View Article Online

Polymer
View Journal

Chemistry
Accepted Manuscript

This article can be cited before page numbers have been issued, to do this please use: S. Li, G. Han and
W. Zhang, Polym. Chem., 2020, DOI: 10.1039/D0PY00627K.
Volume 8
This is an Accepted Manuscript, which has been through the
Polymer
Number 25
21 September 2017
Pages 5255-5446
Royal Society of Chemistry peer review process and has been
accepted for publication.
Chemistry Accepted Manuscripts are published online shortly after acceptance,
rsc.li/polymers

before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.

You can find more information about Accepted Manuscripts in the

Information for Authors.

Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
ISSN 1759-9962 Terms & Conditions and the Ethical guidelines still apply. In no event
PAPER
Huiyuan Wang, Yongzhuo Huang et al.
A mannosylated PEI–CPP hybrid for TRAIL gene targeting
shall the Royal Society of Chemistry be held responsible for any errors
delivery for colorectal cancer therapy

or omissions in this Accepted Manuscript or any consequences arising

from the use of any information it contains.

rsc.li/polymers
 Page 1 of 11 PleasePolymer
do not Chemistry
adjust margins

View Article Online

DOI: 10.1039/D0PY00627K

ARTICLE

The Cross-linking Approaches for Block Copolymer Nano-

assemblies via RAFT-mediated Polymerization-induced Self-

Polymer Chemistry Accepted Manuscript

Received 00th January 20xx,
assembly
Accepted 00th January 20xx
Shenzhen Lia, Guang Hanb and Wangqing Zhang*a,c
DOI: 10.1039/x0xx00000x
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.

Covalent cross-linking is a simple and robust way to stabilize block copolymer nano-assemblies prepared by reversible
addition-fragmentation chain transfer polymerization mediated polymerization-induced self-assembly (RAFT-mediated
PISA). To date, various multi-functional compounds with different reactive moieties have been explored for cross-linking of
block copolymer nano-assemblies, and these cross-linking approaches can be classified into in situ cross-linking and post-
polymerization cross-linking. Owing to the efficient and diverse operations of these cross-linking approaches, various cross-
linked block copolymer nano-assemblies with complex morphologies have been constructed, exhibiting superior structural
stability against solvent switching or external stimulus. The aim of this review is to summarize the current cross-linking
approaches to stabilize block copolymer nano-assemblies obtained via RAFT-mediated PISA process as well as their potential
applications.

multistep synthesis, long equilibration time and the extremely dilute

1 Introduction condition.45-47 By tuning the chain length of polymer blocks, different
morphologies of block copolymer nano-assemblies can be
Now polymer nano-objects with well-defined shapes can be
achieved under mild reaction conditions.48-52
reliably synthesized by using many different techniques.1-4 The
However, amphiphilic block copolymer nano-assemblies
large specific surface area and diverse functional moieties of these
generated via PISA can undergo a structural transition from nano-
nano-objects make them applicable in wide fields, including drug
assemblies to unimers in the presence of surfactants or block
delivery, catalysis, nano-reactors and emulsification.5-9 To meet
selective solvents for core-forming blocks.53-54 Solvent pH or
these practical requirements, preparation of nano-objects with
temperature can also affect their stability of block copolymer nano-
stable size and morphology becomes necessary.10-20
assemblies.55-57 Obviously, this structural instability of block
Polymerization-induced self-assembly (PISA) as an efficient
copolymer nano-assemblies is detrimental to the morphology-
synthetic method for block copolymer nano-assemblies has
dependent performance and inevitably narrows down the scope of
recently attracted much attention.21,22 Block copolymer nano-
their practical applications. As a feasible method for maintaining
assemblies with different morphologies such as spheres, worms,
block copolymer nano-assemblies, the chemical cross-linking of
fibers, vesicles and rods, could be obtained via PISA either in
block copolymer nano-assemblies has received considerable
emulsion or dispersion condition at relatively high polymer
interest recently.58-60 The formation of covalent linkage by using
concentrations (10-50 wt%).23-25 Several living polymerization
certain chemistry leads to the intertwinement of the block
techniques have been utilized to conduct the PISA process.26-41
copolymer chains in the core or shell of block copolymer nano-
Among these, the reversible addition-fragmentation chain transfer
assemblies, thus effectively stabilizing nano-assemblies.
(RAFT) polymerization is definitely the most used method for
Depending on the sequence relationship between cross-linking
synthesis of block copolymer nano-assemblies.42-44 In RAFT
process and PISA process, these cross-linking strategies can be
mediated polymerization-induced self-assembly (RAFT-mediated
classified into the in situ cross-linking approaches and the post-
PISA), amphiphilic block copolymer nano-assemblies can be
polymerization cross-linking approaches.1,61-63 In the in situ cross-
synthesized by using a solvophilic macromolecular chain transfer
linking approaches, chemical compounds with bifunctional vinyl
agent (macro-CTA). Due to the insolubility of the growing second
moieties as cross-linker are directly copolymerized with the
block in dispersed media, self-assembly of block copolymers is
monomers to form stabilized block copolymer nano-assemblies
simultaneously conducted to form block copolymer nano-
under PISA formulation and cross-linkages are expected to evenly
assemblies during the RAFT polymerization, which avoids
distribute in the block copolymer chains.64 Particularly, the employ
of asymmetric cross-linker with different vinyl moieties is expected
a. Key Laboratory of Functional Polymer Materials of the Ministry of Education,
to delay cross-linking process to high monomer conversion and
Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin weaken the hindering effect of cross-linking on the morphological
300071, China. E-mail: wqzhang@nankai.edu.cn. transition of nano-assemblies during PISA process.65 In the post-
b. State Key Laboratory of Special Functional Waterproof Materials, Beijing Oriental
polymerization cross-linking approaches, complementary
Yuhong Waterproof Technology Co., Ltd. Beijing 100123, China.
c. Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), multifunctional compounds are added to stabilize block copolymer
Nankai University, Tianjin 300071, China. nano-assemblies after completion of morphological transition in

