A spiropyran-coumarin platform: An environment sensitive photoresponsive drug delivery system for efficient cancer therapy

Article abstract of DOI:10.1039/c7tb00379j

In spite of inventing several anticancer agents the clinical payoff still remains unsatisfactory because of their severe host toxicity due to their nonspecific biodistribution in the body. To achieve high efficiency in anti-cancer drug delivery, thus, we designed and developed a single component photoresponsive drug delivery system, a fusion of two platforms spiropyran and coumarin, which synchronizes two controlling factors: first, the lower pH of cancer tissue, which acts as an internal control and leads to the ring opening of spiropyran resulting in a distinct colour change and fluorescence activation of coumarin; and second, the release of the anti-tumor drug by the externally controlled light. Highly fluorescent nature and promising biocompatibility make the SP-Cou-Cbl system suitable for cell imaging and in vitro studies.

Full text of DOI:10.1039/c7tb00379j

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Spiropyran-Coumarin Platform: An Environment Sensitive Photoresponsive Drug
Delivery System for efficient cancer therapy
Shrabani Barman,a Joyjyoti Das,b Sandipan Biswas,a T. K. Maiti,b and N. D.
Pradeep Singh*a
Received 00th January 20xx,
Accepted 00th January 20xx
Abstract: In spite of inventing several anticancer agents the clinical payoff still remains unsatisfactory because of their
severe host toxicity due to the nonspecific biodistribution in the body. To achieve high tranquility in the anti-cancer drug
delivery, thus, we designed and developed a single component photoresponsive drug delivery system, a fusion of two
platforms spiropyran and coumarin, which synchronizes two controlling factors: first, the lower pH of cancer tissue, acts as
internal control, leads to the ring opening of spiropyran resulting in distinct colour change and fluorescence activation of
coumarin and second, the release of anti-tumor drug by the externally controlled light. High fluorescent nature and
promising biocompatibility make SP-Cou-Cbl system suitable for cell imaging and in vitro studies.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction:
delivery.19 On the other hand, Coumarin has been tremendously
used as photoresponsive choromophore for drug delivery
Cancer is the most breakneck threat to the mankind at present.
In spite of inventing several anticancer agents the clinical
payoff still remains unsatisfactory because of their severe host
20
(
Scheme 1
(
ii))
because of its natural abundance, nonꢀ
toxicity, bioꢀcompatibility and highly fluorescent nature.21
1
Though the externally triggered photocleavable protecting
toxicity due to the nonspecific biodistribution in the body.
22
group,
coumarin, have several advantages but the main
Vivid discrimination between the cancer cells and the healthy
cells followed by highly precise drug delivery to the diseased
cells is one of the best lead to an efficient chemotherapy.2
In this context, stimuliꢀresponsive drug delivery systems have
proved their potential to optimize therapeutic efficacy and
alleviate unwanted side effects by recognizing tumor
microenvironment followed by targeting cancer cells in a
highly selective manner.3 These intelligent carriers release
cargo as a counter interaction with the intracellular stimuli such
as temperature,4 pH,5 redox,6 enzyme7 etc. The pHꢀsensitive
drug delivery systems attracted a great deal of attention among
all other stimuliꢀresponsive systems because of the acidic
microenvironment of the tumor tissue compared to the normal
tissue. In addition, intervention of an extracorporeal stimulus8
such as light will lead to high spatiotemporal9 control over the
therapeutic delivery 10and extreme dose control.11
drawback is the fluorescent signal is not target specific leading
to zero discrimination between healthy and tumor cells. To
achieve high tranquility in the antiꢀcancer drug delivery, thus,
an ideal system is needed by virtue of which clean release of
drug can be done only at the tumor.
Spiropyran is a wellꢀknown acidochromic12 compound which
shows reversible transformation between two species having
distinguishable absorption spectrum by varying the pH of the
solution. The closed form of spiropyran (SP) contain a CspiroꢀO
bond that cleaved under acidic pH to its zwitterionic
merocyanin (MC) isomer and both of these two form (SP and
MC) are structurally and property wise distinct from each other
(
Scheme 1 (i
)).13 This potential changing ability of structural
Scheme 1: Schematic representation of (i) Acidochromism; (ii) Photoresponsive drug
properties and optical signal output makes spiropyran the ideal
system for optical storage,14 polymer viscosity control,15
photomechanical transduction and actuation,16 bioactivity
switching of proteins,17 tissue engineering18 and drug
delivery from Coumarin moiety; (iii) Spiropyran locked coumarin drug delivery system.
