Biomaterials

Science
View Article Online
REVIEW View Journal
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.

“Smart” self-assembled structures: toward

Cite this: DOI: 10.1039/d0bm01283a
intelligent dual responsive drug delivery systems
a,b
Mahsa Shahriari, Vladimir P. Torchilin,c,d Seyed Mohammad Taghdisi, e
a,f
Khalil Abnous, Mohammad Ramezani *a,b and Mona Alibolandi *a,b

Combination of various polymeric blocks with distinct characteristics such as thermo-responsiveness,

Received 1st August 2020,
Accepted 3rd September 2020
DOI: 10.1039/d0bm01283a
rsc.li/biomaterials-science
non-ionic nature and zwitterionic properties is an interesting approach toward fabricating copolymers
undergoing a smart self-assembly process in an aqueous environment. In some cases, through a so-
called “schizophrenic” self-assembly process, stimuli-induced self-assembly can occur from either
double-hydrophilic or double hydrophobic polymers. In this process, the roles of the blocks forming the
hydrophobic core and hydrophilic shell can be switched by changing the external conditions. This trans-
formation in the solubilization profile leads to the fabrication of “smart” polymeric vehicles which could
potentially control the release of their cargos as well as differentiate between encapsulated agents based
on their charge and polarity properties. The aforementioned changes of the amphiphilicity of polymers in
“schizophrenic” structures offer numerous self-assembly scenarios. In the current review, we summarize
the polymer and peptide-based schizophrenic copolymers which could form micellar and vesicular ( poly-
mersome) systems providing novel structures with beneficial applications.

1. Introduction carriers can be designed for the intelligent release of cargos in

Nanocarriers are currently attracting scientists’ attention to
improve the bioavailability while reducing the side effects of
drugs through releasing them at the site of action.1–7 A promis-
ing strategy for releasing payloads in a site-specific manner is
to employ stimuli-responsive materials including inorganic
nanoparticles, lipids, and polymers. Amphiphilic smart
polymer synthesis and their assembly can provide systems
with the ability to respond to either external (for instance,
temperature, light, ultrasound, electrical stimulus or magnetic
field) or internal stimuli (unique enzymatic activity, pH, or
redox potential). These systems facilitate the controlled release
of their payloads.8–11 As an example, hypoxia-sensitive nano-
a
Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad
University of Medical Sciences, Mashhad, Iran. E-mail: ramezanim@mums.ac.ir;
Fax: +98 51 37112470; Tel: +98 51 37112470
b
Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad
University of Medical Sciences, Mashhad, Iran. E-mail: alibolandim@mums.ac.ir;
Fax: +98 51 38823255; Tel: +98 51 38823255
c
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern
University, Boston, MA 02115, USA
d
Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First
Moscow State Medical University (Sechenov University), Moscow, Russia
e
Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute,
Mashhad University of Medical Sciences, Mashhad, Iran
f
Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran
tumor sites under the hypoxic tumor environment due to the
insufficient blood flow.12 The common stimuli used as triggers
for responsive polymers to develop smart drug delivery systems
(DDS) are temperature and/or pH.13 However, some polymers
change their conformations when they are exposed to an elec-
tric field, a magnetic field or light irradiation.14–17 These
stimuli can change either the polymer chemical structure or
their physical characteristics, reversibly or irreversibly.
Polymeric vehicles are widely utilized for the encapsulation of
hydrophobic agents suffering from unsatisfactory drug
loading, colloidal uniformity, formulation stability, and drug
release to provide improved cellular uptake and longer blood
circulation.18,19
“Schizophrenic” copolymers are among smart polymers
demonstrating ambivalent characteristics based on external
conditions.20 These polymers are usually composed of blocks
with similar features but minor differences. Since 1998, mul-
tiple types of novel water-soluble di-block copolymers have
been reported by the Bütün group21 and they are so called
“schizophrenic” polymers. They designated this name to these
types of copolymers because of their unique features repre-
senting a unique behavior by which they can be self-assembled
in dilute hydrophilic solution without the presence of any
organic co-solvent, thereby producing two discrete micelle
structures. Through changing the temperature, pH, or ionic
strength, each block can be modulated to become hydrophilic
or hydrophobic. The “schizophrenic” phrase describes this

This journal is © The Royal Society of Chemistry 2020 Biomater. Sci.

 View Article Online

Review Biomaterials Science

Table 1 Different copolymers with “schizophrenic” behavior in the presence of ionic or pH stimuli

Polymer Polymerization method Stimulus Description Ref.

2-(Dimethylamino) ethyl methacrylate
(DMAEMA) and 2-(N-morpholino) ethyl
methacrylate (MEMA)
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Group transfer pH and salt Salt concentration and pH value may affect the 21
polymerization (GTP) structure of the diblock copolymer. While DEA-
core micelles are formed at zero salt conc. and pH
8, micelles with a MEMA core may be constructed

in the presence of salt and pH 6.7

Poly(propylene oxide) (PPO) and 2- Atom transfer radical pH and By adding salt solution, the DEA-core micelles 23
(diethylamino)ethyl methacrylate (DEA) polymerization (ATRP) temperature were self-assembled using low temperature while
after exploiting higher pH, the self-assembled
structure was reversed
Poly(4-vinyl benzoic acid-block-2- Atom transfer radical pH This di-block copolymer was synthesized by ATRP. 24
(diethylamino)ethyl methacrylate) (PVBA- polymerization (ATRP) VBA block became insoluble and formed VBA-core
b-DEA) micelles at low pH, whereas micelles with a DEA
core were prepared at higher pH
Poly(N,N-diethylaminoethyl methacrylate) RAFT polymerization pH At lower pH, pDEA was water-soluble, whereas 29
(pDEA) and poly(6-acrylamidohexanoic pAaH showed the water-soluble feature at higher
acid) (pAaH) pH. Hence, pDEA-core micelles were formed at
basic pH, but pAaH-core micelles were prepared at
acidic pH
[(N,N-Diethylaminoethyl methacrylate)-b- RAFT polymerization pH and Micelles with the PNIPAM shell and PDEAEMA 30
(N-isopropyl acrylamide)]s (P(DEAEMA-b- temperature core may be produced at temperature below the
NIPAM)s) critical solution temperature of PNIPAM and pH
higher than PDEAEMA pKa

unusual behavior, which is not observed in conventional small
molecule surfactants.22 The first generation of these micelles
responds to both salt and pH.21 The second generation was
purely thermo-responsive,23 while the third generation was
only pH-sensitive.24 Different types of copolymers with “schizo-
phrenic” behavior in the presence of various stimuli are sum-
marized in Tables 1 and 2.
It is demonstrated that AB di-block copolymers can be
aggregated based on the selectivity of the solvent by either
block A or B in order to form micelles. An AB di-block copoly-
mer based on a tertiary amine methacrylate was developed by
group transfer polymerization (GTP) which can be used to con-
struct reversible micelles in aqueous media with non-solvated
cores consisting of either block A or B through controlling the
pH and electrolyte concentration (Fig. 1).21 In this regard, they
could produce two distinct micelles including one micelle with
block A as the core, and the reverse micelle with block B as the
core, by one di-block copolymer through a change of either pH

Mahsa Shahriari received her Vladimir P. Torchilin is a

Pharma.D. degree in 2014 from
Zabol University of Medical
Sciences, Iran. She is currently a
Ph.D. candidate in pharma-
ceutical biotechnology at the
School of Pharmacy, Mashhad
University of Medical Sciences,
Iran. In 2017, she started her
Ph.D. thesis on HA-based poly-
mersomes under the supervision
of Prof. Alibolandi. Her current
Mahsa Shahriari research interests focus on the
design of drug delivery systems
and their application in cancer.
Distinguished Professor and
Director, Center for
Pharmaceutical Biotechnology
and Nanomedicine,
Northeastern University, Boston.
He graduated from the Moscow
University with MS in Chemistry,
and obtained there his Ph.D.
and D.Sc. in Polymer Chemistry
and Chemistry of Physiologically
Active Compounds in 1971 and
Vladimir P. Torchilin 1980, respectively. In 1991,
Dr Torchilin joined MGH/
Harvard Medical School as the Head of Chemistry Program,
Center for Imaging and Pharmaceutical Research, and Associate
Professor of Radiology. Since 1998, Dr Torchilin has been with
Northeastern University. He was the Chair of the Department of
Pharmaceutical Sciences in 1998–2008. His research interests
include liposomes, lipid-core micelles, biomedical polymers, drug
delivery and targeting, pharmaceutical nanocarriers, and experi-
mental cancer immunology.