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins
ARTICLE
PISA process.56,66-68 A number of cross-linkers with different
chemical structures have been explored in the cross-linking
process, part of which are shown in Fig. 1. Especially, the
incorporation of reactive or reversible covalent bonds in the cross-
linkers can bring with stimulus-responsibilities, and thus the
prepared block copolymer nano-assemblies can undergo cross-
linking or a reverse process under a certain external stimulus, e.g.,
light and redox stimuli, while preserving their structural integrity.63,69
Notably, these symmetrical divinyl cross-linkers were also
employed in the “arm-first” synthesis of star block copolymers,70,71
which appears similar in architecture with core cross-linked
nanoparticles. However, self-assembly of the pre-synthesized star
block copolymers in selective solvent is not involved in the typical
synthesis of core-cross-linked star (CCS) polymers,72-74 so their
corresponding research progresses will not be discussed here.
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.
Besides, the noncovalent cross-linking proposed by Cai and
coworkers is also proved to be valid in stabilization of block
copolymer nano-assemblies,75 which is also beyond the present
discussion. In this review, we aim to highlight the recent progress
in the cross-linking approaches of block copolymer nano-
assemblies generated by RAFT-mediated PISA process. We
attempt to provide an overview to researchers in this field and to
stimulate potential applications of the cross-linked block copolymer
nano-assemblies.
Fig. 1 The chemical structures of typical cross-linkers used for in situ cross-linking
(a) and post-polymerization cross-linking (b).
2 In situ cross-linking approaches
The in situ cross-linking approaches are plausibly the simplest
and most straightforward routes to stabilize block copolymer nano-
assemblies prepared via PISA, in which the bifunctional vinyl
compounds of symmetrical or asymmetrical chemical structures,
such as N,N’-methylene bisacrylamide (MBA) and allyl acrylamide
(ALAM), are widely used as cross-linker.76 Typically, monomers
and bifunctional cross-linkers in a certain proportion (1-3 mol%) are
2 | J. Name., 2012, 00, 1-3
Please do not adjust margins
Page 2 of 11
Journal Name
together introduced into the polymerization system before theOnline
View Article start
of the polymerization. Under the PISA formulation, the
DOI: 10.1039/D0PY00627K
copolymerization, self-assembly and cross-linking steps are
simultaneously carried out after the addition of cross-linkers, thus
the cross-linked block copolymer nanoparticles could be prepared
in one-step operation under relatively mild conditions.60
2.1 Using symmetric cross-linkers
By the in situ cross-linking approaches, the cross-linked
nanoparticles with low cross-linking density generally possess the
Polymer Chemistry Accepted Manuscript
similar particle size to that obtained without cross-linker, and the
superior structural stability of the cross-linked nanoparticles was
exhibited against solvent switching or in biologically relevant
solutions as reported by An and co-workers.58 These properties of
the cross-linked block copolymer nanoparticles would lay the
foundation for the potential applications as functional materials. For
example, Armes and coworkers demonstrated the excellent
boundary lubrication performance of the cross-linked block
copolymer nanoparticles synthesized directly in an industrial
mineral oil, which provided new opportunities for the formulation of
next generation ultralow-viscosity automotive engine oils.77 Poli
and coworkers utilized the core-cross-linked micelles as catalytic
nanoreactors for biphasic hydroformylation.78 By copolymerization
of styrene and 4-[bis(p-methoxyphenyl)phosphino]styrene
(BMOPPS) through a three-step one-pot RAFT polymerization in
emulsion, cross-linked micelles with a bis(p-methoxyphenyl)
phenylphosphine (BMOPPP) ligand functionalized core were
synthesized. It was demonstrated that the cross-linked micelles
showed an excellent reactivity and moderate catalyst leaching in
the aqueous biphasic hydroformylation of 1-octene.
In addition, by using functional monomers with certain
structures, cross-linked block copolymer nano-assemblies can be
designed to respond to a wide variety of stimuli, such as
temperature, pH and redox stimuli.79,80 This stimulus-
responsibilities make the cross-linked nano-assemblies as
excellent materials with the potential applications in drug delivery,
sensing and catalysis. To date, several research groups have
prepared various stable thermo-responsive block copolymer nano-
assemblies with different constituents, by the combination of in situ
cross-linking strategy and PISA process.64,81-83
As well-known, PNIPAM typically exhibits a volume phase
transition around a lower critical solution temperature (LCST) of 32
°C.81 An et al. synthesized the thermos-responsive block copolymer
nanoparticles of poly(N,N-dimethylacrylamide)-b-poly(N-
isopropylacrylamide) (PDMA-b-PNIPAM) and investigated the
cross-linking effect of MBA on the morphological stability.58 After
cooling to room temperature, the PNIPAM block became soluble.
Therefore, the cross-linked PDMA-b-PNIPAM nanoparticles were
in the swollen state below LCST, while the integrity of the
nanoparticles maintained. In contrast, uncross-linked nanoparticles
synthesized under similar conditions but without MBA
disassembled into unimers. Recently, the doubly thermo-
responsive block copolymer nanoparticles with multi-domain were
prepared in water-ethanol mixtures by RAFT mediated dispersion
polymerization by An and co-workers.64 These block copolymer
nanoparticles consisted of a MBA-cross-linked thermo-responsive
PNIPAM core with a higher thermal transition temperature, a
hydrophilic PDMA midblock, and a thermo-responsive
poly(diethylene glycol ethyl acrylate) (PDEGA) outer block with a
lower thermal transition temperature. The unique location of these
This journal is © The Royal Society of Chemistry 20xx
 Page 3 of 11 PleasePolymer
do not Chemistry
adjust margins

Journal Name ARTICLE

two thermo-responsive blocks with different phase transition View Article Online
temperatures in the PDEGA-b-PDMA-b-P(NIPAM-co-MBA) DOI: 10.1039/D0PY00627K
nanoparticles was expected to facilitate thermo-induced gelation
and provided mechanical enhancement. By a simple inverted vial
test, the thermo-induced solution/gelation transition was visually
determined. As shown in Fig. 2, when temperature increased up to
the thermal transition temperature of the outer thermos-responsive
PDEGA, the hydrophobic association of PDEGA block would lead
to physically cross-link of nanogels and thus thermally induced Fig. 3 The synthesis of UCST-type zwitterionic nanogels and their reversible
gelation, while the hydrophilic PDMA mid-block acted as the swelling and shrinking behavior. Reproduced from ref. 83 with permission from
American Chemical Society, copyright 2017.
interconnected bridge. The gelation ability, sensitivity, and

Polymer Chemistry Accepted Manuscript

mechanical properties could be tuned by changing the
polymerization parameters, such as the block ratios and the cross-
linking density.
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.
Besides the thermo-responsive cross-linked polymeric
nanoparticles, the use of cross-linkers containing weak covalent
bonds, e.g., disulfide bond, endows the synthesized nanoparticles
redox-responsive profile and unique intracellular degradability.69,84

N,N’-bis(acryloyl)cystamine (BAC) was widely used in this type of

degradable cross-linkers due to the reductively cleavable nature of
disulfide bond.69 By well-established process in the presence of
dimethylphenyl phosphine (DMPP), tris(n-butyl phosphine) or 1,4-
dithiothreitol (DTT), the BAC cross-linked core could be cleaved at
ambient temperature. The typical GPC curves after degradation
showed that the original distribution of cross-linked nanoparticles
disappeared and a new distribution appeared at high retention time
corresponding to the population of arm polymers.69 In 2018, Zhao
and co-workers systemically investigated the bioreducible cross-
linked nanoparticles with BAC as a cross-linker.69 By using poly(2-
dimethylamino)ethyl methacrylate) (PDMAEMA) as the core block,
several core-shell block copolymer nanoparticles were prepared
with different hydrophilic arm blocks such as poly(poly(ethylene
Fig. 2 (a) Schematic representation of thermally induced gelation, (b) sol-gel glycol) methyl ether methacrylate) (PPEGMA), PDMA and
transition diagram, and (c) the appearance of colloidal solution of PDEGA-PDMA- PDMAEMA, respectively, via dispersion RAFT polymerization. Due
P(NIPAM-co-MBA) nanoparticles. Reproduced from ref. 64 with permission from to the thiol-disulfide exchange reaction with small redox molecules,
American Chemical Society, copyright 2016.
e.g., DTT and glutathione, the reductively cleavable disulfide bond
of BAC as a cross-linkage could be reduced upon exposure in a
Qiao and co-workers utilized difunctional MBA as cross-linker
reductive environment, and thus the cross-linked nanoparticles
and poly(poly (ethylene glycol) methyl ether methacrylate)
were fully degradable. This study provided a facile method to
(PPEGA) as macro-CTA to synthesize LCST-type thermosensitive
prepare reduction-degradable nanoparticles which inhibited
PPEGA-b-P(NIPAM-co-MBA) block copolymer nanogels, based on
potential application for redox-triggered drug release rapidly in
the first sono-chemically induced RAFT polymerization by the PISA
response to the intracellular reductive environment.
process (Sono-RAFT-PISA).82 Because of the reversible collapse
of the cross-linked core block upon heating, these PPEGA-b-
P(NIPAM-co-MBA) nanogels exhibited reproducible successive
shrink/swell behavior. At 45 oC the decreased hydrodynamic size
and the opalescence of the nanogels were observed. After cooling
to 25 oC, the nanogels regained the original size.
Zhao and coworkers reported the use of in-situ cross-linking
strategy for synthesis of upper critical solution temperature (UCST)-
type zwitterionic block copolymer nanogels by RAFT-mediated
PISA process in water-organic mixture.83 These hairy nanogels
were composed of a poly(poly(ethylene glycol) methyl ether
methacrylate)) (PPEGMMA) corona and a thermo-responsive
poly(3-dimethyl(methacryloyloxyethyl)ammonium
propanesulfonate)) (PDMAPS) core cross-linked by N,N’-
methylenebis-(acrylamide) (MBAA). Under heating/cooling cycles, Fig. 4 The synthetic route of cross-linked PNIPAM-b-PS nanoparticles. Reproduced
the electrostatic interaction of PDMAPS blocks caused these from ref. 60 with permission from The Royal Society of Chemistry, copyright 2020.
nanogels to exhibit reversible swelling and shrinking (Fig. 3). The
authors demonstrated that the amount of cross-linker MBAA had However, the simultaneous addition of cross-linkers and
an important influence on their thermo-responsive behavior. monomers into the PISA system usually disrupts the polymerization
through gelation and impedes morphology evolution, and almost
only spherical nanoparticles can be obtained. To keep a good