Herein, we designed and developed a single component
photoresponsive drug delivery system,
a fusion of two
platforms spiropyran and coumarin, which synchronizes two
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controlling factors: first, the lower pH of cancer tissue, acts as
internal control, leads to the ring opening of spiropyran
resulting in distinct colour change and fluorescence activation
of coumarin and second, the release of antiꢀtumor drug by the
externally controlled light (Scheme 1 (iii)). The lower pH of
the cancerous region will trigger the sequence by giving optical
output through colour change and fluorescence activation and
next drug will be released by irradiation of light on the
particular detected area leading to a precise delivery of antiꢀ
tumor agents in very controlled manner.
Experimental
Scheme 2: Synthesis procedure of SP-Cou-Cbl.
Synthesis of SP-Cou-Cbl conjugate (DDS):
Compound
literature procedure.11, 23 Final compound (
refluxing compound and in dry methanol (5 mL) for 3 h,
3
(1 equ.) and
4
(1 equ.) were prepared as per
5) was prepared by
3
4
after cooling to room temperature water (100 mL) was added to
the reaction mixture. The formed purple solid was recovered by
filtration and dried in vacuum, afforded 5. 1H NMR (400 MHz,
acetoneꢀd6): δ = 7.79ꢀ7.78 (d, J = 4 Hz, 1H ), 7.70ꢀ 7.69 (d, J =
4 Hz, 1H), 7.55ꢀ 7.46 (t, J = 8 Hz, 2H ), 7.48ꢀ 7.46 (d, J = 8 Hz,
2H), 7.19ꢀ 7.16 (t, J = 4Hz , 1H ), 7.12ꢀ 7.10 (d, J = 8 Hz, 3H ),
6.89ꢀ6.85 (t, J = 8 Hz, 1H), 6.77ꢀ6.72 (t, J = 8 Hz, 1H), 6.66ꢀ
6.64 (d, J = 8 Hz, 1H ), 6.32 (s, 1H), 6.04ꢀ6.01 ( d, J = 12 Hz,
1H), 5.36 (s, 2H), 3.80ꢀ 3.75 (m, 8H), 2.79 (s, 3H), 2.63ꢀ2.60 (t,
J = 8 Hz, ), 2.55ꢀ2.52 (t, J = 4 Hz, 2H), 1.99ꢀ1.97 (t, J = 4 Hz ,
2H), 1.34 (s, 3H), 1.33 (s, 3H). 13C NMR (100 MHz, acetone-
Figure 1: (a) Absorption; and (b) Emission spctra of SP-Cou-Cbl in different acidic pH.
In acidic pH (pH 5 to pH 3), Nꢀatom of indole moiety gets
protonated and promoting the ring opening of spiropyran. This
phenomenon also assist the localization of πꢀelectrons on the
coumarin moiety, exhibiting blue emission (Figure 1b). The
ring opening of spiropyran ring was further confirmed by the
NMR study.
d6): δ = 172.1, 159.3, 157.4, 150.4, 150.0, 147.2, 144.7, 136.2,
130.0, 129.5, 127.6, 125.2, 122.0, 121.4, 120.1, 119.4, 112.2,
111.6, 109.1, 107.1, 106.9, 105.7, 61.0, 53.0, 51.8, 40.7, 33.6,
32.8, 26.7, 25.2, 19.3, 13.4. HRMS cal. For C35H34Cl2N2O5
[MH+]: 632.1845, found: 632.1815.
