6. Applications of AIE
polymers.
AIE polymers have various applications ranging from using them as tools
in studying reaction mechanisms to different types of sensors to
theranostic applications, and so on.[4, 12,
190-193] In this section, some examples will be highlighted with more
emphasis on theranostic applications, which briefly describes the
importance of AIE polymers and how AIE polymers can improve our daily
activities.
6.1 Theranostics
Theranostics is a novel concept which combines diagnosis (cell imaging)
and therapy treatment (targeted drug release) in a full drug delivery
system where AIE polymers are utilized as drug trackers to monitor the
release of drug molecules after entering the targeted cells. Biological
imaging techniques have played an important role in the field of
biomedical application such as in guiding drug carriers for targeted
cell treatments, cancer cell detection and stem cell transplantation.
Fluorescence imaging garnered worldwide interest as the
“next-generation” technology in high precision imaging at the
subcellular level, with strong PL, high sensitivity and versatility in
the designing of the fluorescent nanoparticles.
Zhang, Wei and co-workers reported red R-PEG series and red R-F127
series fluorescent organic nanoparticles (FONs) in 2013 and 2014
respectively,[86, 194] with excellent cell
compatibility of at least 90% against A549 cells. Ouyang, Zhang, Wei
and co-workers in 2020, reported the facile preparation of AIE-active
PTH-P(BzMA-MPC) FPNs with good water dispersibility and similar cell
compatibility percentage against L02 cells as the previously mentioned
FONs.[150] Similar trend patterns in cell
penetration ability of both types of FONs and FPNs were confirmed by
Confocal Laser Scanning Spectroscopy (CLSM).
Drug delivery systems containing self-guiding carrier molecules for
anti-cancer drug treatment became popular in recent years. The use of
anti-cancer drugs alone led to an increased possibility of drug
resistance development in cancer cells,[195] and
the lack of real-time monitoring of the entire delivery system of drug
contributed to the limited application in cancer cell treatments. In
2018, Liu, Li and co-workers prepared
poly(N 6-carbobenzyloxy-L-lysine)-b -poly(2-methacryloyloxyethyl
phosphorylcholine) (TPE-PLys-b -PMPC) capable of spherical
core-shell self-assembly with encapsulation of DOX in the micelle core
via hydrophobic interactions for intracellular release and tracking
(Figure 10A ).[149] CLSM images were taken
after incubating DOX-loaded TPE-PLys-b -PMPC with HeLa cells,
where the images are taken at timestamps of 2, 4, 6, and 8 h. Red
fluorescence pattern trends revealed that DOX entered the cytoplasm
during the first 4 h after incubation, and slowly diffuses into the cell
nuclei from the 6 h mark onwards, while blue fluorescence pattern trends
suggests that TPE-PLys-b -PMPC remains only in the cell cytoplasm.
TPE-PLys-b -PMPC improves the endocytosis of DOX and degrades
during the first 4 h after incubation through which DOX was released,
that will ultimately diffuse into the cell nuclei and inhibit cancer
cell growth. This mode of mechanism is one of the ways for designing
smart drug delivery systems with triggered biodegradable drug carriers.
Based on similar principles of intracellular drug release, Jia, Tang and
co-workers in 2022 synthesized TPE-PEGA-Hyd-DOX with a slightly
different drug release mechanism, where the hydrazone bond acts as the
linker and conjugated with the anti-cancer drug
DOX.[181] Confocal images of TPE-PEGA-Hyd-DOX,
TPE-PEGA-Hyd, and pristine DOX where taken after incubation with HeLa
cells and NIH3T3 cells respectively with a much stronger fluorescence
registered for TPE-PEGA-Hyd-DOX in both cases. The DOX channel image
represents the extent of release of the drug into the cells. In both
cases, pristine DOX uptake was relatively less readily than
TPE-PEGA-Hyd-DOX, where the merged images confirmed the excellent
performance of this drug carrier delivery system. In addition, Jia, Tang
and co-workers found that drug release was limited in healthy cells
compared to cancer cells as the environment in the cancer cells
encouraged the hydrazone bond cleavage and subsequent release of DOX in
the cell cytoplasm, where it migrated into the cell nuclei to kill the
cells. The combined benefits of AIE and targeted drug delivery enabled
this drug delivery system to monitor drug movement and in vivocellular responses in real-time which can help to revolutionise
traditional methods in direct administration of medicinal drugs.
In another work by Liu, Tang and co-workers in 2012, TPE-functionalized
2-(2,6-bis((E )-4-(phenyl(4′-(1,2,2-triphenylvinyl)-[1,1′-biphenyl]-4-yl)amino)styryl)-4H -pyran-4-ylidene)
malononitrile (TPE-TPA-DCM) with strong PL intensity in the
far-red/near-infrared (FR/NIR) electromagnetic region, was combined with
BSA as the polymer matrix to form uniformly-sized protein nanoparticles
(Figure 10B ).[190] These FPNs were then
examined for their cell compatibilities against MCF-7 breast cancer
cells and murine hepatoma-22 (H22)-tumor-bearing mouse
models. In vivo imaging of BSA-loaded FPNs were determined via
non-invasive fluorescence imaging of the live animals after injection of
the FPNs with images taken at the 3 h, 8 h, 28 h mark for BSA-loaded
FPNs and bare FPNs respectively, where fluorescence intensity was twice
as high for the mice with tumors than for the mice without any tumors.Ex vivo imaging on the different parts of the mice when it was
sacrificed 24 h post-injection helps to confirm the accumulation of the
BSA-loaded FPNs in the tumor areas through visualization of the intense
coloration in that particular area.