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 4 of 11

ARTICLE Journal Name

control on the cross-linking/PISA process, the amount of cross- View Article Online
linkers are limited (< 1%), and thus the stability of the resulting DOI: 10.1039/D0PY00627K
cross-linked block copolymer nanoparticles is not ideal. To solve
this problem, Armes and coworkers delayed the addition of
symmetric ethylene glycol dimethacrylate (EGDMA) after the PISA
process, and successfully synthesized the cross-linked block
copolymer vesicles with a higher cross-linking density.59 Using a
similar synthetic protocol, Howdle and coworkers reported the
preparation of highly cross-linked poly(methyl methacrylate)-b-
poly(4-vinyl pyridine) (PMMA-b-P4VP) particles via dispersion
RAFT polymerization in supercritical CO2.62 Through the delayed

Polymer Chemistry Accepted Manuscript

addition of the cross-linker divinylbenzene (DVB) and a portion of
the core-forming monomer 4-vinyl pyridine (4VP), the precursor
PMMA-b-P4VP particles were crosslinked, and up to 8 wt% of DVB
(relative to the total 4VP) could be added. Recently, Zhang and
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.

coworkers reported the efficient preparation of cross-linked poly(N-

isopropylacrylamide)-b-polystyrene (PNIPAM-b-PS) nanoparticles
by delaying the addition of the cross-linker DVB as shown in Fig.
4.60 After the chain extension of PNIPAM macro-CTA by the second
monomer styrene, linear diblock copolymer PNIPAM-b-PS were
synthesized in the absence of DVB, and aggregated to form a
spherical morphology under the PISA formulation in 80/20
ethanol/water mixture. The following addition of DVB with the
remaining styrene resulted in the efficient cross-linking of the
obtained PNIPAM-b-PS nanoparticles. The solution properties,
thermo-responsibility and interfacial properties of cross-linked
PNIPAM-b-PS nanoparticles were found to be significantly different
from those of linear counterpart. The DLS analysis demonstrated
that the cross-linked PNIPAM-b-PS nanoparticles exhibited a
stable particle size in both common solvents and block-selective
solvents. The cross-linked block copolymer nanoparticles exhibited
a high efficiency in interfacial tension reduction, which promoted
their application as a promising material in various fields. Beside of
dispersion RAFT polymerization, RAFT-mediated emulsion
polymerization is also utilized to prepare crosslinked block
copolymer nano-assemblies with higher-order morphologies, e.g.,
vesicles, in the presence of high content of cross-linker EGDMA.85
2.2 Using asymmetric cross-linkers
Unlike the symmetric cross-linker MBA, ALAM is a typical
asymmetric cross-linker with a pair of C=C double bonds showing
different reactivities.65 The cross-linking process could be delayed
to the late stage of polymerization in PISA by using ALAM.65 The
acrylamide C=C double bond of ALAM has a similar polymerization
reactivity to that of the general acrylamide monomer, so ALAM
could be more uniformly distributed in the polymer chain. After the
completion of the morphology transition, the less reactive vinyl C=C
double-bond of ALAM would mainly participate in radical reactions
leading to cross-linking of the nano-assemblies. Due to the two-
stage of the ALAM-involved cross-linking process, the cross-linked
nano-assemblies possess controlled morphologies which are
similar to those synthesized without cross-linkers.65 Compared with
a symmetric cross-linker, a higher amount of asymmetric cross-
linker ALAM can be introduced into the in situ cross-linking system,
which consequently leads to a higher cross-linking density in the
final block copolymer nano-assemblies. For the polymerization of
acrylate monomers, diverse asymmetric cross-linkers such as vinyl
methacrylate (VMA), allyl methacrylate (AMA), and 4-
allyloxybenzyl methacrylate (ABMA) could be examined.86
Fig. 5 DLS size distributions for linear PDMA-b-PDAAM vesicles (A) and cross-linked
vesicles (C) in water, DMF, and redispersion from DMF to water via dialysis. TEM
micrographs for linear vesicles (B) and cross-linked vesicles (D) after redispersion
from DMF to water. Reproduced from ref. 65 with permission from American
Chemical Society, copyright 2016.
In 2016, An and co-workers reported the successful synthesis
of colloidally stable block copolymer vesicles by using the in situ
cross-linking approach.65 The aqueous dispersion polymerization of
diacetone acrylamide (DAAM) could process smoothly with 2-5
mol% ALAM utilizing PDMA macro-CTA. By varying the targeting
chain length of the poly(diacetone acrylamide) (PDAAM) block, the
solid content and the amount of ALAM, a series of cross-linked
poly(N,N-dimethylacrylamide)-block-poly(diacetone acrylamide-
co-allylacrylamide) (PDMA-b-PDAAM) vesicles were obtained (Fig.
5). Compared to the linear vesicles, the cross-linked vesicles
displayed excellent performance of resisting DMF dissolution and
could maintain their colloidal stability when the solvent switching
from DMF to water. The cross-linked PDMA-b-PDAAM vesicles
could swell in DMF, therefore the particle diameter became bigger.
After redispersion from DMF to water, vesicles almost restored the
original size and the vesicular morphology was kept. Then the
same authors used the in situ cross-linked vesicles as a robust
platform to construct triblock copolymer nano-assemblies with
charged or neutral surface.61 Because the precursor vesicles of
PDMA-b-PDAAM were already cross-linked and the vesicular
morphology was fixed, the growing of the third hydrophilic block of
either neutral PDMA, anionic poly(2-acrylamido-2-methyl-1-
propanesulfonic acid sodium salt) or cationic poly(3-
acrylamidopropyl trimethylammonium chloride) would not induce
morphological transition of vesicles. Therefore, this versatile
method can be used to introduce a third hydrophilic block with
various compositions and an arbitrary length from the vesicle
surface, thus providing a robust synthetic technique to triblock
copolymer vesicles with diverse surface chemistry and enhanced
structural stability.
The application of symmetric bisfunctional cross-linkers to
achieve higher-order block copolymer morphologies, e.g., worms,
lamellae and vesicles, potentially faces great challenges, due to the
hindering effect of the in situ cross-linking process on
morphological transition.87 However, the use of asymmetric cross-
linkers was expected to alleviate this problem. An and coworkers
utilized the asymmetric cross-linker ALAM to synthesize the cross-
linked block copolymer lamellae via PISA.87 Using PDMA as macro-
CTA, thermo-responsive PDMA-b-PDAAM lamellae were prepared