NMR studies showed the molecular level change during the
process of acid induced ring opening. The spectral overlay
study (Figure 2) showed that in the absence of acid (TFA) the
spiro bond of SPꢀCouꢀCbl remains stable in acetoneꢀd6. While
after addition of TFA to SPꢀCouꢀCbl in acetoneꢀd6, a distinct
spectral change due to the opening of CspiroꢀO bond was
noted. The chemical shift changes induced by TFA, is the
indication of Nꢀprotonation. A significant downfield shift from
2.77 to 3.07 ppm of Nꢀmethyl group of SPꢀCouꢀCbl (indicated
as a) with addition of TFA due to increased positive charge
accompanying Nꢀprotonation was observed. The downfield
shift of vinylic proton, indicated as b, from 6.02 to 6.48 ppm,
can be attributed to the ring opening of spiro ring of SPꢀCouꢀ
Cbl. The spectral change has been given below in a tabular
form (Table 1). The acid induced ring opening of SPꢀCouꢀCbl
further confirmed from the RPꢀHPLC study (Figure S8).
Result and discussion:
The synthesis of spiropyranꢀcoumarin baesd drug delivery
system (DDS) has been outlined in Scheme 2. Formylation of
7ꢀhydroxyꢀ4(hydroxymethyl) coumarin (2) has been carried as
depicted in our previous work.11 After that, simply by
esterification reaction in presence of acid chloride of
Chlorambucil and triethylamine (Et3N) in dimethylformamide
◦
for 8 h at 55 C gave compound
3. Next, condensation of
compound
3 with indole derivative, synthesised as per literature
procedure, afforded our targeted DDS, Spiropyranꢀcoumarinꢀ
chlorambucil (SP-Cou-Cbl). The obtained compounds were
characterised by UVꢀFluorescence, NMR, HRꢀMS analysis
(
Figure S1-S7).
Figure 1a and 1b shows the absorption and emission spectra of
SPꢀCouꢀCbl. In neutral pH, absorption spectrum did not show
any absorption in visible region and no fluorescent was also
noted. On the other hand, a broad absorption band (350 nm to
500 nm) (Figure 1a) and appearance of blue fluorescent
To check the photoꢀinduced anticancer drug release property,
photolysis of SP-Cou-Cbl (1×10ꢀ4 M solution) was carried out
in acetonitrileꢀwater mixture (70:30) using visible light (≥ 410
nm, 125 W, incident intensity (I
0) = 2.886 x 1016 quanta s−1).
The drug release by photo irradiation was monitored by RPꢀ
HPLC. The HPLC chromatogram showed three peaks at tR 4.4
min, tR 5.4 min and tR 7.2 min. Peak at tR 4.4 min corresponds
to anticancer drug Cbl, confirmed by injecting authentic sample
was observed on gradual lowering of pH (pH 7.4
Figure 1b).
pH 3.4)
(
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into the HPLC (Figure S9). The photorelease of Cbl further excited state and finally, iii) singlet excited state undergoes
supported by NMR spectra (Figure S10).
heterolytic cleavage to form photoproduct merocyaninꢀ
coumarinꢀmethanol (MC-Cou-OH) and chlorambucil (Cbl).
Table 1: The spectral change of SP-Cou-Cbl upon addition of TFA
Scheme 3: Possible mechanism of ring opening and photorelease of anticancer drug.
Cellular internalization of SP-Cou-Cbl:
To establish SPꢀCouꢀCbl as an efficient photoresponsive DDS,
the cellular uptake capability was studied against human breast
cancer cell line MDAꢀMBꢀ231, procured from NCCS, Pune and
maintained in DMEM media containing 10% FBS (Gibco,
USA), 100 U/ml streptomycin and 100 U/ml penicillin. Cells
were regularly maintained at 370 C in a humidified cell culture
incubator with an atmosphere of 5% CO2. Briefly, 3×105 MDAꢀ
MBꢀ231 cells were seeded per well of a polystyrene –coated 6ꢀ
well cell culture plate and incubated for 12 hours for proper
attachment and proliferation. Thereafter, cells were incubated
with 10µg/ml of the conjugate, SPꢀCouꢀCbl, for 4 h and after
irradiation with visible light (≥ 410 nm), analysed on Olympus
FVꢀ1000 Confocal microscope. Confocal images of the cells
showed blue fluorescence majorly from the cytoplasm and
partially from the nucleus of the cell (Figure 4 d–f). Notably,
no fluorescence was observed in the control cells (Figure 4 a–
Figure 2: 1H NMR spectral changes of SP-Cou-Cbl (2 × 10-4 M) in acetone-d6 in presence
of different concentration of TFA (0-0.08 M).