6.2 pH level fluctuation
sensor
By incorporating stimuli-responsivenes into AIE polymers, it can respond
to environmental variations such as temperature, light, pH and many
more. One of the important modifications performed to AIE polymers is
the ability to detect environmental pH changes, which becomes important
when dealing with biological applications such as intracellular drug
delivery and carrier systems.[196]
Recently, a study was conducted by Li, Sun and co-workers in 2021, where
block copolymer poly(ethylene
glycol)-b -poly(L-lysine) (PEG-b -PLys) was
synthesized and modified with TPE-CHO group to form
PEG-b -P(Lys-TPE) bearing reversible pH-responsive fluorescence
properties.[4] PEG-b -P(Lys-TPE) forms
spheres with a core-shell structure when added to a solvent system
comprising DMF/H2O, and forms vesicles when added to a
solvent system comprising THF/H2O. For the
THF/H2O solvent system, fluorescence intensity dropped
drastically upon reducing pH level from 10.7 to 1.4, postulated to be
the detaching of the TPE moiety from the imine bond, causing the polymer
to lose the AIE characteristics, while regaining strong fluorescence
after increasing the pH level to 12.6, indicating the re-attachment of
the TPE moiety to the polymer via the imine bond (Figure 10C ).
The authors also found that this reversible behavior is only possible in
a mixed solvent system as the polymer exhibited irreversible pH
fluorescence behavior when pH variations were performed in pure water
solvent systems due to the precipitation of TPE residues after
detachment from the polymer. Nevertheless, such a polymer can find
potential use as a pH probe in mixed solvent systems but has limited
applications in single solvent systems.
6.3 Metal ion selective
sensor
Metal ion pollution is a major environmental concern and it is crucial
that these metal ion can be readily detected through the use of probes
that interact with them and provide sensing capabilities. Fluorogenic
probes have the ability to interact with the metal ions via complexation
and other chemical reactions to change their fluorescence properties,
which can be detected by fluorescence
measurements.[197] AIE-based polymer probes can be
designed to take advantage of the metal ion-induced aggregation effect
to detect a single type or multiple types of metal ions by registering a
change in fluorescence intensity.
Metal ion probes can also be designed to detect a single type of metal
ion instead of multiple metal ions. Bai, Zhang and co-workers in 2018,
facilely constructed a hyperbranched AIE poly(acrylamide) HPEAM-TPEAH to
be used as a probe for the detection of Zn2+specifically.[5] An aqueous mixture of
fluorescence HPEAM-TPEAH and different metal ions were prepared to
determine which metal ion is responsive towards HPEAM-TPEA, and the
authors discovered amongst the many metal ions tested such as
Zn2+, Mn2+, Na+,
Ca2+, Mg2+, Fe2+and K+, only Zn2+ ion provided a
significant decrease in fluorescence intensity when mixed with
HPEAM-TPEAH in water and in simulated body fluid. Zn2+ion remained detectable even at low concentration of\(2\times 10^{-5}\ M\), indicating the highly selective and sensitive
“turn-off” response of HPEAM-TPEAH towards Zn2+ ion.
7. Summary and perspective.
This review summarizes some of the many interesting AIE polymer end
product design from a wide range of monomers and some important
applications that AIE polymers can bring about. The unique discovery of
the AIE phenomenon manages to solve problems associated with the ACQ
phenomenon as aggregation is highly encouraged for AIE polymers to be
useful. Due to the versatility of RDRP, various strategies can be used
to incorporate AIE components into polymers such as direct
polymerization of non-AIE monomers and AIE monomers, surface-initiated
polymerization, AIE monomers containing more than one vinyl bond acting
as crosslinkers, AIE components as pendent groups which can be found in
hyperbranched-type polymers, AIE core-functionalized multi-arm star
polymers, AIE end-functionalized polymers, direct linkage of AIE
monomers, and through the unusual AIE fluorescence behavior exhibited
after polymerizing non-AIE monomers. More efforts are being invested in
discovering other possible combinations of monomers and
initiators/crosslinkers to produce unique AIE polymers possessing multi
stimuli-responsive properties for high-throughput new applications or
improving upon currently known applications including their use as cell
imaging agents and drug delivery systems in theranostics applications,
pH sensors, and metal ion selective sensors. An emerging trend in the
AIE polymer field is the shift towards simpler fabrication processes
where multicomponent reactions and one-pot reactions assisted by
microwave or ultrasonic irradiation are favoured over tedious multi-step
preparations. Another exciting area of AIE polymers is the use of
carbohydrate-based monomers and unusual monomers without phenyl groups
but still able to possess AIE characteristics after polymerization such
as acrylonitrile, and epoxide-containing branched monomers, which may
find application for imaging and biological related purposes.
The possibility to combine artificial intelligence (AI) and machine
learning (ML) to AIE polymers fabrication and application opens up
exciting future directions for high-end technologies such as
incorporation of AIE polymers into AI systems with complex logic gates
as multi-sensors, advanced ML models that can rapidly predict
structure-property relationships (SPRs) of AIE/ACQ polymers, ML tools
with the ability to generate fast and accurate information on pathogens
through AIE responsiveness to environmental variations, and so on. In
addition, AI and ML can also be applied to automate polymerization
techniques on the benchtop to quickly screen and identify different SPRs
in a large chemical space for high throughput experiments and high
throughput screening, which would otherwise require laborious work by
researchers. Even though AIE polymers became popular more than a decade
ago, it can only be considered in the infancy stage of development as
many of the applications are being constantly developed and improved
upon. With the unwavering efforts of many researchers around the world,
AIE polymers will become even better and more useful in the future.