4 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 5 of 11 PleasePolymer
do not Chemistry
adjust margins
Journal Name
under RAFT aqueous dispersion condition. The morphology phase
diagram showed that the lamellae existed over an unprecedented
wide phase space. After cooling of the PDMA-b-PDAAM
dispersions, reversible temperature-induced morphological
transitions from lamellae to worms/spheres were observed as
confirmed by rheology experiments, and the kinetics of
morphological transitions was found to be determined by cross-
linking density. An and co-workers synthesized the cross-linked
block copolymer worms by using in situ cross-linking strategy.86 To
investigating the structure effect of cross-linkers on synthesis of
cross-linked worms, they explored three different asymmetric
cross-linkers, including VMA, AMA and ABMA, in the synthesis of
poly[2-(dimethylamino)ethyl methacrylate)-block-poly(benzyl
methacrylate)] (PDMAEMA-b-PBnMA) block copolymer nano-
assemblies. In this research, due to the structural similarity
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.
between ABMA cross-linker and benzyl methacrylate (BnMA)
monomer, the cross-linking with ABMA was proved to be most
robust as confirmed by DMF resistance, and the cross-linked
worms had a similar particle size to those obtained without cross-
linker. In contrast, the cross-linked worms suffered morphology
degradation in a good solution for both blocks. Recently, Tan and
co-workers applied the cross-linking strategy to synthesis of patchy
cylindrical micelles.88 Cylindrical poly(poly(ethylene glycol) methyl
ether methacrylate)-b-poly(N-(2-hydroxypropyl) methacrylamide)
(PPEGMA-PHPMA) micelles cross-linked with ALAM were initially
synthesized and then used as seeds for the seeded photo-PISA of
glycidyl methacrylate (GlyMA). Due to the immiscibility within the
core-forming blocks of and PGlyMA and PHPMA, nanoscale phase
separation took place and formation of a patchy structure with a
uniform cross-link density was observed.
Fig. 6 Schematic illustration of enzyme-assisted photo-PISA for preparing cross-
linked CO2-responsive vesicles. Reproduced from ref. 80 with permission from The
Royal Society of Chemistry, copyright 2019.
In addition to achieving stable high-order morphologies, in situ
cross-linking strategy employing asymmetric cross-linker was also
used to reduce the impact of external stimuli on particle structure of
block copolymer nano-assemblies.80 For example, Tan and co-
workers added an asymmetric cross-linker of allyl methacrylate
(AMA) to the photo-PISA of HPMA and DMAEMA for preparing
reusable CO2-responsive vesicles by using poly(glycerol
monomethacrylate) (PGMA) as the macro-CTA (Fig. 6).80 Because
of the neutralization between CO2 and tertiary amine groups of
PDMAEMA, the hydrophilicity of the core-forming P(HPMA-co-
DMAEMA-co-AMA) block in the PGMA-b-P(HPMA-co-DMAEMA-
co-AMA) block copolymer could be regulated by treating with CO2,
which then resulted in volume expansion of the cross-linked block
copolymer vesicles. By alternating treatment with CO2 and N2, the
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ARTICLE
hydrodynamic diameter of block copolymer vesicles View Articlecould
Online
alternately increase and decrease. The excellent reversibility of
DOI: 10.1039/D0PY00627K
these vesicles demonstrated their potential as smart nano-
capsules for the CO2-responsive release of cargoes.
3 Post-polymerization cross-linking approaches
Because a small perturbation in the block copolymer
composition may lead to the mixed morphologies, the cross-linking
process of high-order block copolymer nano-assemblies is
somewhat problematic, and in most cases only spherical micelles
Polymer Chemistry Accepted Manuscript
could be obtained by the in situ cross-linking approach.58,83
Therefore, preparation of cross-linked block copolymer nano-
assemblies with higher order morphologies and uniform particle
size distribution under PISA formulation has remained a challenge.
The post-polymerization cross-linking is a reliable stabilization
approach to solve this problem.63,89 By this post-polymerization
cross-linking approach, monomers containing reactive
functionalities were polymerized to form nanoparticles with
particular morphology, and then cross-linkers were added to induce
the cross-linking of the obtained nanoparticles. Up to now, much
effort has been made to achieve cross-linking of block copolymer
nano-assemblies, especially those involving stimulus-responsive
bonds.90,91 For example, the thermo-induced Diels-Alder reaction
between bismaleimide cross-linker and the furfuryl units of the
hydrophobic block was employed by Schacher and coworkers to
form cross-linked diblock copolymer micelles.92 Zhang and
coworkers exploited the isocyanate-amine chemistry of
hydrolysable hindered urea to synthesize a new type of cross-
linked and pH-responsive block copolymer vesicles in the presence
of water.93 Besides, the chemical reactions of amino-containing
compounds have attracted the continuous and widespread
attention in the post-polymerization cross-linking because of
abundant reactions and high reaction rate.63 Recently, photo-
chemistry has emerged as a powerful tool to realize cross-linking
PISA-formed nanoparticles under mild conditions.90,91 Compared
with other cross-linking strategies, photo-cross-linking have some
outstanding features, e.g., the real-time and the extent of cross-
linking could be readily achieved by photo-regulation, and no extra-
additives is required.94 Several photo-induced reactions, such as
UV-induced disulfide exchange90 and [2 + 2] cycloaddition,90,95,96
have been applied to stabilize block copolymer nano-assemblies.
3.1 Condensation, esterification or alkylation
involving the amino groups
The outstanding nucleophilicity of amine compounds to
electrophilic reagents, e.g., acetone, aldehyde and carboxylic acid,
leads to rapid chemical reaction with a high yield under mild
condition.97 The amino-involved reactions are usually abundant,
such as alkylation with halo-alkanes,98 dehydration condensation
with aldehyde or ketone83, and transesterification with ester99.
Therefore, benefiting from the highly efficient chemical reaction,
diamines have come into wide use in the covalent cross-linking of
polymer nanoparticles.
An and coworkers applied the condensation reaction between
β-ketoester and alkoxylamine to decorating and cross-linking block
copolymer nanoparticles.67 Using PPEGMMA macro-CTA, the
multi-functional monomer 2-(acetoacetoxy)ethyl methacrylate
(AEMA) was polymerized in ethanol to afford PPEGMMA-b-
PAEMA block copolymer nano-assemblies via PISA. By tuning the
J. Name., 2013, 00, 1-3 | 5
 PleasePolymer
do not Chemistry
adjust margins Page 6 of 11

ARTICLE Journal Name

solids, nanospheres and vesicles bearing reactive β-ketoester View Article Online
groups in the core PAEMA block were produced. Subsequently, DOI: 10.1039/D0PY00627K
these nanospheres and vesicles were cross-linked employing O,O′-
1,3-propanediylbisoxylamine (PBOA) which reacted with β-
ketoester groups to form oxime. These cross-linked block
copolymer nano-assemblies maintained their original morphologies
in DMF as a good solvent, while the particle size distribution was
slight broader as confirmed by the TEM and DLS analysis. Armes
and coworkers exploited the ketone moiety in the PDAAM block for
cross-linking of poly(N,N-dimethylacrylamide)-block-
poly(diacetone acrylamide) (PDMAC-b-PDAAM) block copolymer

Polymer Chemistry Accepted Manuscript

nanoparticles (Fig. 7).89 The PISA processes was conducted at pH
2.5 to form well-defined PDMAC-b-PDAAM nanospheres,
anisotropic worms or polydisperse vesicles. To achieve the
covalent stabilization of these nano-assemblies, water-soluble
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.