Biomater. Sci. This journal is © The Royal Society of Chemistry 2020

 View Article Online

Biomaterials Science Review

Table 2 Different copolymers with “schizophrenic” behavior in the presence of temperature

Polymerization
Polymer method Stimulus Description Ref.

N-Isopropylacrylamide (NIPA) and 3-[N-(3- RAFT polymerization Temperature Higher temperature may result in NIPA-core 52
methacrylamidopropyl)-N,N-dimethyl] aggregates, whereas lower temperature may
ammoniopropane sulfonate (SPP) produce NIPA-shell micelles
Poly(3-dimethyl(methacryloyloxyethyl) RAFT polymerization Temperature At temperatures below the UCST, 53
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.

ammonium propane sulfonate) (PdMMAEAPS) PdMMAEAPS-core micelles were formed, but at

and poly(N,N-diethylacrylamide) (PdEA)
2-[Dimethylamino] ethyl methacrylate (DMA) and
2-[N-morpholino] ethyl methacrylate (MEMA)
temperature above the LCST, the micelles with
the PdEA core were prepared
Group transfer Temperature GTP-synthesized DMA–MEMA diblock 31
polymerization copolymer using 1, 3 propane sultone under
(GTP) mild conditions gave the thermo-sensitive
SBMA–MEMA diblock micelles. Lower
temperature produced SBMA-core micelles,
while higher temperature provided MEMA-core
micelles

or electrolyte concentration. Their results showed that 2-(di-
ethylamino)ethyl methacrylate (DEA)-core micelles were con-
structed at pH 8, while the reverse micelles with a 2-(N-mor-
pholino)ethyl methacrylate (MEMA) core appeared at pH 6.5 in
aqueous media containing 1.0 M salt (Na2SO4). Later, a poly
( propylene oxide)-tertiary amine methacrylate di-block copoly-
mer was synthesized by atom transfer radical polymerization
(ATRP) with the ability to respond to both pH and temperature
changes.23
2. Polymer-based “schizophrenic”
systems
Block copolymers have attracted great attention due to their
remarkable capability of creating various types of mor-
phologies including micelles and vesicles which are dependent
on the length of blocks, the concentration of the polymer, the
composition of the solvent and the type of external stimulus.
The use of a smart stimuli-responsive system is considered
as a great strategy that can control the delivery of drugs. In this
regard, the most explored stimuli for "schizophrenic" systems
are pH, ionic and temperature strength.
2.1. Ionic strength and pH responsive systems
There are systems that are able to respond to more than one
stimulus such as pH/ionic strength. These dual-stimuli respon-
sive systems control drug release in more complex environ-
ments. In this regard, Bütün et al. reported a di-block copoly-
mer which was used to prepare micelles using 2-(diethyl-
aminoethyl) methacrylate (DEA) as a pH responsive block
forming the core by pH adjustment and reverse micelles with a
MEMA (2-(N-morpholino)ethyl methacrylate core by adding a
high concentration of salt as an ionic strength responsive

Seyed Mohammad Taghdisi Khalil Abnous is currently a dis-

Heidarian received his Ph.D.
degree in 2012 in
Pharmaceutical Biotechnology
from the Mashhad University of
Medical Sciences, Iran. He
obtained his Pharma.D. degree
from Mazandaran University of
Medical Sciences in 2007. In
2011, he joined a short-term vis-
iting scholar program in the
University of Bonn, Germany
Seyed Mohammad Taghdisi under the supervision of Prof.
Gunter Mayer. In 2013, he
started his career as an assistant professor in the Targeted Drug
Delivery Research Center at the School of Pharmacy, Mashhad
University of Medical Sciences, Iran. His research topic focuses on
the design of aptamers and aptasensors (electrochemical, colori-
metric and fluorescent aptasensors). He is also interested in cell-
SELEX, SELEX, targeted drug delivery.
tinguished professor at the
School of Pharmacy, Mashhad
University of Medical Sciences,
Iran. He obtained his Pharma.D.
degree from Mashhad University
of Medical Sciences and Ph.D.
from the Department of
Chemistry, Carleton University,
Canada. The main focus of
Abnous’s research is aptamer
design and its application in bio-
Khalil Abnous sensors and targeted drug deliv-
ery. He is also interested in pro-
teomics, genomics and genetically modified mesenchymal stem
cells.

This journal is © The Royal Society of Chemistry 2020 Biomater. Sci.


Review
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Fig. 1 Schematic illustration of micelle formation for an AB diblock copolymer including 2-(dimethylamino) ethyl methacrylate (DMAEMA), and 2-
(N-morpholino) ethyl methacrylate (MEMA). Reproduced from ref. 21 with permission from the American Chemical Society, Copyright © 1998.
block. They exploited a group transfer polymerization tech-
nique for living polymerization of methacrylates at ambient
temperature. They developed micelles with a DEA core at
higher pH and reverse micelles with a MEMA core at lower pH
along with 0.1 M salt.21,25
Mohammad Ramezani is cur-
rently a distinguished professor
at the School of Pharmacy,
Mashhad University of Medical
Sciences, Iran. He obtained his
Pharma.D. degree from Mashhad
University of Medical Sciences
and Ph.D. from the Department
of Chemistry, Dalhousie
University, Canada. The main
focus of Ramezani’s research is
the development of functional
Mohammad Ramezani nanomaterials for targeted gene
and drug delivery purposes, and
biosensor design based on
aptamers.
Biomater. Sci.
View Article Online
Biomaterials Science
Liu and coworker developed a pH-sensitive di-block copoly-
mer with unusual behavior which was composed of poly[4-
vinylbenzoic acid-block-2-N-(morpholino)ethyl methacrylate]
(VBA63-b-MEMA123). The ATRP method was used for the syn-
thesis and the copolymer exhibited “schizophrenic” behavior
Mona Alibolandi received her
Ph.D. degree majoring in
medical biotechnology in 2015
from Mashhad University of
Medical Sciences, Iran. In 2015,
she started her career as an
assistant professor in the
Pharmaceutical Research Center
at the School of Pharmacy,
Mashhad University of Medical
Sciences, Iran. From 2016 up to
now, she has served as the Head
Mona Alibolandi of Nude Mice and Nanomedicine
Laboratory at Mashhad
University of Medical Sciences, Iran. Her research topic focuses on
the design of smart hybrid material nanostructures for targeted
drug and gene delivery purposes. She is also interested in the
design and fabrication of polymersomes and their application in
cancer research.
This journal is © The Royal Society of Chemistry 2020

