3. AIE polymers via
RAFT
The RAFT polymerization was first reported and invented by Moad,
Rizzardo and Thang in 1998 from the Commonwealth Scientific and
Industrial Research Organisation (CSIRO) in Australia, as one of the
most powerful and versatile polymerization techniques to synthesize
uniquely complex polymer architectures.[46, 47, 77,
78] Coincidentally within a short period of time, Rhodia’s chemists,
patented xanthates and coined the term “Macromolecular Design by
Interchange of Xanthate” (MADIX).[79] Due to this
coincidence, while both RAFT and MADIX master patents are based off on
identical polymerization mechanisms and similarly use thiocarbonylthio
compounds (RAFT agents) such as trithiocarbonates, dithioesters,
xanthates and dithiocarbamates, the slight difference lies in MADIX only
covering xanthates as RAFT agents.[80]
With over 15,000 papers on RAFT polymerization presently, RAFT is
considered technique that emulates an ideal living polymerization due to
its ability to continue polymerization after adding more monomers, has
good control over end product polymer molecular weight, generates low
dispersity (Ð ) values, excellent tolerance to wide range of
monomers bearing functional groups, and the ability to synthesize
complex architectures (i.e. brush-shaped, star, hyperbranched, network,
etc.)[62] for various applications such as
diagnostic components and biomedical implants,[81]environmentally-sustainable materials,[82] and
other materials science and medicine-related
applications.[83] Hence, RAFT is suitable for use
as a polymerization technique to synthesize AIE polymers.
3.1 RAFT AIE amphiphilic block
copolymers
As mentioned in early sections, RAFT allows the preparation of polymers
with well-designed structure, well-controlled molecular weights and low
dispersity, and these polymer characteristics are critical in the
preparation of polymer nano-objects via different types of self-assembly
methods, such as solution self-assembly and polymerization-induced
self-assembly (PISA). With the more commonly known applications of AIE,
the AIE component were also incorporated into block copolymers via RAFT
to prepare nano-objects with AIE property for practical applications.
For example, in 2019, Li, Dong and co-workers, used the RAFT technique
to synthesize a new class of AIE amphiphilic copolymers, namely,
poly(N -(2-methacryloyloxyethyl)pyrrolidone)-b -poly(lauryl
methacrylate-co -1-ethenyl-4-(1,2,2-triphenylethenyl) benzene),
PNMP-b -P(LMA-co -TPE) that can self-assemble into various
polymer morphologies such as spheres, worms and vesicles in water andn -dodecane solvents.[84] The degree of
polymerization (DP) of the PNMP block was kept constant at 35 while
varying the P(LMA-co -TPE) block. At 1 wt% aqueous solution,
spherical micelles of 30-40 nm were formed for
PNMP35-b -P(LMA9-co -TPE0.9),
while worms become dominant for
PNMP35-b -P(LMA24-co -TPE2.7)
and
PNMP35-b -P(LMA55-co -TPE6.3).
These AIE-active amphiphilic copolymers could act as luminescent probes
and were applied in bioimaging using HeLa cells as substrates.
Interestingly, quantum yields (QY) of
PNMP35-b -P(LMA38-co -TPE4.7)
and
PNMP35-b -P(LMA55-co -TPE6.3)
were found to be greatly enhanced compared to others due to higher DP of
the AIE-active TPE moiety. Polymer morphology also played a role in
enhancing QY where worms were found to increase QY more than spheres.
The authors noted that biotoxicity of the polymers increases at higher
solid content however, even at a high 40 wt% solid content of
PNMP35-b -P(LMA55-co -TPE6.3),
cell viability of HeLa cells is still greater than 85%. This trend was
also observed upon increasing copolymer concentration from 10 µg
mL-1 to 100 µg mL-1 at a constant 40
wt% solid content. Under appropriate conditions, these polymers are
expected to serve as excellent and highly efficient bioimaging probes.