adipic acid dihydrazide (ADH) was then added to the aqueous

dispersion of PDMAC-b-PDAAM nano-assemblies. The hydrazide
groups of ADH underwent nucleophilic substitution with the
pendent ketone to form hydrazone linkages, resulting in the post-
polymerization cross-linking of these block copolymer nano-
assemblies. By varying the ADH concentration, the extent of cross-
linking could be specifically regulated. Under exposure to the good
solvent of methanol, the morphologies of the cross-linked PDMAC-
b-PDAAM nano-assemblies remained intact, while a substantial
swelling was observed for the slightly cross-linked vesicles.
Fig. 7 The preparation of cross-linked PDMAC-b-PDAAM nanoparticles via PISA.
Reproduced from ref. 89 with permission from American Chemical Society,
copyright 2017.
Lu and coworkers synthesized the salicylaldehyde
functionalized block copolymer nano-assemblies by RAFT
dispersion polymerization under PISA formulation.100 As shown in
Fig. 8, by tuning the degree of polymerization of the core-forming
block of poly(3-formyl-4-hydroxybenzyl methacrylate) (PFHMA),
various morphologies could be accessed using the PHPMA macro-
CTA as the stabilizing block. Based on the condensation reaction
between the aldehyde groups in PFHMA and hydrazine, stabilized
PISA-formed block copolymer nano-assemblies were obtained via
post-polymerization cross-linking. Moreover, the newly formed
salicylaldazines moieties also endowed the nano-assemblies with
a strong luminescent feature even in the solid state. Pan and
coworkers conducted the cross-linking of benzaldehyde-containing
block copolymer nanoparticles by using 1,4-butanediamine (BDA)
to form imine bonds at room temperature.63 Due to the acidic
hydrolysis of the imine linkages, the cross-linked block copolymer
nanoparticles exhibited pH responsibility. In weakly acidic solutions
the cross-linked nanoparticles could dissociate, but were stable at
pH-neutral condition.
Fig. 8 Synthesis of AIE-featured and cross-linked stable PHPMA-b-PFHMA block
copolymer nanoparticles. Reproduced from ref. 100 with permission from The
Royal Society of Chemistry, copyright 2016.
Sumerlin and coworkers demonstrated the successful
application of amidation between acid and diamine to achieve the
cross-linked block copolymer nanoparticles via PISA.66 Their
research was focused on the polymerization induced thermal self-
assembly (PITSA) of LCST-type thermo-responsive polymers,
such as PNIPAM. After the chain extension above LCST, block
copolymer nanoparticles with certain morphologies are formed in
dispersion polymerization. However, the uncross-linked
nanoparticles were susceptible to dissociation in water at ambient
temperatures. To facilitate the characterization of the block
copolymer nanoparticles, Sumerlin and coworkers added a small
fraction of acrylic acid (AA) to copolymerize with DMA.
Subsequently, the pendant acid groups of AA units in the
nanoparticles were cross-linked by addition of ethylenediamine in
the presence of carbodiimide.
O’Reilly and coworkers utilized a disulfide-containing
cystamine as cross-linker to synthesize redox-responsive block
copolymer nanoparticles which could undergo glutathione triggered
disassembly.101 Using poly(ethyleneglycol) macro-CTA, photo-
induced RAFT polymerization of an activated ester monomer of
pentafluorophenyl methacrylate (PFMA) were carried out in
anhydrous DMSO, resulting in formation of block copolymer
nanoparticles via PISA. Subsequently, O’Reilly and coworkers
used the amide-forming reaction between cystamine and the
activated ester to cross-link these block copolymer nanoparticles.
The FT-IR spectroscopic analysis indicated the cross-linking
efficiency of cystamine reached 88%. To assess the glutathione-
responsiveness of the nanoparticles, the cross-linked nanoparticles
were treated with PBS buffer of glutathione and then disassembled
into their constituent polymers.
In addition to condensation reaction and amidation reaction,
epoxy-opening reaction and quaternization reaction have also been
applied to the cross-linking of PISA-formed block copolymer
nanoparticles.102,103 Tan and coworkers prepared the epoxy-
functionalized block copolymer nanoparticles using GlyMA as the
core-forming monomer under a photo-PISA formulation at room
temperature.102 These block copolymer nanoparticles were then
treated with a bifunctional primary amine reagent ethylenediamine
(EDA) in ethanol/water mixture to achieve further cross-linking. To
demonstrate the cross-linking efficiencies, the nanoparticles after
the reaction with EDA were dispersed in a good solvent THF, and
TEM confirmed the maintained morphologies of worms and

