Angewandte
Chemie
DOI: 10.1002/anie.201402189
Cancer Nanotechnology
Conjugated-Polyelectrolyte-Based Polyprodrug: Targeted and Image-
Guided Photodynamic and Chemotherapy with On-Demand Drug
Release upon Irradiation with a Single Light Source**
Youyong Yuan, Jie Liu, and Bin Liu*
Abstract: Nanomaterials that combine diagnostic and thera-
peutic functions within a single nanoplatform are highly
desirable for molecular medicine. Herein we report a novel
theranostic platform based on a conjugated-polyelectrolyte
(CPE) polyprodrug that contains functionality for image,
chemo- and photodynamic therapy (PDT), and on-demand
drug release upon irradiation with a single light source.
Specifically, the PEGylated CPE serves as a photosensitizer
and a carrier, and is covalently conjugated to doxorubicin
through a linker that can be cleaved by reactive oxygen species
(ROS). Under appropriate light irradiation, the CPE can
generate ROS, not only for PDT, but also for on-demand drug
release and chemotherapy. This nanoplatform will offer on-
demand PDTand chemotherapy with drug release triggered by
one light switch, which has great potential in cancer treatment.
the combination of PDTwith chemotherapy has the potential
to induce antitumor immunity[6] or revert multidrug resistan-
ce.[5c] Current delivery systems are largely based on the
coloading of both PSs and chemotherapeutic drugs into the
same carrier. The drugs in these systems are uncontrollable,
which could readily lead to side effects with limited ther-
apeutic efficiency owing to premature burst drug release in
the blood circulation as well as slow diffusional release after
their accumulation at the tumor site. As a consequence, the
development of drug-delivery systems that show “on-
demand” drug release only at the targeted site is much
preferred. Stimuli-responsive nanocarriers have been devel-
oped for “triggered” drug release through activation by
environmental stimuli.[7] Among these stimuli, light has
attracted much attention because it is an orthogonal external
stimulus that provides the advantages of a noncontact mode
and precise controllability, as well as the controlled release of
encapsulated substances both spatially and temporally.[8]
However, as most light-responsive systems are activated by
UV light, whereas the majority of PSs respond to visible light,
two light sources are often needed to activate each for
combined chemotherapy and PDT. Sequential irradiation
makes it difficult to focus the two light beams on the same
position. It remains challenging to develop a platform for
combined chemotherapy and PDT with on-demand drug
release upon irradiation with a single light source.
M
ultifunctional nanomaterials in which medical diagnos-
tics, drug delivery, and efficient therapy (theranostics) are
integrated into a single nanodelivery system have emerged as
promising tools in personalized medicine.[1] These so-called
image-guided systems are particularly useful for photoregu-
lated cancer therapy, as the tumor can be monitored, and then
light can be precisely applied to the detected region while
leaving normal tissues untouched.[2] Tumor-targeting strat-
egies have also been widely used to enhance the accumulation
of nanocarriers at tumor sites through conjugating appropri-
ate targeting moieties to the delivery systems.[3]
Conjugated polyelectrolytes (CPEs) have attracted great
attention for sensing and image applications.[9] In comparison
with small-organic-molecule dyes, the backbone of CPEs has
a great number of light-absorbing units, which result in high
absorption coefficients and bright fluorescence under irradi-
ation with light. This feature, together with their great
biocompatibility and good photostability, make them a new
generation of bioimage agents.[9] Furthermore, some CPEs
were also found to be able to generate ROS under appro-
priate irradiation with light, and were successfully used for
PDT and antimicrobial study.[10] Recent reports that thioketal
groups can be readily cleaved by ROS[11] inspired us to
develop a nanoplatform that combines PDT and chemo-
therapy with on-demand drug release regulated by one light
source. Such a system can be constructed by introducing
a ROS-cleavable linker between the PS and the drug; upon
illumination, the generated ROS causes drug release through
the cleavage of the linker. Although intracellular ROS are an
indicator of cancer, in view of their low concentration in cells
as well as their short lifetime (< 0.1 ms) and limited range of
action (10–20 nm), it should be more effective to generate
ROS in situ by the use of a ROS-sensitive drug-delivery
system.
Photodynamic therapy (PDT), a photoregulated non-
invasive medical technology, has been widely utilized for
cancer therapy through the generation of reactive oxygen
species (ROS) to destroy cancer cells upon the illumination of
photosensitizers (PSs).[4] To enable a better therapeutic
outcome, novel concepts of combining PDT and chemo-
therapy have been developed.[5] The combination of two
therapeutic modalities is helpful in overcoming limitations
encountered by each therapy when used alone. For example,
[*] Dr. Y. Yuan, Dr. J. Liu, Prof. Dr. B. Liu
Department of Chemical and Biomolecular Engineering
National University of Singapore
4 Engineering Drive 4, Singapore, 117576 (Singapore)
E-mail: cheliub@nus.edu.sg
Prof. Dr. B. Liu
Institute of Materials Research and Engineering
3 Research Link, Singapore 117602 (Singapore)
[**] We thank the Singapore National Research Foundation (R-279-000-
390-281), the Ministry of Defense (R279-000-340-232), and the JCO
(IMRE12-8P1103).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 7163 –7168
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7163