Biomaterials Science
because of the low charge density on VBA and MEMA at pH
6.2. They demonstrated that this zwitterionic di-block copoly-
mer in the presence of salt had the ability to switch from
micelles with a VBA block in the core to micelles with a MEMA
core. The main difference between the di-block copolymer fab-
ricated in this study and other reported di-block copolymers
was the precipitate formation at the isoelectric point in the
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
absence of salt. After salt addition, precipitation with both
types of micelles with either a VBA or MEMA core occurred at
20 °C. MEMA-core micelles were constructed in acidic pH.26
Wang et al. reported the kinetics of inversion between the
two types of core shell micelles developed in a previous study.
They demonstrated that structural conversion might take place
because of MEMA insolubility at pH 12. Various pathways were
suggested for altering the structure from MEMA-core to VBA-
core micelles. The intensities of scattered light were reduced
uniformly with time before stabilizing out, suggesting that the
fast decomposition into particular chains did not occur.
Moreover, a micelle splitting mechanism was tentatively
suggested for the inversion of MEA-core to VBA-core micelles
(Fig. 2).27
Moreover, through the change of the medium to an electro-
lyte solution, the transition of self-assembly can occur. For
example, Vasantha et al. developed a novel type of dual hydro-
philic di-block copolymers (BCPs) containing poly(ethylene
glycol) (PEG) and zwitterionic polysulfabetaine (PSB) via
radical polymerization. The main difference between these two
blocks is that while PEG is soluble in water, PSB is soluble in
salt solution. The main structure consisted of poly(ethylene
Fig. 2 The micellar inversion of VBA-core and MEMA-core micelles under two different conditions, either after the addition of salt (Na2SO4), or by
a pH change. Reproduced from ref. 27 with permission from the American Chemical Society, Copyright © 2006.
This journal is © The Royal Society of Chemistry 2020
View Article Online
Review
oxide)-b-poly-[2-(dimethyl(4-vinyl-benzyl)ammonio)ethyl
sulfate] [(EG)-b-(ZSB)]. This copolymer formed “conventional”
micelles with PZSB cores and PEG shells. However, after the
addition of salt solution, inverse micelles with PEG cores and
PZSB shells were prepared.28
2.2. pH and temperature responsive systems
Among different stimuli, pH and temperature provide interest-
ing features for the fabrication of intelligent systems. It should
be noted that imbalance and alteration in physiological pH or
temperature might lead to different diseases comprising
cancer, diabetes, Parkinson’s disease, etc.
Drug delivery systems with a smart release profile which are
also proficient in releasing their cargo in response to both
elevated temperatures and reduced pH could provide guided
cargo delivery and offer reduced systemic toxicity and a better
therapeutic index. This idea has encouraged investigators to
develop thermo- and pH dual responsive smart polymeric
structures.
In this regard, Andre et al. reported that polymers which
are exploited for thermo- or pH-sensitivity are mainly com-
posed of a segment showing a LCST and having a neutral or
ionic hydrophilic fragment. Before this report, there were only
a few studies on dual pH and thermo-sensitive systems with
“schizophrenic” behavior. Other studies used poly( propylene
oxide)-b-PDEAEMA,31 poly(tert-butyl acrylate-co-acrylic acid)-b-
poly(N-isopropylacrylamide),32 and poly[oligo(ethylene glycol)
methacrylate]-b-poly([(diethylamino)ethyl methacrylate]-co-
(methacrylic acid)).33 However, in a study presented by Andre
Biomater. Sci.

Review
et al., a poly(acrylic acid)-b-poly(N,N-diethylacrylamide) (PAA-b-
PDEAAMm) copolymer was synthesized through sequential
anionic polymerization of tert-butyl acrylate (tBA) and N,N-di-
ethylacrylamide (DEAAm) in the presence of Et3Al. In this
system, while higher temperature induced PDEAAm-core
micelle formation, a pH change induced PAA-core micelle
formation.34
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Star polymers have exceptional properties with at least
three arms radiating from a core. In comparison with linear
polymers, star polymers have several advantages including
their smaller diameter, higher drug loading capacity, low
CMC, distinctive crystallization performance and faster stereo-
complex formation.35,36 Design of dual responsive star-shaped
copolymers introduced interesting characteristics for the
preparation of versatile intelligent vehicles.
The Liu group synthesized a star-shaped miktoarm copoly-
mer. They used N-isopropylacrylamide (NIPAM) and 2-(diethyl-
amino)ethyl methacrylate (DEA) to synthesize a PNIPAM-b-
PDEA di-block copolymer. In this system, low pH and high
temperature produced PNIPAM-core micelles due to the inso-
lubility of PNIPAM at temperature higher than 32 °C and solu-
bility of PDEA in acidic pH. In this regard, higher pH at room
temperature led to PDEA-core micelle formation. It should be
noted that the miktoarm type of the above polymer was pre-
pared through the ATRP method, while a linear one was syn-
thesized via the RAFT polymerization method.37
Another type of “schizophrenic” nanoparticle is based on a
polypeptide hybrid di-block copolymer. In this context, Rao
Fig. 3 (A) Schematic representation of the coil-to-helix transition of dual sensitive PNIPAM-PLGA. Reproduced from ref. 38 with permission from
the American Chemical Society, Copyright © 2007. (B) TEM images of BCPs 1[(EG)105-b-(ZSB 1)23] (a) and 2 [(EG)105-b-(ZSB 2)8] (b) in DI water.
Reproduced from ref. 28 with permission from The Royal Society of Chemistry, Copyright © 2015.
Biomater. Sci.
View Article Online
Biomaterials Science
et al. fabricated poly(N-isopropylacrylamide)-b-poly(L-glutamic
acid) (PNIPAM-b-PLGA) by the ROP method. They used
PNIPAM and PLGA as the thermo-sensitive and pH-sensitive
blocks, respectively. The prepared di-block copolymer was
soluble in aqueous solution at higher pH and ambient temp-
erature while micelles with a PNIPAM core appeared at higher
temperature. On the other hand, a coil-to-helix transition of
the PLGA block occurred under acidic conditions leading to
the formation of the PLGA-core micelles (Fig. 3).38
The Butun group also synthesized another di-block copoly-
mer based on poly( propylene oxide) (PPO) and 2-(diethyl-
amino)ethyl methacrylate (DEA) using an atom-transfer radical
polymerization (ATRP) strategy in order to fabricate “schizo-
phrenic” micelles. In contrast to their previous work, these two
types of micelles could be constituted through a discrete
choice of both pH and temperature. The solubility of DEA is
different at various pH values, meaning that DEA is
soluble in acidic pH, but insoluble at neutral pH. Moreover,
PPO is insoluble at 20 °C, but soluble in cold solutions.
Hence, it can be concluded that the PPO-DEA copolymer can
be dissolved in hydrophilic solutions with pH 6.5 at 5 °C. After
salt addition to a solution at 5 °C and pH 8.5 or higher,
micelles with DEA cores and PPO coronas were constructed.
For the preparation of reverse micelles with PPO cores, temp-
erature elevation is needed to make the PPO block insoluble
(Fig. 4).23
In 2002, the first examples of “schizophrenic” block copoly-
mers were introduced in which transitions between micelles to
This journal is © The Royal Society of Chemistry 2020

Biomaterials Science
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Fig. 4 Schematic representation of PPO-core and DEA-core micelle construction at different pH values. Reproduced from ref. 23 with permission
from WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany, Copyright © 2001.
inversed micelles could occur by pH or temperature changes
and the structures were unstable at room temperature.
Smith et al. synthesized a block copolymer from poly[(N,N-
diethylaminoethyl methacrylate)-b-(N-isopropyl acrylamide)]
(P(DEAEMA-b-NIPAM)s) by RAFT polymerization. Self-assembly
of these aggregates can be dependent on the block length, pH
and temperature. For this purpose, spherical micelles with
PNIPAM shells and PDEAEMA cores can be created at tempera-
ture below the critical solution temperature of PNIPAM and at
pH higher than the pKa of PDEAEMA. In contrast, at tempera-
ture higher than 42 °C, micelles with PNIPAM cores were
formed.30
Also, block copolymers can be grafted onto graphene oxide
as a fluorescent label. In a report, the surface of polycaprolac-
tone (PCL)-block-poly(2,20-dimethyl aminoethyl methacrylate)
(PDMAEMA) was grafted to GO through consecutive ROP
and ATRP methods in order to prepare a GO-g-(PCL-b-
PDMAEMA) copolymer. By this modification, the fluorescence
characteristic of GO was improved. This system was thermo-
and pH-responsive due to the PDMAEMA segment. Because of
the reversible protonation and deprotonation of copolymer
chains, this system produced different types of vesicles at
different pH and temperature. At pH 9.2, a transition from
vesicles to gigantic aggregates after changing the temperature
from 26 to 38 °C occurred. Additionally, pH could change the
aggregation form from a blowhole vesicle at pH 7 to a core–
shell form at pH 4.39
Another smart micelle was synthesized by Chang et al. They
prepared a poly(N-isopropylacrylamide-co-3-(trimethoxysilyl)
propyl methacrylate)-b-poly(2-(diethyl-amino)ethyl methacry-
This journal is © The Royal Society of Chemistry 2020
View Article Online
Review
late) (P(NIPAAm-co-MPMA)-b-P(DEA)) copolymer by RAFT
polymerization. They examined the structural changes of
micelles in order to prove the temperature and pH sensitivity
of the micelles owing to the thermo-sensitivity of PNIPAAm
and pH-sensitivity of DEA. They utilized an inorganic silica-
based cross-linking strategy for cross-linking of P(NIPAAm-co-
MPMA) blocks to form P(NIPAAm-co-MPMA)-b-P(DEA).
Moreover, they claimed that their group investigated cargo
release from dual responsive cross-linked micelles, for the first
time. These cross-linked micelles may improve the stability of
the micelles in the body fluids. DEA became soluble at acidic
pH and higher temperature (45 °C) producing DEA-shell
micelles, whereas P(NIPAAm-co-MPMA) was soluble at alkaline
pH and lower temperature (20 °C) (Fig. 5).40
Jiang et al. also developed two types of shell-cross-linked
(SCL) micelles with uncommon behavior. They employed poly
(2-(2-methoxyethoxy)ethyl methacrylate)-b-poly(2-(dimethyl-
amino)ethyl methacrylate)-b-poly(2-(diethylamino)ethyl meth-
acrylate) (PMEO2MA-b-PDMA-b-PDEA), an ABC triblock copoly-
mer using the ATRP method. PMEO2MA-b-P(DMA-co-QDMA)-b-
PDEA, in which QDMA is quaternized 2-(dimethyl amino)ethyl
methacrylate, was produced through the reaction of the pre-
pared tri-block copolymer with propargyl bromide in anhy-
drous THF in order to obtain “schizophrenic” properties.
PMEO2MA-core micelles were formed at acidic pH and the
CMC could be changed by incorporating oligo(ethylene glycol)
methyl ether methacrylate (OEGMA) into PMEO2MA to provide
thermo-induced micelles. Two types of SCLs were prepared
which were sensitive to temperature and pH. As shown in
Fig. 6, PMEO2MA-core micelles were formed at elevated temp-
Biomater. Sci.