Variations in the chemical structure of the TPE moiety was also explored
by Li and coworkers in 2019 by synthesizing poly(ethylene glycol mono
methyl ether)-b -poly[(2-(diethylamino)ethyl
methacrylate)-co -3-(4-(1,2,2-triphenylvinyl)phenoxy)propyl
methacrylate)] (PEG-b -P(DEAEMA-co -TPEMA)) amphiphilic
block copolymer where RAFT agent was first coupled to the hydrophilic
PEG moiety, with CO2-responsive PDEAEMA block and AIE
active PTPEMA (Figure 4A ).[85] The unique
reversible transformation process from vesicles to micelles was achieved
by reducing the interfacial tension between the hydrophobic blocks and
the aqueous solution through adding non-selective co-solvents or upon
exposure to CO2. The reverse transformation from
micelles to vesicles can be achieved by bubbling the same solution with
argon gas, promoting the release of any encapsulated hydrophilic
molecules inside the vesicular compartments, mainly due to the
protonation and deprotonation of the DMAEMA block in the polymersomes.
The design of AIE molecules need not be limited to molecules bearing
only a single vinyl group, it also applies to molecules bearing two or
more of such groups. Zhang, Wei and co-workers in 2013, facilely
incorporated a symmetrical cross-linkable AIE dye termed R-E with a
vinyl end group on both sides into poly(ethylene glycol mono methyl
ether methacrylate) to synthesize R-PEG-20 and R-PEG-40 AIE-based FPNs
(Figure 4B ).[86] The obtained amphiphilic
FPNs is capable of self-assembly in aqueous solution which produces
nanoparticles of uniform size, high water dispersibility, strong red
fluorescence and excellent biocompatibility, enabling them to serve in
cell imaging applications. Cell-counting kit-8 (CCK8) assays were
performed to determine cell viability of these FPNs, and the authors
determined excellent cellular uptake levels by A549 cells greater than
90%, even at high concentrations of 80 µg mL-1. These
FPNs can also be produced from a wide range of monomers and impart
greater stability compared to those nanoparticles formed from
self-assembly, as FPNs prepared via self-assembly are often unstable in
physiological solution due to the weak interactions among these
amphiphilic fluorescent molecules. Similar studies have also been
conducted by the same group and other groups on preparing AIE dyes via
RAFT polymerization capable of self-assembly with similar
characteristics since 2014 such as AIE
crosslinkers,[87-94] AIE pendent groups with
non-AIE monomers block copolymers,[95-103] AIE
end-functionalized block copolymers,[48, 49,
104-107] and AIE-functionalized
monomers,[108-119] which helped to expand the
library of AIE-functionalized polymers.
Another variation of the commonly known TPE moiety chemical structure
was explored by Huang, Liu, Wei and co-workers in
2019,[120] by combining a novel AIE dye
tetraphenylethene-functionalized distyrene (TPES) with poly(ethylene
glycol mono methyl ether methacrylate) (PEGMA) to form poly(ethylene
glycol mono methyl ether
methacrylate)-b -poly((Z)-3-(4-(1,2,2-triphenylvinyl)phenyl)-2-(4’-vinyl-[1,1’-biphenyl]-4-yl)acrylonitrile))
(PEG-b -TS) polymers. PEG-TS1 and PEG-TS2 self-assembled into FPNs
with measured diameters of 150 nm and 400 nm respectively in aqueous
solutions. Similar to R-PEG-20 and R-PEG-40 reported by Zhang, Wei and
co-workers,[86] PEG-TS series polymers showed
greater than 90% cellular viability with HepG2 cells at a concentration
of 80 µg mL-1.
A less bulky symmetrical TPE-based
poly(N -isopropylacrylamide-co -(E )-1,2-diphenyl-1,2-bis(4-((4-vinylbenzyl)oxy)phenyl)ethene)
(P(NIPAm-co -TPE2St)) was synthesized by Yang, Lin and co-workers
in 2022, using thermo-responsive NIPAm blocks and AIE-responsive TPE
cross-linking blocks via RAFT technique.[94] The
polymers displayed an emission wavelength of approximately 485 nm and
the highest PL intensity when the water fraction reached 90% in a
water/THF mixture solvent system. It was also discovered that HepG2
liver cancer cells at a concentration of 2 µg mL-1absorbed over 80% of the polymers. Such polymers can find applications
in controlled/target drug delivery, cell imaging and tracking.
