM at biological pH of 7.4. The photo
reactivity of 1 and IR797-acac was demonstrated by the rapid
decrease in absorbance at 790 nm and a concomitant gradual
increase at 410 nm when exposed to near-IR light (Figure 1b,
Figure S10, Supporting information). The half-lives (t1/2L) of
photodecomposition were found to be ~ 40 secs and 2 min for
IR797-acac and 1 respectively. They exhibited considerable
stability in dark conditions with t1/2D of ~ 10 h and 20 h respectively
(Figure S11, Table S1, Supporting information).
The light affected reaction course was discerned from LC-
MS chromatographic elution of the photo-exposed solutions of 1
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10.1002/anie.201806911
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COMMUNICATION
Unmodified heptamethine cyanines display poor singlet
oxygen generation quantum yields.[17b] However, heavy atoms
when aptly incorporated in a fluorogenic scaffold tend to increase
the singlet oxygen generation via populated triplet excited
states.[13b,18] The near-IR light induced rapid decrease in the
absorbance of 1,3-diphenylisobenzofuran (DPBF) at 415 nm in
presence of complex 1 (t1/2DPBF = 30 sec, φΔ = 0.15) demonstrated
the generation of singlet oxygen (Figure 2b and c, Figure S25,
near-IR light-mediated cytotoxicity (IC50 = 0.12-2 μM) with a 30-
60-fold enhancement in potency with light (Figure 4a and b, Table
1). The toxicity caused by 1 in unexposed cells was comparable
to 2 and cisplatin under similar conditions. Consistent with other
heptamethine cyanine dyes, IR797-acac was toxic on its own. [16b]
However, neither IR797-acac alone or in combination with
Supporting information). In comparison, free IR797acac showed
DPBF
much weaker singlet oxygen production (t1/2
= 6 min, φΔ =
0.017). Therefore, complex 1 is expected to have dual-modes of
cytotoxicity through reactive Pt(II) and PDT.
Figure 3. Computational studies using B3LYP/LANL2DZ (for Pt) and 6-
31+G (for O,N,C and H) functionals performed on 1 to obtain (a) energy-
minimized structure and (b-d) the electronic distributions of molecular
orbitals involved in transitions in the near-IR region. The heteroatoms are
labelled and hydrogen atoms are omitted for clarity.
cisplatin showed much enhancement in potency with light. (Table
1 and S7, Supporting information). The cytotoxic activity of 1
relied on light-induced reactive oxygen species, which initiated
cellular
apoptosis
as
demonstrated
by
DCFDA
(dichlorofluorescein diacetate) and annexinV-FITC (fluorescein
isothiocyanate) assays (Figures S33, S34, Supporting
information). Confocal microscopic experiments showed notable
co-localization of 1 in the mitochondria and lysosomes (Figure 4c,
Figure S35 Supporting information). This emphasizes the
Figure 2. (a) ESI-MS of photolysed samples of 1 and pyridine showing
m/z peaks assignable to P6 and P7 (for full spectra, vide SI). (b)
Decrease in absorbance of DPBF treated with complex 1 (3 μM in 0.1%
DMSO-PBS) and irradiated with light of 720-740 nm (first reading at 30s
and then at intervals of 1 min). (c) Scatter plot comparing decrease in
absorbance of DPBF for 1 (gray squares) and IR797-acac (black circles)
at 415 nm with time of irradiation in near-IR light.
The cleavage of Pt(II)-O bonds with near-IR light is
unprecedented. To better understand this process, we performed
theoretical calculations. DFT (density functional theory) optimized
geometry of 1 revealed a square planar Pt(II) and one of the
indole rings in a parallel orientation with the acac moiety (Figure
3a, Tables S3). The computed transitions showed that near-IR
excitation of 1 involves charge transfer from orbitals having
significant localization on both cyanine and Pt(II) (Figure 3b-d,
Table S4, Supporting information). Characterization of the photo-
dissociating excited triplet state depicted involvement of d*
orbitals of Pt and elongation of the Pt(II)-O and Pt(II)-N bonds by
~0.15 Å in the optimized geometry (Figure S26, Table S5,
Supporting information). This rationalizes the observed photo-
induced bond-dissociation in 1.[19] Also predicted transitions of the
1,2-dioxetanes (P1a/ P1b) resulted in weak near-IR absorption
which indicates that they can only thermally degrade to form the
products P2-P4 (Figure S27, Table S6, Supporting information).