Review
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Fig. 5 (A) Schematic representation of the “schizophrenic” behavior of (P(NIPAAm-co-MPMA)-b-P(DEA)) copolymers. (B) TEM images of CCL
micelles (a) and SCL micelles (b). Reproduced from ref. 40 with permission from the American Chemical Society, Copyright © 2009.
erature and acidic pH, whereas PDEA-core micelles were self-
assembled at lower temperature and alkaline pH (Fig. 6).41
Liu et al. reported a double hydrophilic platform based on a
poly(N-isopropylacrylamide)-b-poly(2-vinylpyridine)
(PNIPAM38-b-P2VP43) copolymer offering temperature and pH
responsiveness. In this research, RAFT polymerization was
employed for the synthesis. Because of the intermediate
unimer state through changes in temperature and pH, both
P2VP-core and PNIPAM-core micelles could be formed. Above
the LCST, PNIPAM became insoluble and more hydrophobic.
At higher pH, protonation of the P2VP block was diminished
leading to a lower water solubility of the P2VP block.42
Another dual sensitive block copolymer was prepared from
a penta-block terpolymer (five blocks with three different poly-
mers) using a combination of PNIPAM as a thermo-sensitive
block, PMA as a pH-sensitive block and PEG. In this regard, a
core–shell–corona micelle was formed. Since macromolecules
with low polydispersity may be obtained by the RAFT polymer-
ization method, they synthesized PMAA-b-PNIPAM-b-PEG-b-
PNIPAM-b-PMAA with two consequent steps of RAFT polymer-
ization. Micelles with PMA core-PNIPAM shell-PEG coronas
were formed at acidic pH and ambient temperature, in con-
trast to those formed at neutral pH and higher temperature
having PNIPAM core-mixed PEG and PMA coronas (Fig. 8B).43
A penta-block terpolymer was fabricated from poly(2-(N,N-di-
ethylamino)ethylmethacrylate)-b-poly(N-isopropylacrylamide)-b-poly
Biomater. Sci.
View Article Online
Biomaterials Science
(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-poly(2-(N,N-diethyl-
amino) ethylmethacrylate (PDEAEMAx-b-PNIPAAMy-b-PEGz-b-
PNIPAAMy-b-PDEAEMAx). The sensitivity of this polymer was evalu-
ated using pH and temperature changes. They demonstrated that
when a longer PDEAEMA block was used, at low pH and ambient
temperature, PDEAEMA-shell micelles with mixed PNIPAAM and
PEG-cores were obtained, whereas by elevating the pH from 3 to 9,
PDEAEMA-core micelles were formed. By increasing the tempera-
ture up to 39 °C, PDEAEMA-core micelles were prepared but at
higher temperature and low pH, the contribution of the PNIPAAM
block was dominant and micelles with PNIPAAM cores were
produced.44
Most reports mentioned the use of sulfabetaines as UCST
polymers but Zhang et al. fabricated copolymers using either a
poly(dimethylaminoethyl methacrylate) (PDMAEMA) block or
poly(methoxy oligo-ethyleneglycol methacrylate) (PmOEGA)
without polybetaines. Moreover, a third phase transition was
suggested from the state of inverted micelle to the precipitated
state at high temperature. A transition could be attained by
changing the pH and the trivalent anion concentration.45
2.3. pH responsive systems
Materials with pH responsiveness are interesting, mainly for
developing drug delivery systems. The implementation of
these systems enables smart delivery of cargos into tumor cells
at lower environmental pH.
This journal is © The Royal Society of Chemistry 2020
 View Article Online

Biomaterials Science Review

Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.

Fig. 6 Schematic representation of the “schizophrenic” behavior of PMEO2MA45-b-P(DMA0.65-co-QDMA0.35)47-b-PDEA36. PMEO2MA-core micelles

were formed at acidic pH and the CMC could be changed by incorporating oligo(ethylene glycol) methyl ether methacrylate (OEGMA) into
PMEO2MA to provide thermo-induced micelles. Two types of SCLs were prepared which were sensitive to temperature and pH. Reproduced from
ref. 41 with permission from the American Chemical Society, Copyright © 2009.

In a research study accomplished by Enomoto et al., a pH-
sensitive di-block copolymer composed of poly(N,N-diethyl-
aminoethyl methacrylate) ( pDEA) and poly(6-acrylamidohexa-
noic acid) ( pAaH) was synthesized through RAFT polymeriz-
ation. The pDEA block in pDEA-b-pAaH was water soluble at
lower pH, in contrast to the pAaH block which was dissolved at
higher pH. Hence, two different micelle types could be con-
structed by a pH change. Accordingly, micelles with a pDEA
core were made at basic pH, while pAaH-core micelles were
formed under acidic conditions (Fig. 7A).29
Liu and Eisenberg developed vesicles using an amphiphilic
tri-block polymer of poly(acrylic acid)-block-polystyrene-block-
poly(4-vinyl pyridine) (PAA26-b-PS890-b-P4VP40). Two mecha-
nisms of action were suggested for this inversion. First one
was inversion without the single chain participation while the
second one involved single chain contribution. At basic pH,
neutralization of the PAA block led to the increased repulsive
interactions among PAA shells while decreasing the repulsive
interactions among the P4VP blocks. Inverse repulsive inter-
actions occurred at acidic pH due to the quaternization of
P4VP blocks.47
Based on other research, the Armes group developed a di-
block copolymer which could be self-assembled spontaneously
at room temperature only by a pH change. The ATRP synthesis
method was used to synthesize poly(4-vinyl benzoic acid-block-
2-(diethylamino)ethyl methacrylate) (PVBA-b-DEA). At low pH,
VBA became insoluble while DEA was soluble in an acid as a
cationic polyelectrolyte, consequently forming VBA-core
micelles. However, at pH above 7.1, VBA became soluble and
DEA-core micelles were constructed. They mentioned that this
copolymer can be used as a pigment dispersant and for
protein separation and purification (Fig. 8A).24
Zhang et al. synthesized double hydrophilic block copoly-
mers using poly(ε-caprolactone) and poly(6-acetoxyl-ε-caprolac-
tone)-b-poly(4-N-piperilactone) (PCCL-b-PPIL) through a
reduced oxygen packaging (ROP) method. Then, the self-
assembly feature was assessed and the obtained results
demonstrated that the aggregate formation could change with
pH. It means that at acidic pH, PCCL-core micelles were
formed while micelles with PPIL cores were reassembled at
higher pH (Fig. 7B).46
Recently, polymerization-induced self-assembly was
exploited in order to provide a highly convenient and efficient
method to prepare ampholytic di-block copolymeric nano-
particles. In a study, RAFT-mediated polymerization-induced
self-assembly (PISA) was applied to provide pH-responsive di-
block copolymers based on a poly(2-(diethylamino)ethyl meth-
acrylate) (PDEA88) macro-CTA which was chain-extended by

This journal is © The Royal Society of Chemistry 2020 Biomater. Sci.