In 2017, Liu, Zhang, Wei and co-workers successfully incorporated AIE
molecules into polymer particles by combining all multiple reactants
together in a multicomponent reaction (MCR) termed the ‘three-component
mercaptoacetic acid locking imine (MALI) reaction, with RAFT technique
in a “one-pot” reaction to synthesize poly(polyethylene glycol mono
methyl ether
methacrylate)-co -poly(10-undecenal)-poly(((Z )-3-(4-aminophenyl)-2-(10-hexadecyl-10H-phenothiazin-3-yl)acrylonitrile)
(PPEGMA-co -PUCL-Phe1 and PPEGMA-co -PUCL-Phe2)
(Figure 4C ).[121] Luminescent organic
nanoparticles (LONs) are capable of self-assembly when dispersed in
aqueous medium and are found to possess multiple traits such as AIE
features, good brightness, good water dispersibility and excellent
biocompatibility. Incubation of HeLa cells with
PPEGMA-co -PUCL-Phe2 LONs at a concentration of 120 µg
mL-1 resulted in over 95% cell viability within 24 h,
and excellent staining ability at a concentration of 20 µg
mL-1 believed to be a result of cellular endocytosis.
The incorporation of AIE components into amphiphilic block copolymers
enables the preparation of photoluminescent nanoobjects with different
morphologies. More recently, with the rising of PISA, AIE-active
nano-objects can be prepared directly during polymerization. As opposed
to the previous section on self-assembly, PISA emphasizes on the
self-assembly of these morphologies induced/triggered by in situpolymerization and not by adding any external agents or stimuli.
For example, in 2017, Wang, Wei, Yuan and co-workers employed the
RAFT-PISA process to synthesize
poly(N,N -dimethylaminoethyl)-b -poly[benzyl
methacrylate-co -1-ethenyl-4-(1,2,2-triphenylethenyl)benzene]
(PDMA-b -P(BzMA-TPE)) capable of self-assembling into different
morphologies such as spheres, worms and vesicles during polymerization
(Figure 5A ).[122] The authors found that
PL intensity and QY increases in the order:
PDMA39-P(BzMA-TPE)-120 (micelles) <
PDMA39-P(BzMA-TPE)-240 (worms) <
PDMA39-P(BzMA-TPE)-360 (vesicles), and that all polymer
samples displayed stronger PL intensities when dissolved in water than
in ethanol.
Recently in 2022, our group expanded the scope of this area by using the
RAFT technique to perform PISA to synthesize photoluminescent polymer
assemblies with rarely-achieved inverse mesophases such as spongosomes,
cubosomes and hexosomes (Figure 5B ).[123]The resultant polymer PDMA-(PTBA-r -PTPE)-CDPA possesses both
H2O2 responsiveness from the boronic
moiety and AIE PL properties from the TPE moiety, allowing the polymer
to be stimuli-responsive in addition to luminescence. These higher order
morphologies bear high specific surface area and ability to load
hydrophilic and hydrophobic chemicals for drug delivery systems and
targeted drug release applications.
Similarly, in 2020, Xing and co-workers also realized the unique
behavior of DMAEMA when exposed to changes in pH levels and
CO2 presence. They prepared
CO2-responsive polymer morphologies endowed with AIE
properties using alcohol RAFT dispersion polymerization to synthesize
poly(2-(2-hydroxyethoxy) ethyl methacrylate)-poly(methacryloxyethoxy)
benzaldehyde)-poly(2-(dimethylamino)ethyl
methacrylate)-poly(4-(1,2,2-triphenylvinyl)phenyl methacrylate)
(P(HEO2MA)-b -P(MAEBA-co -DMAEMA-co -TPEMA))
(Figure 5C ).[124] These nano-objects
formed via PISA, transformed from spheres to vesicles following an
increase in PL intensity. Upon CO2 bubbling, existing
spheres can also transform into a mixture of hemispherical
“jellyfish”-like structures and vesicles, while existing vesicles can
transform into higher order complex vesicles. The authors also
discovered that treatment with CO2 caused an increase in
nano-object sizes from 142 nm to 314 nm (dissolved in methanol) and 146
nm to 358 nm (dissolved in water) over a period of 60 min. A few other
similar examples include RAFT-PISA processes in nonsynchronous synthesis