6 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 7 of 11 PleasePolymer
do not Chemistry
adjust margins
Journal Name
vesicles. Recently, Armes and coworkers evaluated 1,2-bis(2-
iodoethoxy)ethane (BIEE) as cross-linker to stabilize
poly(dimethylsiloxane)-b-poly(2-(dimethylamino)ethyl
methacrylate) (PDMS-b-PDMA) block copolymer nano-
assemblies.103 This bifunctional cross-linker could quaternize the
tertiary amine moieties in the core-forming block of PDMA via
Menshutkin reaction at ambient temperature. However, the
sufficient cross-linking of block copolymer nano-assemblies
required a relatively long time, which may restrict the practical
application.
3.2 Hydrolysis-condensation of siloxane
Alkoxysilanes can undergo irreversible hydrolysis and
condensation in the aqueous phase to form dense cross-linked
network,104 therefore they are always used as the valuable
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.
industrial materials in adhesive, sealant and cable industries. The
hydrolysis and condensation are dependent on the chemical
structure of alkoxysilanes, the reaction temperature and the
solution pH.105 In addition, alkoxysilanes with multi-functionalities
recently served as cross-linkers for the preparation of the cross-
linked block copolymer nano-assemblies via PISA.104,106 Since the
functional alkoxysilane bonds could connect more than two
polymer chains at the same time, the introduction of alkoxysilanes
into the polymer chains results in the high-density cross-linked
polymer network, which provides the enhanced stability against the
solvents.
Fig. 9 Reaction scheme illustrating worm core cross-linking chemistry. Reproduced
from ref. 104 with permission from American Chemical Society, copyright 2016.
Armes and coworkers described the synthesis of cross-linked
copolymer worms via RAFT aqueous dispersion polymerization,
based on the hydrolysis-condensation of the siloxane moieties
within the core-forming block.104 A series of poly(glycerol
monomethacrylate)-poly(2-hydroxypropyl methacrylate-stat-
glycidyl methacrylate) (PGMA-P(HPMA-stat-GlyMA)) block
copolymer nano-assemblies were prepared by PISA. Subsequently,
3-aminopropyltriethoxysilane (APTES) was utilized to modify the
glycidyl-functional core of PGMA-P(HPMA-stat-GlyMA). As shown
in Fig. 9, the pendent epoxide groups within the core-forming block
were ring-opened via nucleophilic attack by the primary amine
group in APTES, and then the hydrolysis-condensation between
the newly-formed siloxane moieties and the hydroxyl groups in the
PHPMA segment induced the intermolecular cross-linking of block
copolymer worms. The 1H NMR analysis indicated epoxy ring-
opening and the cross-linking almost occurring simultaneity.
Using reactive alkoxysilane moieties in the middle block,
Thickett and coworkers synthesized interfacially cross-linked
triblock copolymer nanoparticles via RAFT-mediated PISA.106 The
triblock copolymers were featured with an ABC-type composition,
consisting of a hydrophilic poly(ethylene glycol) ethyl ether
methacrylate (PEGMA) block, a short poly(3-(trimethoxysilyl)propyl
methacrylate) (PMPS) block and a hydrophobic poly(benzyl
methacrylate) (BzMA) block. A series of optimizations were
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ARTICLE
performed on the hydrolysis and condensation process ofOnline
View Article the
alkoxysilane moieties in the PMPS block. DOI:With regard to the
10.1039/D0PY00627K
catalyst type and concentration, the relatively high efficiency of
cross-linking was achieved by using moderate water-soluble
triethylamine (TEA) as catalyst. The catalytic hydrolysis and
subsequent condensation of the alkoxysilane groups in the middle
PMPS block led to the controlled growth of silica domains, and
ultimately created capsules and nanoparticles with a cross-linked
interface.
3.3 UV-induced disulfide exchange
Polymer Chemistry Accepted Manuscript
As reported previously,101 disulfide bonds in the degradable
BAC-cross-linked block copolymer nanoparticles could undergo
reversible cleavage via thiol-disulfide exchange. Furthermore,
disulfides can also participate in the UV-induced exchange by
disulfide homolysis and recombination.107,108 Recently, Cai and
coworkers utilized this to the photo-cross-linking of stabilized
polyion complex (PIC) vesicles obtained by visible light-initiated
polymerization-induced electrostatic self-assembly (PIESA).90 The
trithiocarbonate (TTC) radicals under UV-light irradiation could
decompose to thiyl radicals which could then trigger the disulfide
exchange. As shown in Fig. 10, UV-light irradiation promoted the
exchange of locally confined/enriched disulfide groups in the PIC
vesicles. With UV irradiation time prolonging, continuous thiol-
disulfide exchange caused crosslinking of the polymer backbones.
The cross-linked PIC spheres, micrometer-sized lamellae and
vesicles could be successively achieved in 4 min and exhibited the
outstanding shape/size stability against the solvent exchange by
adding ethanol into aqueous dispersion and subsequent dialysis.
Fig. 10 Schematic illustration of the synthesis and photo-cross-linking of disulfide-
containing PIC vesicles. Reproduced from ref. 90 with permission from American
Chemical Society, copyright 2019.
3.4 UV-light induced [2 + 2] cycloaddition
Under UV-light irradiation, some chromophore moieties, e.g.,
anthracene, coumarin, cinnamate, thymine, and stilbene, can
dimerize by [2 + 2] cycloaddition,109,110 thus they are utilized in some
photo-responsive applications such as self-healing materials. The
incorporation of these moieties into polymers allows the fabrication
of photo-cross-linked polymer nanoparticles. Recently, several
research groups have applied the reversible dimerization to the
synthesis of photo-cross-linkable block copolymer nanoparticles
via PISA.91
In 2017, Pan and coworkers demonstrated the 365 nm UV-
light triggered [2+2] cycloaddition of the coumarin moieties for the
membrane cross-linking of block copolymer vesicles (Fig. 11).91
Using PHPMA as macro-CTA, two functional monomers of 2-
(diisopropylamino)ethyl methacrylate (DIPEMA) and 7-(2-
methacryloyloxy-ethoxy)-4-methylcoumarin (CMA) were
J. Name., 2013, 00, 1-3 | 7
 PleasePolymer
do not Chemistry
adjust margins
ARTICLE
copolymerized via RAFT dispersion formulation, while the
coumarin moieties were anchored in the membrane. Under UV-
light irradiation, dimerization of the coumarin groups led to cross-
linking vesicular membrane. The extent of membrane cross-linking
can be conveniently regulated by changing UV-light irradiation time.
Upon switching pH values, the cross-linked vesicles underwent
through a swelling/shrinking change and maintained the vesicular
morphology, which indicated the superior structural stability of the
cross-linked vesicles.
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.
Fig. 11 Fabrication of vesicles with pH-regulated permeability by polymerization-
induced self-assembly and reorganization (PISR) and UV light irradiation induced
membrane crosslinking of the vesicles. Reproduced from ref. 91 with permission
from American Chemical Society, copyright 2017.
In the same year, Lu and coworkers reported the synthesis of
homogeneously photo-crosslinked block copolymer nanoparticles
using [2 + 2] cycloaddition chemistry.95 By using poly(2-
hydroxypropyl methacrylate) (PHPMA) as macro-CTA, they
conducted RAFT dispersion polymerization of 2-((3-(4-
(diethylamino)phenyl) acryloyl)oxy)ethyl methacrylate (DEMA) at a
high solid concentration. By varying the chain length of the PDEMA
core-forming block, various block copolymer nano-assemblies, i.e.,
spheres, worms and vesicles, were obtained. Under UV-light
irradiation, the cinnamate moieties within the core of the nano-
assemblies could easily dimerize through [2 + 2] cycloaddition, thus
the as-prepared block copolymer nano-assemblies were stabilized
by photo-crosslinking. Lu and coworkers also inhibited the potential
application of the multifunctional nanoparticles generated via PISA
as templates for in situ formation of Au/polymer hybrids. Boyer and
coworkers utilized the 7-[4-(trifluoromethyl)coumarin]
methacrylamide (TCMAm) as a co-monomer to realize the photo-
cross-linking of block copolymer nanoparticles generated via
photoinduced PISA.96 Due to the wavelength orthogonality of the
red-light-induced RAFT polymerization and UV-induced [2 + 2]
coumarin cycloaddition, the PISA and cross-linking process could
be successively conducted in a one-pot approach, allowing for
retention of the block nanoparticle morphology in organic solvents.
4 Summary and outlook
Covalent cross-linking provides a robust and efficient
approach to stabilize block copolymer nano-assemblies obtained
via RAFT-mediated PISA process. With the continuous
improvement, new cross-linking approaches, which can be
classified into the in situ cross-linking and the post-polymerization
cross-linking, have been developed. Particularly, the utilization of
asymmetric cross-linkers with two different vinyl moieties in the in
situ cross-linking can delay the cross-linking process to the late
polymerization stage when morphology transition has completed.
8 | J. Name., 2012, 00, 1-3
Please do not adjust margins
Page 8 of 11
Journal Name
Moreover, by using the cross-linkers containing reactive moieties,
View Article Online
such as cinnamate or disulfide, block copolymer nano-assemblies
DOI: 10.1039/D0PY00627K
can undergo cross-linking or its reverse process under a certain
external stimulus such as light and redox stimuli while preserving
the structural integrity. Although considerable progresses have
been made, researchers still face with some significant problems
and the further efforts are required to promote the practical
applications of the cross-linked block copolymer nano-assemblies.
The appropriate amount of cross-linkers usually needs to be
determined through tedious comparison experiment. With
excessive cross-linkers, unwanted cross-linking between the
Polymer Chemistry Accepted Manuscript
copolymer nano-assemblies can occur sometimes at a high solid
and thus cause gelation. In contrast, with a low concentration of
cross-linkers, the cross-linking will be inefficient, inevitably
remaining a lot of uncross-linked linear polymers. In addition, it is
still a great challenge to achieve a high cross-lining density of block
copolymer nano-assemblies without an obvious impact on their
morphology transition by in situ cross-linking approaches. The high
cross-linking density will be necessary to improve the anti-swelling
properties of block copolymer nano-assemblies to external stimulus
or in good solvents, which are important to guarantee intended
performance in some applications. For example, as the drug
carriers, block copolymer nano-assemblies with a low cross-linking
density would possibly become swollen and porous in the blood,
resulting in the premature release of the loaded medicine before
reaching the target. In post-polymerization cross-linking
approaches, the delayed introduction of cross-linkers may induce a
heterogeneous distribution of cross-linkage in the obtained nano-
assemblies, which will reduce their morphological stability.
Therefore, the mild and efficient reactions for cross-linking of block
copolymer nano-assemblies are still highly desirable. Smart cross-
linkers with reversible chemical bonds can be designed to stabilize
block copolymer nano-assemblies under certain external stimulus,
which potentially provides the possibility of cross-linked nano-
assemblies as degradable nano-materials.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The financial support by the National Science Foundation of
China (No. 21525419 and 21931003) and the Ministry of Science
and Technology of the People's Republic of China
(2016YFA0202503) is gratefully acknowledged.
Notes and references
1 J. Rieger, Macromol. Rapid Commun. 2015, 36, 1458-1471.
2 X. Wang, L. Shen, Z. An, Progress in Polymer Science 2018, 83,
1-27.
3 Y. Mai, A. Eisenberg, Chem. Soc. Rev. 2012, 41, 5969-5985.
4 J. Rodriguez-Hernandez, F. Chécot, Y. Gnanou, S.
Lecommandoux, Prog. Polym. Sci. 2005, 30, 691-724.
5 W. J. Zhang, C. Y. Hong, C. Y. Pan, Macromol. Rapid Commun.
2019, 40, 1800279.
6 G. Cheng, J. Pérez-Mercader, Macromol. Rapid Commun.
2019, 40, 1800513.
7 V. Ladmiral, M. Semsarilar, I. Canton, S. P. Armes, J. Am.
Chem. Soc. 2013, 135, 13574-13581.
8 J. Tan, D. Liu, X. Zhang, C. Huang, J. He, Q. Xu, X. Li, L. Zhang,
RSC Adv. 2017, 7, 23114-23121.
This journal is © The Royal Society of Chemistry 20xx
 Page 9 of 11 PleasePolymer
do not Chemistry
adjust margins

Journal Name ARTICLE

9 G. H. Teo, R. P. Kuchel, P. B. Zetterlund, S. C. Thickett, Polym. 40 G. Wang, M. Schmitt, Z. Wang, B. Lee, X. Pan, L.View Fu,Article
J. Yan, S.
Online
Chem. 2016, 7, 6575-6585. Li, G. Xie, M. R. Bockstaller.DOI:K.10.1039/D0PY00627K
Matyjaszewski,
10 W. J. Zhang, C. Y. Hong, C. Y. Pan, Biomacromolecules 2016, Macromolecules 2016, 49, 8605-8615.
17, 2992-2999. 41 G. Wang, Z. Wang, B. Lee, R. Yuan, Z. Lu, J. Yan, X. Pan, Y.
11 X. F. Xu, C. Y. Pan, W. J. Zhang, C. Y. Hong, Macromolecules Song, M. R. Bockstaller, K. Matyjaszewski, Polymer 2017,
2019, 52, 1965-1975. 129, 57-67.
12 Z. Sadrearhami, J. Yeow, T. K. Nguyen, K. K. Ho, N. Kumar, C. 42 F. D'Agosto, J. Rieger, M. Lansalot, Angew, Chem. 2019, Early
Boyer, Chem. Commun. 2017, 53, 12894-12897. View.
13 A. Bagheri, C. Boyer, M. Lim, Macromol. Rapid Commun. 43 J. Zhou, H. Yao, J. Ma, Polym. Chem. 2018, 9, 2532-2561.
2019, 40, 1800510. 44 A. B. Lowe, Polymer 2016, 106, 161-181.
14 D. E. Mitchell, J. R. Lovett, S. P. Armes, M. I. Gibson, Angew. 45 M. Semsarilar, V. Ladmiral, A. Blanazs, S. P. Armes, Polym.
Chem. Int. Ed. 2016, 55, 2801-2804. Chem. 2014, 5, 3466-3475.
15 L. D. Blackman, S. Varlas, M. C. Arno, A. Fayter, M. I. Gibson, 46 C. Gonzato, M. Semsarilar, E. R. Jones, F. Li, G. J. Krooshof, P.