Review
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Fig. 7 (A) Schematic illustration of the pH-induced aggregation behav-
ior of pDEA-b-pAaH in aqueous solution containing 1.1 M NaCl under
various pH conditions, and formation of vesicles upon removal of NaCl
using a dialysis method. Reproduced from ref. 29 with permission from
Elsevier, Copyright © 2014. (B) The size distribution and TEM images of
PCCL25-b-PPIL50 micelles in aqueous solution at (a) pH 5 and (b) pH 8.
Reproduced from ref. 46 with permission from The Royal Society of
Chemistry, Copyright © 2017.
RAFT polymerization of benzyl methacrylate (BzMA) and
methacrylic acid (MAA) at pH 2.5.48
Other types of polymers exhibited reversible solubility be-
havior at different pH values. It is demonstrated that tertiary
amine methacrylate copolymers showed pH-sensitive charac-
teristics due to the protonation of the tertiary amine moieties
at acidic pH, while deprotonation may occur at higher pH. The
advantages of using this type of polymer include not produ-
cing deleterious substances and having adjustable pKa
imparted by changing the chemical structure.49 In this regard,
Feng and co-workers introduced a diblock copolymer contain-
ing tertiary amine groups [(N,N-diethylaminoethyl methacry-
late)] (PDEAEMA) synthesized via RAFT polymerization. It was
the first example of a system in which a transition of micelles
from unimers to vesicles occurred. The reaction of a PDEAEMA
block with CO2 could occur in aqueous solution in order to
produce a charged ammonium bicarbonate. This product had
the ability to be recovered upon CO2 removal. In the presence
Biomater. Sci.
View Article Online
Biomaterials Science
of CO2, the PDEAEMA blocks became protonated and soluble
in water, and consequently led to vesicle disassembly. By
raising the temperature (above the LCST of PNIPAM), spherical
micelles were formed. The advantage of this system was the
utilization of “green” stimuli, CO2, and temperature.50
A tri-block copolymer composed of ( poly[(2-succinyloxyethyl
methacrylate)-b-(N-isopropylacrylamide)-b-[(N-4-vinylbenzyl),N,
N-diethylamine]]) [P(SEMA-b-NIPAAm-b-VEA)] was investigated.
They exploited the RAFT polymerization technique to achieve
an ABC polymer. Then, an anticancer agent, doxorubicin, was
loaded into the micelles to achieve toxicity in MCF7 cells. At
pH 10, micelles with PSEMA shells were formed, whereas at
pH 3, micelles with VEA shells were formed.51
2.4. Temperature responsive systems
Stimuli-responsive copolymers can be advantageous for manu-
facturing controlled drug delivery systems. In this regard,
Laschewsky and co-workers developed dual temperature-
responsive hydrophilic blocks from the nonionic monomer
N-isopropylacrylamide (NIPA) and the zwitterionic monomer 3-
[N-(3-methacrylamidopropyl)-N,N-dimethyl ammonio]-propa-
nesulfonate (SPP) through reversible addition–fragmentation
chain transfer or RAFT polymerization. In water, these blocks
exhibited thermo-responsive behavior. In this regard, a poly-
NIPA block could form the core of colloidal hydrophobic aggre-
gates at higher temperature, whereas a poly-SPP block could
constitute the core at lower temperature. In this manner,
reversible temperature-sensitive aggregates were provided
without the use of any additive.52
In a similar study, di-block copolymers consisting of poly(3-
dimethyl(methacryloyloxyethyl) ammonium propane sulfo-
nate) (PdMMAEAPS) and poly(N,N-diethylacrylamide) (PdEA)
were prepared by the RAFT polymerization method. In this
system, at temperatures below the UCST, PdMMAEAPS blocks
formed the core of the micelles, while at temperatures above
the LCST, PdEA-core micelles were constructed.53
Unlike the Laschewsky report, another tertiary amine meth-
acrylate-based copolymer was efficiently synthesized by the
block copolymerization of 2-[dimethylamino] ethyl methacry-
late (DMA) and 2-[N-morpholino] ethyl methacrylate (MEMA)
through group transfer polymerization (GTP) followed by the
selective quaternization of DMA residues using 1,3-propane
sulfone. These methacrylate-based SBMA-MEMA copolymers
could be synthesized in high yield using GTP. Micelles with
SBMA cores were constructed at temperature below the LCST
(about 20 °C), while MEMA-core micelles were formed at temp-
erature above the UCST (about 50 °C).31 Tenhu and co-workers
developed copolymers using poly(N-isopropyl acrylamide)-
block-poly(3-[N-(3-methacrylamido-propyl)-N,N-dimethyl]-
ammonio propane sulfonate) (PNIPA-b-PSPP). They studied the
thermo-responsive behavior of this copolymer in pure and
saline solutions. They exploited NaCl to increase the solubility
of one block (the zwitterionic block, PSPP) while decreasing
the solubility of the PNIPA block at low temperature.54
Preparation of “schizophrenic” block copolymers in order
to obtain temperature-sensitive micelles requires a polymer
This journal is © The Royal Society of Chemistry 2020
 View Article Online

Biomaterials Science Review

Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.

Fig. 8 (A) Schematic representation of “schizophrenic” behavior in aqueous solution. At low pH, VBA became insoluble while DEA was a soluble
acid as a cationic polyelectrolyte, consequently forming VBA-core micelles. However, at pH above 7.1, VBA became soluble and DEA-core micelles
were constructed. Reproduced from ref. 24 with permission from WILEY-VCH Verlag CmbH, Fed. Rep. of Germany, Copyright © 2002. (B)
(a) Transmission electron microscopy (TEM) image of a pentablock terpolymer of PMAA-b-PNIPAM-b-PEG-b-PNIPAM-b-PMAA at pH 5 and (b) SEM
image of the pentablock terpolymer in the solid state. Reproduced from ref. 43 with permission from Informa UK Limited, trading as Taylor & Francis
Group, Copyright © 2017.

with LCST behavior and another polymer with less UCST
(upper critical solution temperature) behavior.
Di-block copolymers were prepared by the Shih group. They
synthesized nonionic and zwitterionic, poly(N-isopropyl-
acrylamide)-block-poly(sulfobetaine methacrylate) (PNIPAAm-b-
PSBMA) copolymers by ATRP. PSBMA-core micelles with
PNIPAAm shells were formed at temperatures lower than the
UCST of the PSBMA block. However, the reversed micelles with
PNIPAAm cores were prepared at temperature higher than the
LCST of the PNIPAAm block. At temperatures between the
UCST and LCST, both types of soluble blocks were obtained
(Fig. 9).20
Triple thermo-responsive copolymers were developed by
Zhang et al. In this system, transitions occurred from conven-
tional to reverse micelles and eventually to a precipitated form
at high temperature.
Thermo-sensitive copolymer micelles was constructed by
Can and co-workers using poly(methyl acrylate) (PMA) and
poly(diethylene glycol ethyl ether acrylate) (PDEGEA) homopo-
lymers through ATRP. They demonstrated the “schizophrenic”
behavior of the developed copolymer in 35% ethanol. Actually,
the inversion of the core and corona can be achieved by a com-
bination of LCST and UCST thermo-sensitive behavior through
temperature changes. Low temperature leads to aggregates
with PMA as a solvophobic block, whereas at high temperature
(above the UCST transition of PMA), PDEGEA plays the role of
a solvophobic block.55 Another di-block copolymer was syn-
thesized by Ghamkhari and co-workers. They exploited [ poly(2-
succinyloxyethyl methacrylate)-b-poly[(N-4-vinylbenzyl),N,N-di-
ethylamine]; PSEMA-b-PVEA] by the RAFT polymerization
method. This technique was chosen because of its convenient
work-up without the need for any metal contaminants.56
Another self-assembly block copolymer which behaves as a
“schizophrenic” copolymer was developed by Hildebrand et al.
They used poly(N-isopropyl methacrylamide) as a non-ionic
segment which represented a coil-to-globule collapse tran-

This journal is © The Royal Society of Chemistry 2020 Biomater. Sci.