of raspberry-like nanoparticles,[125] in drug
delivery systems of where in situ drug loading of doxorubicin
(DOX) via PISA with azoreductase-responsive
PEG-b -P(BMA-co -TPE-AZO-MMA),[126]and for in situ monitoring and understanding of the photo-PISA
process mechanism.[127]
3.3 AIE block copolymers via Surface-initiated
RAFT
AIE molecules can also be polymerized with surface grafted polymers to
impart fluorescent properties to the resulting particles via
surface-initiated RAFT polymerization. In 2021, Qiao, Pang and
co-workers prepared a novel multi-stimuli responsive, multi-functional
polymeric nanoparticle poly(2-(dimethylamino)ethyl
methacrylate)-co -poly((4-vinylphenyl)
ethene-1,1,2-triyl)tribenzene) with PDMAEMA as the organic carrier,grafted from SiO2 surface as the inorganic
carrier with asymmetrical encapsulation of
Fe3O4 nanoparticles
(Fe3O4@SiO2@P(DMAEMA-co -TPEE))
(Figure 6A ).[128] The resulting composite
nanoparticle possesses a yolk-shell (YS) morphology with the AIE-active
TPEE block, allowing for real-time monitoring of any changes to
environmental magnetic field, temperature and pH levels, with the added
ability to detect CO2 presence in aqueous solution. In
addition to the commonly known pH/thermo-responsiveness of the PDMAEMA
block, the incorporation of Fe3O4 endows
the polymer with superparamagnetism where higher PL intensity was
observed for shorter distance to the source of magnetism. Similar to the
works by Li et al .[85] and Xinget al. [124], the authors observed
reversible CO2 detection ability where the PL intensity
decreased gradually from pH ~9.5 to pH
~5.5 after bubbling CO2 for 10 min, and
returned to the original pH after bubbling with N2 gas
for the same amount of time. The relative “free” TPE units allowed the
polymer brush to respond sensitively and accurately towards these
external environmental changes through fluorescence variation. Notably,
the solution of YS-NPs exhibited high colloidal stability during the
changes, and surface aggregation-induced emission (SAIE) process was
proposed for the aggregation of TPE units on the surface of YS-NPs.
Another similar study was conducted by Tian, Zhang, Wei and co-workers
where fluorescent nanodiamonds (FNDs)-poly(2-methacryloyloxyethyl
phosphorylcholine (MPC) (FNDs-polyMPC) composites was fabricated using
surface-initiated photoRAFT technique and tested for their high water
dispersibility and excellent cellular uptake as cell imaging
agents.[129]
3.4 Hyperbranched AIE block copolymers via
RAFT
To prove the versatility of AIE molecules, Bai, Zhang and co-workers in
2018, successfully employed RAFT technique to synthesize a
thermo-responsive hyperbranched copoly(bis(N,N -ethyl
acrylamide)/(N,N -methylene bisacrylamide)) (HPEAM-MBA) and
copoly(bis(N,N -ethyl
acrylamide)/4-(2-(4-(allyloxy)phenyl)-1,2-diphenylvinyl)phenol)
(HPEAM-TPEAH) polymers (Figure 6B ) with impressive
Zn2+ detection ability as measured directly from
fluorescence intensity in the [Zn2+] range of 4 –
18 µmol L-1.[5] Upon interaction
with Zn2+ ions, the RIM effect was induced on TPE
moieties due to a change in the polymer lower critical solution
temperature (LCST) and thereby results in fluorescence, which was
considered as a “turn-off” response. The rationale of using
Zn2+ as opposed to other metal ions such as
Na+, K+, Mg2+,
Mn2+, Ca2+, and
Fe2+ is due to the significant effect on the LCST of
the hyperbranched copolymer that Zn2+ caused, even at
concentrations less than \(1\times 10^{-5}\ M\). HPEAM-TPEAH also
showed greater than 95% cell viability in HeLa cells within 24 h of
incubation time for concentration range of \(1.0\times 10^{-6}\ M\) to\(5.0\times 10^{-5}\ M\). Another form of hyperbranched polymers is
dendritic polymers synthesized by Gao and co-worker in 2013 for the
investigation into the cage effect imposed by these polymers on AIE
pendent groups, affording the rarely observed solid-state-emissive blue
light for such dendrimers.[130]