Polymer Chemistry Accepted Manuscript

R. K. O’Reilly, ACS Macro Letters 2017, 6, 1263-1267.
16 L. D. Blackman, S. Varlas, M. C. Arno, Z. H. Houston, N. L.
Fletcher, K. J. Thurecht, M. Hasan, M. I. Gibson, R. K. O’Reilly,
ACS Central Sci. 2018, 4, 718-723.
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.
Wyman, O. O. Mykhaylyk, R. Tuinier, S. P. Armes, J. Am.
Chem. Soc. 2014, 136, 11100-11106.
47 A. N. Albertsen, J. K. Szymański, J. Pérez-Mercader, Sci Rep.
2017, 7, 1-8.

17 B. Karagoz, L. Esser, H. T. Duong, J. S. Basuki, C. Boyer, T. P. 48 B. P. Bastakoti, J. Perez-Mercader, Angew. Chem. Int. Ed.
Davis, Polym. Chem. 2014, 5, 350-355. 2017, 56, 12086-12091.
18 X. Liu, M. Sun, J. Sun, J. Hu, Z. Wang, J. Guo, W. Gao, J. Am. 49 B. P. Bastakoti, S. Guragain, J. Perez-Mercader, Chem. Eur. J.
Chem. Soc. 2018, 140, 10435-10438. 2018, 24, 10621-10624.
19 C. Ma, X. Liu, G. Wu, P. Zhou, Y. Zhou, L. Wang, X. Huang, ACS 50 G. Mellot, J. M. Guigner, L. Bouteiller, F. Stoffelbach, J.
Macro Letters 2017, 6, 689-694. Rieger, Angew. Chem. 2019, 131, 3205-3209.
20 M. Chen, W. G. Zhang, J. W. Li, C. Y. Hong, W. J. Zhang, Y. Z. 51 Q. Xu, T. Huang, S. Li, K. Li, C. Li, Y. Liu, Y. Wang, C. Yu, Y. Zhou,
You, Sci. China Chem. 2018, 61, 1159-1166. Angew. Chem. 2018, 130, 8175-8179.
21 J. Yeow, C. Boyer, Adv. Sci. 2017, 4, 1700137. 52 X. Y. Zhang, D. M. Liu, X. H. Lv, M. Sun, X. L. Sun, W. M. Wan,
22 X. Wang, C. A. Figg, X. Lv, Y. Yang, B. S. Sumerlin, Z. An, ACS Macromol. Rapid Commun. 2016, 37, 1735-1741.
Macro Letters 2017, 6, 337-342. 53 H. Chen, S. Kim, W. He, H. Wang, P. S. Low, K. Park, J. X.
23 V. J. Cunningham, A. M. Alswieleh, K. L. Thompson, M. Cheng, Langmuir 2008, 24, 5213-5217.
Williams, G. J. Leggett, S. P. Armes, O. M. Musa, 54 K. L. Thompson, P. Chambon, R. Verber, S. P. Armes, J. Am.
Macromolecules 2014, 47, 5613-5623. Chem. Soc. 2012, 134, 12450-12453.
24 M. J. Derry, L. A. Fielding, S. P. Armes, Polym. Chem. 2015, 6, 55 N. J. Penfold, Y. Ning, P. Verstraete, J. Smets, S. P. Armes,
3054-3062. Chem. Sci. 2016, 7, 6894-6904.
25 S. Li, H. Nie, S. Gu, Z. Han, G. Han, W. Zhang, ACS Macro 56 P. Chambon, A. Blanazs, G. Battaglia, S. P. Armes, Langmuir
Letters 2019, 8, 783-788. 2012, 28, 1196-1205.
26 S. Qu, R. Liu, W. Duan, W. Zhang, Macromolecules 2019, 52, 57 X. Wang, G. Liu, J. Hu, G. Zhang, S. Liu, Angew. Chem. Int. Ed.
5168-5176. 2014, 53, 3138-3142.
27 C. Gao, H. Zhou, Y. Qu, W. Wang, H. Khan, W. Zhang, 58 Z. An, Q. Shi, W. Tang, C. K. Tsung, C. J. Hawker, G. D. Stucky,
Macromolecules 2016, 49, 3789-3798. J. Am. Chem. Soc. 2007, 129, 14493-14499.
28 Y. Zhang, G. Han, M. Cao, T. Guo, W. Zhang, Macromolecules 59 P. Chambon, A. Blanazs, G. Battaglia, S. P. Armes,
2018, 51, 4397-4406. Macromolecules 2012, 45, 5081-5090.
29 J. Sarkar, L. Xiao, A. W. Jackson, A. M. van Herk, A. Goto, 60 S. Qian, R. Liu, G. Han, K. Shi, W. Zhang, Polym. Chem. 2020,
Polym. Chem. 2018, 9, 4900-4907. 11, 2532-2541.
30 E. Groison, S. Brusseau, F. D’Agosto, S. Magnet, R. Inoubli, L. 61 L. Zhang, Q. Lu, X. Lv, L. Shen, B. Zhang, Z. An,
Couvreur, B. Charleux, ACS Macro Letters 2012, 1, 47-51. Macromolecules 2017, 50, 2165-2174.
31 X. G. Qiao, M. Lansalot, E. Bourgeat-Lami, B. Charleux, 62 G. He, T. M. Bennett, K. Alias, L. Jiang, S. T. Schwab, M.
Macromolecules 2013, 46, 4285-4295. Alauhdin, S. M. Howdle, Polym. Chem. 2019, 10, 3960-3972.
32 D. Cordella, F. Ouhib, A. Aqil, T. Defize, C. Jérôme, A. Serghei, 63 L. Qiu, C. R. Xu, F. Zhong, C. Y. Hong, C. Y. Pan, Macromol.
E. Drockenmuller, K. Aissou, D. Taton, C. Detrembleur, ACS Chem. Phys. 2016, 217, 1047-1056.
Macro Letters 2017, 6, 121-126. 64 Y. Li, Z. Ye, L. Shen, Y. Xu, A. Zhu, P. Wu, Z. An,
33 Y. Sha, M. A. Rahman, T. Zhu, Y. Cha, C. W. McAlister, C. Tang, Macromolecules 2016, 49, 3038-3048.
Chem. Sci. 2019, 10, 9782-9787. 65 Q. Qu, G. Liu, X. Lv, B. Zhang, Z. An, ACS Macro Letters 2016,
34 J. C. Foster, S. Varlas, L. D. Blackman, L. A. Arkinstall, R. K. 5, 316-320.
O'Reilly, Angew. Chem. 2018, 130, 10832-10836. 66 C. A. Figg, A. Simula, K. A. Gebre, B. S. Tucker, D. M.
35 S. Varlas, J. C. Foster, L. A. Arkinstall, J. R. Jones, R. Keogh, R. Haddleton, B. S. Sumerlin, Chem. Sci. 2015, 6, 1230-1236.
T. Mathers, R. K. O’Reilly, ACS Macro Letters 2019, 8, 466- 67 W. Zhou, Q. Qu, W. Yu, Z. An, ACS Macro Letters 2014, 3,
472. 1220-1224.
36 S. Shin, K. Y. Yoon, T. L. Choi, Macromolecules 2015, 48, 1390- 68 W. Zhou, Q. Qu, Y. Xu, Z. An, ACS Macro Letters 2015, 4, 495-
1397. 499.
37 C. Grazon, P. Salas-Ambrosio, E. Ibarboure, A. Buol, E. 69 Q. Chen, F. Han, C. Lin, X. Wen, P. Zhao, Polymer 2018, 146,
Garanger, M. W. Grinstaff, S. Lecommandoux, C. Bonduelle, 378-385.
Angew. Chem. Int. Ed. 2020, 59, 622-626. 70 Q. Chen, X. Cao, Y. Xu, Z. An, Macromol. Rapid Commun.
38 O. L. Torres-Rocha, X. Wu, C. Zhu, C. M. Crudden, M. F. 2013, 34, 1507-1517.
Cunningham, Macromol. Rapid Commun. 2019, 40, 1800326. 71 T. G. McKenzie, E. H. Wong, Q. Fu, A. Sulistio, D. E. Dunstan,
39 Q. Xu, C. Tian, L. Zhang, Z. Cheng, X. Zhu, Macromol. Rapid G. G. Qiao, ACS Macro Letters 2015, 4, 1012-1016.
Commun. 2019, 40, 1800327. 72 W. Zhou, W. Yu, Z. An, Polym. Chem. 2013, 4, 1921-1931.
73 X. Shi, M. Miao, Z. An, Polym. Chem. 2013, 4, 1950-1959.