Review
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Fig. 9 Schematic representation of temperature-responsive polymers: (a) PNIPAAm polymer, (b) PNIPAAm-b-PSBMA copolymer, and (c) PSBMA
polymer. Reproduced from ref. 20 with permission from the American Chemical Society, Copyright © 2012.
sition of the LCST type conjugated to one of the poly(sulfobe-
taine methacrylate) categories of the UCST type which played a
role in tuning their coil-to-globule collapse transition. A com-
bination of thermo-sensitive non-ionic and zwitterionic moi-
eties led to the preparation of a dual thermo-sensitive copoly-
mer through RAFT polymerization. They varied the structural
properties of the poly(sulfobetaine) segment in order to
prepare a library with the same non-ionic block, poly(N-iso-
propylmethacrylamide) pNIPMAM.57
Vishnevetskaya et al. combined a non-ionic thermo-sensi-
tive block with a thermo- and salt-sensitive zwitterionic block.
They used either poly(N-isopropylacrylamide) (PNIPAM) or
poly(N-isopropyl-methacrylamide) (PNIPMAM) as a non-ionic
block which exhibited a LCST in hydrophilic solution. Poly(4-
((3-methacryl-amidopropyl) dimethylammonio) butane-1-sulfo-
nate) (PSBP) (a type of polysulfabetaine) was used as a zwitter-
ionic block with UCST features. Two different di-blocks (PSBP-
b-PNIPAM and PSBP-b-PNIPMAM) were synthesized imple-
menting consecutive RAFT polymerization. The main idea for
choosing PSBP was its higher clearing point than the cloud
point of PNIPAM or PNIPMAM in aqueous solutions (Fig. 10).
In this research, an orthogonally switchable system was used
as the trigger. Micelles with either PNIPAM or PSBP shells
were formed below and above the cloud point of PNIPAM,
respectively.58 This group also synthesized orthogonally tuned
thermo-responsive di-block copolymers using poly(4-((3-metha-
crylamidopropyl) dimethylammonio) butane-1-sulfonate)
(PSBP) and poly(N-isopropyl methacrylamide) (PNIPMAM) via
the RAFT polymerization method. PNIPMAM was a nonionic
block and served as the LCST segment with poly(sulfobetaine
Biomater. Sci.
View Article Online
Biomaterials Science
methacrylamide) as the UCST block which could be tuned by
the electrolyte concentration. They suggested that the compo-
sition and length of di-blocks affected the shape and size of
the assembly structures.59
Ranka et al. used the RAFT polymerization method in order
to synthesize a poly(sulfobetaine methacrylamide)-poly(N-iso-
propyl methacrylamide)21 diblock copolymer in which
polySBMA and polyNIPMAM were implemented as either the
UCST (16 °C) or LCST blocks, respectively. In the aforemen-
tioned system, polymer conjugation to siloxane was used to
avoid polymeric layer desorption and losing its function at
high temperature.60
The first example of the preparation of a tri-block copoly-
mer which consisted of poly(methoxyethylene glycol) (MPEG)
and poly([2-(methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-
ammonium hydroxide) (PSBMA) as a UCST block, and poly[2-
(N,N-dimethylamino)ethyl methacrylate] (PDMAEMA) as a
LCST block to exhibit a temperature/carbon dioxide-dual-sensi-
tive behavior was reported by Tang et al. In this study, MPEG
can impart a hydrophilic shell to stabilize the micelles. The
principal advantages of using carbon dioxide (CO2) include
the availability, cost-efficiency, and safety features of this inac-
tive gas. Using temperature below the UCST, aggregates with
PSBMA cores and PDMAEMA and MPEG shells were formed,
but at temperatures above the LCST, hydrophobic PDMAEMA
formed the core with MPEG and PSBMA as the shell. After
using CO2, the tertiary amine groups of PDMAEMA was proto-
nated.61 In a similar research study, PDMAEMA-b-PSBMA was
fabricated by the ATRP method. Thermo-sensitive behavior
was observed because at temperature below the UCST, micelles
This journal is © The Royal Society of Chemistry 2020

Biomaterials Science
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Fig. 10 Schematic phase diagrams of aqueous solutions of diblock
copolymers from a zwitterionic block showing UCST behavior (red) and
a nonionic block showing LCST behavior (blue). Phase behavior envi-
saged with the PSBP-b-PNIPAM and PSBP-b-PNIPMAM systems. Red
dashed line: CPUCST (cloud point) of the PSPB block; blue dash-dotted
line: CPLCST of the PNIPAM/PNIPMAM block. Phase diagrams of PSBP-b-
PNIPAM and PSBP-b-PNIPMAM in dependence on temperature and salt.
Reproduced from ref. 58 with permission from the American Chemical
Society, Copyright © 2018.
with PSBMA cores were formed, while PDMAEMA-core micelles
were fabricated at temperature above the LCST. Owing to the
sensitivity of the PDMAEMA block to pH and CO2, and the sen-
sitivity of PSBMA to salt, this copolymer can be used in dual
pH and thermo-sensitive systems. Moreover, the aforemen-
tioned polymer may be used in pH and CO2-sensitive systems
due to pH-tunable and CO2-swichable behaviors.62
3. Peptide-based “schizophrenic”
nanoparticles
Polypeptide-based nanoparticles can offer more advantages in
comparison with lipid nanostructures especially in drug deliv-
ery. For the first time, “schizophrenic” polypeptide di-block
copolymers were reported by Lecommandoux’s group demon-
strating their self-assembly behavior in water as a function of
pH. They utilized two distinct polypeptide fragments for the
construction of a zwitterionic di-block copolymer using poly(L-
glutamic acid)-b-poly(L-lysine) (PGA-b-PLys). The synthesized
copolymer had positively charged lysine and negatively
charged glutamic acid at neutral pH. In this regard, at low pH,
the poly(L-glutamic acid) block was neutralized and it exhibited
decreased solubility to form PGA-core aggregates, while PLys
formed the shells of aggregates. At higher pH, PLys-core aggre-
This journal is © The Royal Society of Chemistry 2020
View Article Online
Review
gates were constructed due to their neutralization, and they
became insoluble. Interestingly, at intermediate pH, precipi-
tation occurred due to the disassembly of the prepared struc-
tures. The aforementioned platform can be applicable for drug
and protein encapsulation (Fig. 11).63
Moreover, other kinds of polypeptide di-block copolymers
were developed by this group based on polybutadiene-b-poly(L-
glutamic acid) (PB-b-PGA) and polyisoprene-b-poly(L-lysine) (PI-
b-Plys) to show the capability of preparing self-organized vesi-
cles and micelles in water in response to pH changes. They
demonstrated that self-assembly may depend on the rod-to-
coil block molar ratio, meaning that vesicles were formed for a
peptide mol percent lower than 65%, while spherical micelles
were obtained when the peptide mol percent was higher than
65%.64
RAFT polymerization of an N-acryloyl-L-phenylalanine (AP)
monomer was used to obtain tertiary amine and amino acid-
based copolymers using poly(amino acid)-b-poly(tertiary
amino methacrylate), PDEA-b-PAP (Fig. 12).65 Poly( propylene
oxide)-block-poly(L-lysine) (PPO-b-PK) block copolymers were
formed by “click chemistry” reaction to prepare copolymers
with dual sensitivity toward temperature and pH. PPO-b-PK
showed a remarkable shift at various pH values, which is
related to the helix-to-coil transition of the poly(lysine) block
because of the lower hydrophobicity in the core block (PPO).66
4. Application of “schizophrenic”
polymers in drug delivery
The use of a smart stimuli-responsive delivery system is con-
sidered as an great strategy that can control the delivery of
drugs.
The “schizophrenic” behavior of copolymers means that
AB-type diblock copolymers are able to produce two particular
micelles with A core or B core structures which can be
switched by different stimuli. In this regard, a controlled
release system was fabricated by Bastakoti using a diblock
copolymer of poly(acrylic acid-block-poly(N-isopropyl-
acrylamide) (PAA-b-PNIPAM). PNIPAM-core micelles were
formed using higher solution temperature (above the lower
critical solution temperature of the PNIPAM), while PAA-core
micelles were constructed through decreasing the pH (lower
than the pKa of PAA). Additionally, a cationic agent such as
doxorubicin (DOX) can be electrostatically bonded with an
anionic pH-sensitive part of the PAA domain. At mildly acidic
pH (4.5), the DOX release was significantly faster than at phys-
iological pH (7.4).67
In another study, a triblock copolymer, {poly[(2-succinylox-
yethyl methacrylate)-block-(N-isopropylacrylamide)-block-[(N-4-
vinylbenzyl),N,N-diethylamine]]} [P(SEMA-b-NIPAAm-b-VEA)],
was synthesized to investigate the behavior of the copolymer
under pH and thermal stimuli, then doxorubicin (DOX) was
loaded in the micellar core. PSEMA-core micelles at lower pH
were formed, and also by the increase of temperature, the
polymer (especially PNIPAAm segment) starts to aggregate,
Biomater. Sci.