The plot (Figure 3a) of percent of drug release against
irradiation time (min) showed that about 82% of drug got
released within 30 min and the ‘ONꢀOFF’ experiment (Figure
3b) proves that the light is solely responsible
for drug
delivery.
c).
Figure 3: (a) Amount of drug (chlorambucil) released from SP-Cou-Cbl at different UV-
light (≥ 365 nm) irradiation time; (b) HPLC peak area of the released chlorambucil vs
Time curve under bright and dark conditions.“ON” indicates the beginning of UV light
irradiation;“OFF” indicates the ending of light irradiation.
Based on the literature survey, we can propose that, the possible
mechanism (Scheme 3) could be i) Nꢀatom of SPꢀCouꢀCbl gets
protonated in acidic pH followed by spiro ring opening of of
SPꢀCouꢀCbl; ii) upon visible light irradiation merocyaninꢀ
coumarinꢀchlorambucil (MCꢀCouꢀCbl) goes to its singlet
Figure 4: Confocal images from the cells treated and untreated with SP-Cou-Cbl for 4 h
: (a–c) control cell; (d–f) SP-Cou-Cbl. (a and d ) bright field; (b and e) blue fluorescence;
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(c and f) overlay images of the bright and fluorescence fields (scale bar = 20 μm). The
nuclear localization is indicated by a black circle.
Anticancer efficacy of SP-Cou-Cbl before and after UV light
irradiation:
Cell cycle analysis
The mode of action of SPꢀCouꢀCbl in MDAꢀMBꢀ231 cells was
investigated through flow cytometry on a BD FACS Aria flow
cytometer. Prior to the experiment, 3×105 MDAꢀMBꢀ231 cells
were seeded in each well of a 6ꢀwell plate and after proper
attachment, they were synchronized by incubation in
incomplete DMEM media for 24 hours. Cells were then treated
or untreated with 20 µg/ml SPꢀCouꢀCbl and after 4 h of
incubation, irradiated with visible light (≥ 410 nm) for 30 min.
After 24 h of irradiation, treated and control cells were analysed
by flow cytometry. As shown in Figure 7a, 8.6% subꢀG0/G1,
57.3% G0/G1, 12.3% S and 21.2% G2/M phase cells were
found in the nonꢀirradiated drug treated control whereas, the
visible light irradiated drug treated cells (Figure 7b) had 12.1%
subꢀG0/G1, 32.4% G0/G1, 16.3% S, and 38.2% G2/M phase
cells after 24 h of incubation. The effect of the photo released
drug, chlorambucil was prominent in the SPꢀCouꢀCbl treated
samples where there was a significant decrease in G0/G1 phase
and corresponding increase in G2/M population confirming
arrest in G2/M phase. A concomitant rise in the sub G0/G1 cell
population is indicative of apoptotic cell death, which was
clearly observed in the visible light irradiated SPꢀCouꢀCbl
treated cells (Figure 7b). In conclusion, SPꢀCouꢀCbl upon
irradiation releases the drug of interest, which induces an arrest
in the G2/M phase of the cell cycle with a simultaneous
increase in the subꢀG0/G1phase of the cells and a decrease in
the G0/G1 phase of the cells.
The anticancer activity of SPꢀCouꢀCbl was evaluated against
human breast cancer cell line MDAꢀMBꢀ231 by MTT (3ꢀ(4,5ꢀ
dimethylthiazolꢀ2ꢀyl)ꢀ2,5ꢀdiphenyltetrazolium bromide) assay.
Briefly, 104 MDAꢀMBꢀ231 cells per ml were seeded in 96 –
well cell culture plates and incubated for 12 h for proper
attachment. Thereafter, various treatments, viz., photoproduct
(PP:MCꢀCouꢀOH), Caged compound (SPꢀCouꢀCbl) and Cbl at
different concentrations (1.25, 2.5, 5, 10, and 20 ꢁg/ mL) were
added in triplicates and appropriate wells were irradiated by
visible light (≥ 410 nm) for 30 min. The plate was then
◦
incubated for 72 hours at 37 C. MTT was then added to the
wells at 4 mg/ml and absorbance data recorded at 595 nm using
a microplate spectrophotometer, MultiSkan Go (Thermo Fisher
Scientific, USA).
