Semiconductor quantum dots photosensitizing release of anticancer drug

Article abstract of DOI:10.1039/c0cc04676k

A new photo-controlled anticancer drug release system is reported based on the photo-induced electron transfer (PET) between semiconductor quantum dots (QDs) and N-methyl-4-picolinium (NAP) ester 1 under the excitation of visible light.

Full text of DOI:10.1039/c0cc04676k

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Semiconductor quantum dots photosensitizing release of anticancer drugw
Zhenzhen Liu, Qiuning Lin, Qi Huang, Hui Liu, Chunyan Bao,* Wenjin Zhang,
Xinhua Zhong and Linyong Zhu*
Received 29th October 2010, Accepted 18th November 2010
DOI: 10.1039/c0cc04676k
A new photo-controlled anticancer drug release system is
reported based on the photo-induced electron transfer (PET)
between semiconductor quantum dots (QDs) and N-methyl-4-
picolinium (NAP) ester 1 under the excitation of visible light.
as an excellent PET-based photolabile group by the Falvey
group, allowing activation by a wide variety of photo-
reductants.12,13 In addition, semiconductor quantum dots
(QDs) are often used as excellent photosensitizers due to their
appropriate reduction potentials at ca À1.1 V vs Fc/Fc+14 and
outstanding photosensitive property that can generate 4 or
more electron-hole pairs upon photoexcitation.15 Based on
these properties, we prepared a new NAP ester 1 linked with
an anticancer drug 5-fluorouracil acid (5-FUA) as an electron
acceptor to generate photo-controlled release. In this
system, water soluble QDs capped by pentaerythritol tetra-
(3-mercaptopropionate)-polyacrylic acid (PTMP-PAA) and
L-cysteine were used as the photosensitizer and electron donor,
respectively. Herein, the QDs are expected to act as net
electron shuttles to transfer an electron between the electron
donor and the NAP ester 1 (as shown in Scheme 1). To
the best of our knowledge, this is the first example of the
application of PET method to photo-responsive drug release
system.
Recently, photo-responsive controllable releases have
attracted more and more attention and interest for their
amazing applications in the area of drug delivery and cancer
therapy, where light offers a highly orthogonal external
stimulus and provides a control at a specific time and location
for phototherapy.1–3 Generally, changes in physical and
chemical properties induced by light controls the photo-
responsive release. For example, the use of photothermal
effects of gold nanomaterials to achieve photo-controlled
release is a typical physical method.4 For chemical methods,
there are two strategies for facilitating photo-responsive
controllable release. The first strategy is often referred as
‘‘caging’’ and involves temporarily deactivating a biologically
active drug molecule by employing a phototrigger. Commonly
used phototriggers include nitrobenzyl alcohol,5 phenacyl
ester,6 and coumarinyl7 derivatives. The second strategy is to
utilize bistable photoswitches, such as the use of azobenzene
derivatives to control release by the photoisomerization of
azobenzene.8 One significant limitation of the aforementioned
strategies is the use of UV light, the intensity of which is
attenuated quickly in tissue.9 Among many attempts to avoid
using cytotoxic UV light, one effort is to design new photo-
triggers that can absorb at higher wavelengths.10 However this
approach encounters difficulty of synthesizing and extending
the conjugation of the phototriggers without adversely
affecting the bond cleavage rates and selectivity. Another
approach is to utilize two-photon excitation,11 however it is
expensive due to the need of a fs-mode laser and less sensitive
due to the low two-photon absorption cross section.
NAP ester 1 was synthesized using general ester synthesis
techniques, and water soluble PTMP-PAA-capped QDs were
prepared as usual (see supporting informationw). Generally,
NAP ester 1 was mixed with QDs and electron donor in
phosphate-buffered saline (PBS solution) (pH
= 7.4,
0.01M). The obtained solutions were then purged with
N2 for ten minutes and irradiated with visible light (UV-cut,
l > 400 nm, 62 mW cmÀ2) for prescribed periods of time, and
then analyzed by HPLC spectroscopy.
The feasibility of a photorelease mechanism for this system
was first supported by two characterizations as follows.
In this paper we demonstrate a new anticancer drug release
system based on sensitized photo-induced electron transfer
(PET) upon the irradiation with visible light. In this system, an
excited sensitizer initiates an electron transfer to a photolabile
group, which induces the release of the attached drug molecule
(as shown in Scheme 1). This promising method decouples the
light absorption step from photo-responsive release, and
makes it possible to optimize each of the two steps inde-
pendently. The N-alkyl-4-picolinium (NAP) has been reported
Key Laboratory for Advanced Materials, Institute of Fine Chemicals,
East China University of Science and Technology, Shanghai, 200237,
China. E-mail: baochunyan@ecust.edu.cn, linyongzhu@ecust.edu.cn;
Fax: +86-21-64253742; Tel: +86-21-64253742
w Electronic supplementary information (ESI) available: Full experi-
mental details and the Stern–Volmer analysis. See DOI: 10.1039/
c0cc04676k
Scheme 1 Schematic presentation of QDs photosensitized drug
release process by photo-induced electron transfer mechanism.
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1482 Chem. Commun., 2011, 47, 1482–1484
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insignificant amount of 5-FUA, which suggested that the
release occurred effectively upon the irradiation of light only
when photosensitizer QDs, NAP ester 1, and electron donor