Review
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Fig. 11 Schematic representation of the self-assembly into “schizo-
phrenic” vesicles of the di-block copolymer poly(glutamic acid)-b-poly-
lysine. At low pH, the poly(L-glutamic acid) block was neutralized and it
exhibited decreased solubility to form PGA-core aggregates, while PLys
formed the shells of aggregates. At higher pH, PLys-core aggregates
were constructed due to their neutralization and they became insoluble.
Reproduced from ref. 63 with permission from the American Chemical
Society, Copyright © 2005.
and results in phase separation which demonstrates suitable
thermo-responsibility features for biomedical applications
such as enhanced drug delivery.51
Multifunctional nanoparticles can be obtained using a
supramolecular approach by combining the tumor targeting
function, a cell penetration agent and chemotherapeutic mole-
cules. For instance, nanofibrils were fabricated by the conju-
gation of an endogenous self-associating nucleotide (guano-
sine monophosphate) and a hydrophobic nucleoside analogue
agent (clofarabine), and then transformed to spherical nano-
particles by assembling with a fructose/ethanolamine-functio-
nalized starlike poly(glycidyl methacrylate)-based cationic
polymer. Noncovalent cavities within the nanoparticles were
constructed by the nucleotide self-association, and conju-
gation of the hydrophilic cationic polymer and the chemother-
apeutic agent.19
Another amphiphilic polymer structure was developed with
an equal amount of free amine and carboxyl moieties in the
Biomater. Sci.
View Article Online
Biomaterials Science
Fig. 12 (A) Cationic shells at pH 2 and anionic shells at pH 12 can be
achieved by direct dissolution in water and the solvent switch method.
(B) Z-Averaged vesicle size distribution of the Py-PDEA76-b-PAP44-D
diblock copolymer vesicles by direct dissolution at different pH values
determined by DLS analysis. The insets are TEM images of vesicles at pH
2 (right) and 12 (left) without staining. Reproduced from ref. 65 with per-
mission from WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim,
Copyright © 2010.
side chains to achieve “schizophrenic” features due to a pH-
sensitive reversible interchange of the side-chain amphiphili-
city. Firstly, copolymerization of tert-butyl carbamate (Boc)-L-
alanine (VBA) and Boc-L-alanyl-L-leucine conjugated styrenic
(VBD) monomers with an L-alanine-appended maleimide
(NMA) monomer by reversible addition–fragmentation chain
transfer (RAFT) polymerization was performed to prepare a
series of alternating copolymers. They could be deprotected to
obtain amphiphilic copolymers consisting of an equal number
of amine and carboxyl groups as copolymerization of styrenic
monomers with maleimide producing a poly(styrene-alt-male-
imide) skeleton. To investigate the potential ability of the copo-
lymers toward in vitro drug delivery applications, fluorescence
spectroscopic analysis was used to demonstrate that the doxo-
rubicin release from the vesicle was comparatively lower at pH
7.4 in comparison with that at pH 5.4.68
Different schizophrenic diblock copolymers with distinct
chemistry can be considered as potential candidates in drug
delivery applications, generally due to their exceptional
physicochemical characteristics. In conclusion, further studies
This journal is © The Royal Society of Chemistry 2020

Biomaterials Science
are needed in order to evaluate the capability of this platform
for translational research.
5. Conclusion and future
perspectives
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Stimuli-responsive materials have been extensively studied in
the past few decades due to their fascinating characteristics
for application in controlled therapeutic delivery. In this
regard, stimuli-responsive amphiphilic copolymers have
attracted much attention because they are enabling structures
for constructing nano-systems through the self-assembly
process.
In recent years, there has been growing interest in “schizo-
phrenic” block copolymers as a smart, dual or multi-respon-
sive platform. It has been suggested that these self-assembled
structures seem to be sophisticated vehicles for drug/gene
delivery in a trigger-responsive controlled manner.
The fundamental advantage is that the block copolymers
have the potential to be used for the preparation of micelles or
vesicles and their inverted counterparts in dilute solutions
through changing conditions including pH, temperature,
redox potential and ionic strength.
Designing such switchable copolymers allows the inversion
of self-assembled micellar and vesicular structures implement-
ing molecularly dissolved or precipitation/aggregation states.
The transition between these states would be advantageous for
intelligent drug delivery applications. For example, encapsula-
tion of drugs may occur at low temperatures with their cargo
release at high temperatures when the self-assembled struc-
tures are inverted. The aforementioned inversion would
control the release of the encapsulated drug, which is crucial
for pharmaceutical development.
Moreover, the self-assembled micelles as a stabilizer can be
used for fabricating coated nanoparticles or Pickering emul-
sions, which can modify the polarity upon an external
stimulus.69,70 Furthermore, such stabilization is advantageous
for biomedical applications, given the intelligent complexity of
the multicomponent systems.
Common di- or tri-block copolymers summarized in the
current review offer the modest structure, providing an oppor-
tunity to evaluate the switching process behavior in the sim-
plest structures comprising micelles and vesicles. The afore-
mentioned switching manner can be investigated in more
complex structures, comprising gel-forming multi-block copo-
lymers and graft copolymers. In this regard, it was illustrated
that such copolymers by creating more complex constructs
may be switched between the liquid and gel forms by changing
the temperature, pH or ionic strength.71,72
The capability of fabricating block copolymers with tunable
hydrophilicity through the combination of stimuli-responsive
blocks offers a valuable opportunity for the development of
smart dual or multi-responsive self-assembly systems (“schizo-
phrenic” platforms), which could intelligently control the
release of their cargo at the site of action.
This journal is © The Royal Society of Chemistry 2020
View Article Online
Review
Concerning the future use of these exceptional carrier
systems, “schizophrenic” copolymers could potentially offer an
important step toward the development of some more con-
trolled intelligent drug delivery systems in the complex biologi-
cal environments. However, one of the most important draw-
backs of these structures that needs to be investigated is
associated with their structural integrity because micellar
structures may hardly remain stable after being diluted in
gastric fluid or body fluids during cargo release.73
In this regard, the full-depth, large-scale structural evalu-
ation of this schizophrenic behavior is not still clearly
elucidated.
It should be noted that still some questions remain to be
answered, such as the way in which the zwitterionic and nonio-
nic blocks interact, whether this interaction is subdued by
other block chemistries and how the switching pathways are
mechanistically controlled at the respective transitions.74
Conflicts of interest
The authors declare that they have no conflicts of interest.
Acknowledgements
The authors are grateful to the Mashhad University of Medical
Sciences (No. 950160).
References
1 M. Alibolandi, K. Abnous, F. Hadizadeh, S. M. Taghdisi,
F. Alabdollah, M. Mohammadi, H. Nassirli and
M. Ramezani, J. Controlled Release, 2016, 241, 45–56.
2 M. Alibolandi, M. Ramezani, K. Abnous, F. Sadeghi,
F. Atyabi, M. Asouri, A. A. Ahmadi and F. Hadizadeh,
J. Controlled Release, 2015, 209, 88–100.
3 M. Alibolandi, M. Ramezani, K. Abnous, F. Sadeghi and
F. Hadizadeh, J. Nanopart. Res., 2015, 17, 76.
4 M. Alibolandi, M. Ramezani, F. Sadeghi, K. Abnous and
F. Hadizadeh, Int. J. Pharm., 2015, 479, 241–251.
5 M. Alibolandi, F. Sadeghi, K. Abnous, F. Atyabi,
M. Ramezani and F. Hadizadeh, Eur. J. Pharm. Biopharm.,
2015, 94, 521–531.
6 M. Alibolandi, F. Sadeghi, S. H. Sazmand, S. M. Shahrokhi,
M. Seifi and F. Hadizadeh, Int. J. Pharm. Invest., 2015, 5,
134.
7 M. Shahriari, S. M. Taghdisi, K. Abnous, M. Ramezani and
M. Alibolandi, Int. J. Pharm., 2019, 572, 118835.
8 Y. Lee and D. H. Thompson, Wiley Interdiscip. Rev.:
Nanomed. Nanobiotechnol., 2017, 9, 1450.
9 F. Li, J. Lu, X. Kong, T. Hyeon and D. Ling, Adv. Mater.,
2017, 29, 1605897.
10 X. Liu, Y. Yang and M. W. Urban, Macromol. Rapid
Commun., 2017, 38, 1700030.
Biomater. Sci.