The cell viability tests of the before and after photolysis are shown in
Figure 5(a) and Figure 5(b) respectively. The cytotoxicity of PP
and SPꢀCouꢀCbl was significantly lower than Chlorambucil at any
given concentration, for nonꢀirradiated samples. However, for
irradiated samples, SPꢀCouꢀCbl showed a higher cytotoxicity than
free chlorambucil (Figure 5b). This may be due to the efficient
release of the anticancer drug chlorambucil inside the cancer cell. On
the other hand, cells incubated with PP only, post irradiation,
showed insignificant cell death, indicating that the photoreleased
anticancer drug Chlorambucil is solely responsible for the
cytotoxicity. IC50 of SPꢀCouꢀCbl was obtained close to 10 µg/ml.
To further confirm the results, 3×105 MDAꢀMBꢀ231 cells per well
of a 6ꢀwell plate were incubated with 20 ꢁg/ ml of SPꢀCouꢀCbl for 4
hours and irradiated by visible light (≥ 410 nm) for varying lengths
of time (5, 10, 20 and 30 min). The plate was then incubated for 24
hours at 37 ◦C in a humidified cell culture incubator with an
atmosphere of 5% CO2. Confocal microscopy images (Figure 6),
revealed that cells incubated with SPꢀCouꢀCbl showed a decrease in
cell viability (as indicated by increased round floating cell
population) with an increase in the irradiation time (0–30 min),
confirming the controlled drug release. The higher cytotoxicity of
SPꢀCouꢀCbl treated cells compared to free chlorambucil treated
cells, after UV light irradiation suggests that SPꢀCouꢀCbl can
effectively enhance the efficiency of the intracellular delivery of the
drug chlorambucil and be an excellent drug delivery system.
Figure 6: Anticancer activity study of SP-Cou-Cbl in MDA-MB-231 by confocal
microscopy: Top panel shows fluorescence images and bottom panel shows bright field
images. (a) Cells without irradiation; Cells with visible light (≥ 410 nm) irradiation Cells
after (b) 5 min (c) 10 min, (d) 20 min and (e) 30 min. (scale bar = 20 μm). White arrows
indicate dead cells. (i) Fluorescent field; (ii) Bright field.
Figure 5: The cell viability studies of SP-Cou–Cbl, MC-Cou-OH and Cbl (0.1–10 mg mL-1)
was depicted (a) before photolysis; and (b) after photolysis.
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Figure 7: Cell cycle analysis: Flow cytometry for cell cycle analysis of the (A) control
cells after 24 h and (B) cells + 20 µg/mL SP-Cou-Cbl, irradiated for 30 min and incubated
for 24 h.
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Conclusion:
Here, we have demonstrated for the first time a spiropyran
locked coumarin system for efficient photoregulated drug
delivery. It can locate tumor by the appearance of blue
fluorescent color due to the unlocking of the coumarin ring by
the acidic nature of tumor cell. Drug can be released in a dose
controlled manner by the use of externally regulated light
source. High fluorescent nature and promising biocompatibility
make SPꢀCouꢀCbl system suitable for cell imaging and MDAꢀ
MBꢀ231 cells was used for in vitro studies.
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Acknowledgements
We thank the DST (SERB) for financial support and the DSTꢀ
FIST for 400 MHz NMR. We are grateful to the Indian Institute
of Technology Kharagpur and UGC (India) for our research
fellowships.
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Notes and references
[a] Prof. N. D. Pradeep Singh, Shrabani Barman, Sandipan Biswas,
Department of Chemistry, Indian Institute of Technology Kharagpur
721302,
West
Bengal,
India
*Eꢀmail: ndpradeep@chem.iitkgp.ernet.in
[b] Prof.T. K. Maiti, Joyjyoti Das. Department of Biotechnology, Indian
Institute of Technology Kharagpur 721302, West Bengal, India
†
Electronic Supplementary Information (ESI) available: [General
experimental procedure, Characterization of compounds 2, 3, 4 and 5, the
physical characteristics of compound 5, HPLC chromatogram of photolysis
and ring opening of compound 5.
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