Encouraged by the ability of 1 to both produce singlet
oxygen and release DNA-binding Pt(II) species in near-IR light,
we next assessed the cytotoxic effects of 1 in a panel of human
cancer cell lines (Figure 4a and b, Table 1, Figures S28-S32,
Table S7, Supporting information). Complex 1 exhibited excellent
Figure 4. Cell viability plots showing % viability as obtained in 1 treated
(a) C-33 A and (b) MCF-7 cells for 4 h in dark and either photoexposed
(near-IR light, 45 mins, red circles) or unexposed (dark, black squares)
conditions. c) Confocal microscopic images in C-33 A cells showing
DAPI(4',6-diamidino-2-phenylindole, nuclear stain) in 1st column, trackers
(Mito-Tracker® Green, 1st row; Lyso Tracker® Red DND-99, 2nd row) in
2nd column, complex 1 in 3rd column and merged of all three channels in
4th column. The near-IR emission of complex 1 is reproduced in orange
colour. Scale bar = 10 μm. The scatter plots show degree of overlap
between images in 2nd and 3rd column. Higher Pearson correlation
coefficient (P.C.C.) indicates higher co-localization.
important role of heptamethine cyanine backbone which
successfully directs
1 towards the cytoplasmic organelles.
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COMMUNICATION
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Furthermore, 1-treated and light-exposed cells had higher Pt
content (quantified by ICP-MS) in the nuclear fractions (Table S8,
Supporting information) as compared to dark controls. This
supports light-promoted release and migration of active Pt(II)
species to the nuclear DNA following a similar mechanism known
for cisplatin, carboplatin and oxaliplatin.[2]
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In conclusion, here we demonstrate both active Pt(II)- and
PDT-mediated cytotoxicity in near-IR light of a new Pt(II)-cyanine
conjugate. The dual roles of platinum in triggering singlet oxygen
production and bond-dissociation offer an innovative strategy for
simultaneous realization of PDT and uncaging of anticancer
agents. Moreover, the retention of strong absorption and emission
features in the near-IR region in these C-substituted
heptamethine cyanines makes them attractive theranostic agents
for clinical applications. Also, the subcellular distribution of 1 is
important considering the recent paradigm shift for targeting
anticancer agents to cytoplasmic organelles. We are hopeful that
our findings will open up heretofore unexplored avenues of metal-
based photo-chemotherapeutics offering non-surgical and
externally regulated modalities for cancer treatment.
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Compound
C-33 A
MCF-7
Light[b]
Dark
Light[b]
Dark
Complex 1
IR797-acac
CP[c]
0.14 ± 0.05
0.30 ± 0.07
16.1 ± 1.5
0.25 ± 0.15
8.4 ± 1.4
1.2 ± 0.1
17.7 ± 1.5
1.4 ± 0.8
0.65 ± 0.23
4.7 ± 0.8
18.2 ± 3.2
5.9 ± 0.3
25.0 ± 2.2
2.6 ± 1.4
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22.5 ± 3.2
0.88 ± 0.17
CP +
IR797-acac
[a]Cells treated with compounds for 4 h in the dark. [b]Cells treated with
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Acknowledgements
This research was supported by grant funding from Virginia’s
Commonwealth Health Review Board (236-03-16). The ESI
instrument is part of the MCC Proteomics Resources supported
by CCSG grant NCI 5P30CA16059-35. The authors thank Mr. N.
A. Abrigo, Dr. F. White, Dr. J. Turner and Dr. R. Cao for their help
with HPLC, confocal, ICP-MS and lifetime measurements.
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Res. 2016, 49, 1731-1740.
Keywords: Platinum • photodynamic therapy • cancer • cyanines
• imaging agents
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Entry for the Table of Contents
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A platinum(II) complex of
Koushambi Mitra, Charles E. Lyons,
Matthew C. T. Hartman*
heptamethine cyanine, IR797-
Platin, showed near-IR light
induced Pt-O bond dissociation
leading to enhanced DNA
platination. IR797-Platin also
showed significant singlet oxygen
generation which resulted in
mitochondria-targeted PDT effects
in cancer cells.
Page 1. – Page 5.
A Novel Platinum(II) Complex of
Heptamethine Cyanine For Photo
Enhanced Cytotoxicity and
Cellular Imaging in Near-IR Light
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