L-cysteine coexisted in the system as a supramolecular
complex. Here, the photosensitizer QDs and not the prodrug
adsorbed the light, and then the sensitized QDs transferred an
electron to NAP ester 1 which induced the cleavage of the
5-FUA. The donor in the system then supplied an electron to
QDs which promoted the progress of cleavage (as shown in
Scheme 2).12 The allowance of the light absorption step
decoupling from the drug release provided the opportunity
to tune the properties of QDs to optimize the release, thus
permitting more control over the wavelengths of light used in
the release process.
The precise control of the photolytic release was demon-
strated by monitoring the progress of 5-FUA release after
periods of exposure to light and dark conditions, as shown in
inset of Fig. 1a. The distinctive ‘‘stepped’’ profile revealed that
the drug release proceeded under light conditions and realized
the ‘‘light-controlled precise release’’. HPLC analysis profiles
in Fig. 1b further confirmed that the release of 5-FUA was
increased in line with the consumption of prodrug under
visible light irradiation. In the HPLC detection process, the
radical fragment of N-methyl-4-picolinium (NAP) salt
generated from NAP ester 1 was not found. It may be
attributed to the radical decays through a variety of pathways,
since the fate of radical fragment under these conditions was
not known with certainty.12
Fig. 1 (a) Time course of photolysis process for drug release of
5-fluorouracil acid in PBS solution (pH = 7.4) under different
conditions. Inset is the partial process for drug release of the
PET-based drug release system (NAP ester 1 + QDs + L-cysteine)
under bright and dark conditions. ‘‘ON’’ indicates the beginning of
light irradiation; ‘‘OFF’’ indicates the ending of light irradiation.
(b) HPLC charts detected at 254 nm for the system of NAP ester 1 +
QDs + L-cysteine subjected to visible light irradiation for different
lengths of time. The concentrations are 0.6 mM for NAP ester 1,
0.1 mM for QDs (lem = 602 nm), and 0.03 M for L-cysteine,
respectively. The data in Fig. 1a were determined by HPLC analysis,
relative to NAP ester 1 in dark conditions, and the used light was
visible light (UV-cut, l > 400 nm, 62 mW cmÀ2).
To optimize the release conditions, NAP ester 1 was
subjected to filtered (l > 400 nm) irradiation with two kinds
of CdSe/ZnS QDs with different emission wavelength, as
shown in Table 1. In both cases, 5-FUA was released
efficiently under identical photolysis conditions. The drug
release for QDs with the emission at 625 nm (QDs625) was
lower than that of QDs602; we attribute this to the relatively
larger reduction potentials which promoted the photolysis
process. The higher electron transfer rate constant for
QDs602 also agreed with the higher release efficiency
(see supporting informationw). Recently, transition metal
ion-doped quantum dots not containing heavy metal ions have
attracted much attention because of their low toxicity
compared to CdSe QDs.17 In this work, Mn doped
ZnSe (Mn:ZnSe) QDs (lem = 585 nm) was used as a photo-
sensitizer for release of 5-FUA. As shown in Table 1,
5-FUA was released successfully with 64% drug release
achieved after 30 min irradiation. These studies indicate that
we have the chance to optimize our drug release system
by using suitable QDs with longer emission wavelength and
less toxic components.
Firstly, from the thermodynamics calculations, the driving
force for the electron transfer step was estimated by the
reduction potential, Ered, of NAP ester 1 and QDs. The
reduction potential of NAP ester 1 was À0.91 V vs Fc/Fc+,
determined by cyclic voltammetry (CV) experiments at a scan
rate 100 mV sÀ1, and the reduction potential of PTMP-PAA
capped water-soluble CdSe/ZnS QDs was around À1.1 V vs
Fc/Fc+, which was sufficiently negative to reduce our NAP
ester 1 in a mediated PET mechanism (see supporting
informationw ).Secondly, the Stern–Volmer analysis (see sup-
porting informationw) also indicated that the NAP ester reacts
rapidly with the singlet states of the photosensitizer QDs with
the rate constants ca B1011 MÀ1
cantly larger than the diffusion controlled kinetics (near 1 Â
1010 MÀ1 À1).16 This analysis also suggested some type of
S
À1, which is signifi-
S
binding interaction, and NAP ester 1 should be absorbed on
the surface of the QDs by electrostatic action in the drug
release system, which promotes the process of PET-based
release mechanism.
To further confirm the PET-based release, control photo-
lysis experiments that lack either photosensitizer QDs or the
combination of QDs and L-cysteine were carried out as shown
in Fig. 1a. The lack of any components resulted in an
Scheme 2 Proposed mechanism for QDs-based photolysis release.
Chem. Commun., 2011, 47, 1482–1484 1483
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Table 1 Data for NAP ester 1 photolysis release experiments with different QDs and different donors
a
[NAP ester 1] (mM)
[QD] (0.1 mM) lem
Ered
Donor (0.03 M)
Drug release (%)
NAP ester 1 consumed (%)
1
2
3
4
5
6
0.6
0.6
0.6
0.6
0.6
0.6
CdSe/ZnS QD602
CdSe/ZnS QD625
CdSe/ZnS QD602
CdSe/ZnS QD602
CdSe/ZnS QD602
Mn:ZnSe QD585
À1.14
À1.06
À1.14
À1.14
À1.14
À1.16
L-cysteine
L-cysteine
DTT
TEA hydrochloride
EDTA
L-cysteine
53.6
36.0
56.3
12.0
7.9
75.3
38.0
87.4
14.0
11.3
75.0b
64.0b
Light source: UV-cut, l > 400 nm, 62 mW cmÀ2; irradiation time is 15 min.a Reduction potential using ferrocene as internal standard.
b
Irradiation time is 30 min.
The effect of electron donors for this PET-induced photo-
Notes and references
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release by external manipulation of irradiation time,
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