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 9

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 10 of 11

ARTICLE Journal Name

74 J. Ferreira, J. Syrett, M. Whittaker, D. Haddleton, T. P. Davis, 93 J. Tan, H. Lei, D. J. Liaw, X. Chen, L. Ma, C. Cui,View Q. Article
Zhong, Y.
Online
C. Boyer, Polym. Chem. 2011, 2, 1671-1677. Cheng, Y. Zhang, Macromol. RapidDOI: Commun. 2019, 40,
10.1039/D0PY00627K
75 Q. Zhao , Q. Liu , C. Li , L. Cao , L. Ma , X. Wang, Y. Cai, Chem. 1900149.
Commun. 2020, 56, 4954-4957. 94 M. Chen, M. Zhong, J. A. Johnson, Chem. Rev. 2016, 116,
76 G. Liu, Q. Qiu, W. Shen, Z. An, Macromolecules 2011, 44, 10167-10211.
5237-5245. 95 J. Huang, D. Li, H. Liang, J. Lu, Macromol. Rapid Commun.
77 M. J. Derry, T. Smith, P. S. O’hora, S. P. Armes, ACS Appl. 2017, 38, 1700202.
Mater. Inter. 2019, 11, 33364-33369. 96 S. Xu, J. Yeow, C. Boyer, ACS Macro Letters 2018, 7, 1376-
78 S. Chen, A. F. Cardozo, C. Julcour, J. F. Blanco, L. Barthe, F. 1382.
Gayet, M. Lansalot, F. D'Agosto, H. Delmas, E. Manoury, R. 97 S. France, D. J. Guerin, S. J. Miller, T. Lectka, Chem. Rev. 2003,
Poli, Polymer 2015, 72, 327-335. 103, 2985-3012.
79 W. Shen, Y. Chang, G. Liu, H. Wang, A. Cao, Z. An, 98 M. Sola, A. Lledos, M. Duran, J. Bertran, J. L. M. Abboud, J.
Macromolecules 2011, 44, 2524-2530. Am. Chem. Soc. 1991, 113, 2873-2879.

Polymer Chemistry Accepted Manuscript

80 L. Yu, Y. Zhang, X. Dai, Q. Xu, L. Zhang, J. Tan, Chem. Commun.
2019, 55, 11920-11923.
81 A. Halperin, M. Kröger, F. M. Winnik, Angew. Chem. Int. Ed.
2015, 54, 15342-15367.
Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.
99 M. I. Gibson, E. Fröhlich, H. A. Klok, J. Polym. Sci. Pol. Chem.
2009, 47, 4332-4345.
100 J. Huang, H. Zhu, H. Liang, J. Lu, Polym. Chem. 2016, 7, 4761-
4770.

82 S. Piogé, T. N. Tran, T. G. McKenzie, S. Pascual, M. 101 B. Couturaud, P. G. Georgiou, S. Varlas, J. R. Jones, M. C.

Ashokkumar, L. Fontaine, G. Qiao, Macromolecules 2018, 51,
8862-8869.
83 W. Fu, C. Luo, E. A. Morin, W. He, Z. Li, B. Zhao, ACS Macro
Letters 2017, 6, 127-133.
84 P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J. L. Wietor, J. K.
Sanders, S. Otto, Chem. Rev. 2006, 106, 3652-3711.
85 X. Dai, L. Yu, Y. Zhang, L. Zhang, J. Tan, Macromolecules 2019,
52, 7468-7476.
86 B. Zhang, X. Lv, A. Zhu, J. Zheng, Y. Yang, Z. An,
Macromolecules 2018, 51, 2776-2784.
87 X. Wang, J. Zhou, X. Lv, B. Zhang, Z. An, Macromolecules
2017, 50, 7222-7232.
88 X. Dai, Y. Zhang, L. Yu, X. Li, L. Zhang, J. Tan, ACS Macro Letters
2019, 8, 955-961.
89 S. J. Byard, M. Williams, B. E. McKenzie, A. Blanazs, S. P.
Armes, Macromolecules 2017, 50, 1482-1493.
90 L. Huang, Y. Ding, Y. Ma, L. Wang, Q. Liu, X. Lu, Y. Cai,
Macromolecules 2019, 52, 4703-4712.
91 W. J. Zhang, C. Y. Hong, C. Y. Pan, ACS Appl. Mater. Inter.
2017, 9, 15086-15095.
92 J. K. Elter, P. Biehl, M. Gottschaldt, F. H. Schacher, Polym.
Chem. 2019, 10, 5425-5439.
Arno, J. C. Foster, R. K. O'Reilly, Macromol. Rapid Commun.
2019, 40, 1800460.
102 J. Tan, D. Liu, C. Huang, X. Li, J. He, Q. Xu, L. Zhang, Macromol.
Rapid Commun. 2017, 38, 1700195.
103 M. J. Rymaruk, C. T. O’Brien, S. L. Brown, C. N. Williams, S. P.
Armes, Macromolecules 2019, 52, 6849-6860.
104 J. R. Lovett, L. P. D. Ratcliffe, N. J. Warren, S. P. Armes, M. J.
Smallridge, R. B. Cracknell, B. R. Saunders, Macromolecules
2016, 49, 2928-2941.
105 Z. Pu, W. J. van Ooij, J. E. Mark, J. Adhes. Sci. Technol 1997,
11, 29-47.
106 G. H. Teo, P. B. Zetterlund, S. C. Thickett, J. Polym. Sci. Pol.
Chem. 2019, 57, 1897-1907.
107 H. Otsuka, S. Nagano, Y. Kobashi, T. Maeda, A. Takahara,
Chem. Commun. 2010, 46, 1150-1152.
108 F. Fan, S. Ji, C. Sun, C. Liu, Y. Yu, Y. Fu, H. Xu, Angew. Chem.
Int. Ed. 2018, 57, 16426-16430.
109 G. Kaur, P. Johnston, K. Saito, Polym. Chem. 2014, 5, 2171-
2186.
110 C. Cardenas-Daw, A. Kroeger, W. Schaertl, P. Froimowicz, K.
Landfester, Macromol. Chem. Phys. 2012, 213, 144-156.

10 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 11 of 11 PleasePolymer
do not Chemistry
adjust margins

ARTICLE

View Article Online

The Table of Contents Entry DOI: 10.1039/D0PY00627K

The Cross-linking Approaches for Block Copolymer Nano-assemblies via RAFT-mediated

Polymerization-induced Self-assembly

Shenzhen Li, Guang Han and Wangqing Zhang*

Polymer Chemistry Accepted Manuscript

Published on 09 June 2020. Downloaded by Uppsala University on 6/16/2020 4:13:45 PM.

This minireview summarizes the current cross-linking approaches to stabilize block copolymer
nano-assemblies obtained via RAFT-mediated PISA process.

Please do not adjust margins