Review
11 M. Shahriari, M. Zahiri, K. Abnous, S. M. Taghdisi,
M. Ramezani and M. Alibolandi, J. Controlled Release, 2019,
308, 172–189.
12 Z. Xu, C. Pan and W. Yuan, Biomater. Sci., 2020, 8, 3348–
3358.
13 F. Oroojalian, M. Babaei, S. M. Taghdisi, K. Abnous,
M. Ramezani and M. Alibolandi, J. Controlled Release, 2018,
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
288, 45–61.
14 G. Filipcsei, J. Fehér and M. Zrínyi, J. Mol. Struct., 2000,
554, 109–117.
15 P. M. George, D. A. LaVan, J. A. Burdick, C.-Y. Chen,
E. Liang and R. Langer, Adv. Mater., 2006, 18, 577–581.
16 J. S. Katz and J. A. Burdick, Macromol. Biosci., 2010, 10,
339–348.
17 N. N. Reddy, Y. M. Mohan, K. Varaprasad, S. Ravindra,
P. A. Joy and K. M. Raju, J. Appl. Polym. Sci., 2011, 122,
1364–1375.
18 S. Lv, Y. Wu, K. Cai, H. He, Y. Li, M. Lan, X. Chen, J. Cheng
and L. Yin, J. Am. Chem. Soc., 2018, 140, 1235–1238.
19 D. Yu, N. Zhang, S. Liu, W. Hu, J.-J. Nie, K. Zhang, B. Yu,
Z.-G. Wang and F.-J. Xu, ACS Mater. Lett., 2020, 2, 550–556.
20 Y.-J. Shih, Y. Chang, A. Deratani and D. Quemener,
Biomacromolecules, 2012, 13, 2849–2858.
21 V. Bütün, N. Billingham and S. Armes, J. Am. Chem. Soc.,
1998, 120, 11818–11819.
22 V. Bütün, S. Liu, J. Weaver, X. Bories-Azeau, Y. Cai and
S. Armes, React. Funct. Polym., 2006, 66, 157–165.
23 S. Liu, N. C. Billingham and S. P. Armes, Angew. Chem., Int.
Ed., 2001, 40, 2328–2331.
24 S. Liu and S. P. Armes, Angew. Chem., Int. Ed., 2002, 41,
1413–1416.
25 V. Bütün, S. P. Armes, N. C. Billingham, Z. Tuzar,
A. Rankin, J. Eastoe and R. Heenan, Macromolecules, 2001,
34, 1503–1511.
26 S. Liu and S. P. Armes, Langmuir, 2003, 19, 4432–4438.
27 D. Wang, J. Yin, Z. Zhu, Z. Ge, H. Liu, S. P. Armes and
S. Liu, Macromolecules, 2006, 39, 7378–7385.
28 V. A. Vasantha, S. Jana, S. S.-C. Lee, C.-S. Lim, S. L.-M. Teo,
A. Parthiban and J. G. Vancso, Polym. Chem., 2015, 6, 599–
606.
29 R. Enomoto, M. Khimani, P. Bahadur and S.-I. Yusa,
J. Taiwan Inst. Chem. Eng., 2014, 45, 3117–3123.
30 A. E. Smith, X. Xu, S. E. Kirkland-York, D. A. Savin and
C. L. McCormick, Macromolecules, 2010, 43, 1210–1217.
31 J. Weaver, S. Armes and V. Bütün, Chem. Commun., 2002,
2122–2123.
32 G. Li, L. Shi, Y. An, W. Zhang and R. Ma, Polymer, 2006, 47,
4581–4587.
33 G. Gotzamanis and C. Tsitsilianis, Macromol. Rapid
Commun., 2006, 27, 1757–1763.
34 X. Andre, M. Burkhardt, M. Drechsler, P. Lindner,
M. Gradzielski and A. H. Müller, Polym. Mater.: Sci. Eng.,
2007, 96, 560.
35 P. Xie, J. Wang, J. Li, Q. Cheng, K. Zhou and J. Ren,
J. Polym. Sci., Part A: Polym. Chem., 2019, 57, 814–826.
36 X. Yan, J. Li and T. Ren, e-Polym., 2018, 18, 559–568.
Biomater. Sci.
View Article Online
Biomaterials Science
37 Z. Ge, Y. Cai, J. Yin, Z. Zhu, J. Rao and S. Liu, Langmuir,
2007, 23, 1114–1122.
38 J. Rao, Z. Luo, Z. Ge, H. Liu and S. Liu, Biomacromolecules,
2007, 8, 3871–3878.
39 N. Maity, A. Kuila, D. P. Chatterjee, D. Mandal and
A. K. Nandi, J. Polym. Sci., Part A: Polym. Chem., 2016, 54,
3878–3887.
40 C. Chang, H. Wei, J. Feng, Z.-C. Wang, X.-J. Wu, D.-Q. Wu,
S.-X. Cheng, X.-Z. Zhang and R.-X. Zhuo, Macromolecules,
2009, 42, 4838–4844.
41 X. Jiang, G. Zhang, R. Narain and S. Liu, Langmuir, 2009,
25, 2046–2054.
42 D. Liu, C. Wei, G. Yan and G. Sun, Polym. Test., 2018, 65,
97–102.
43 L. Ahmadkhani, M. Abbasian and A. Akbarzadeh, Des.
Monomers Polym., 2017, 20, 406–418.
44 G. Isapour, R. Lund, K. Zhu, Z. Quan, K. D. Knudsen and
B. Nyström, Eur. Polym. J., 2015, 70, 79–93.
45 Q. Zhang, J.-D. Hong and R. Hoogenboom, Polym. Chem.,
2013, 4, 4322–4325.
46 J. Zhang, Y. Xiao, X. Luo, L. Wen, A. Heise and M. Lang,
Polym. Chem., 2017, 8, 3261–3270.
47 F. Liu and A. Eisenberg, J. Am. Chem. Soc., 2003, 125,
15059–15064.
48 S. L. Canning, T. J. Neal and S. P. Armes, Macromolecules,
2017, 50, 6108–6116.
49 J. Hu, G. Zhang, Z. Ge and S. Liu, Prog. Polym. Sci., 2014,
39, 1096–1143.
50 A. Feng, C. Zhan, Q. Yan, B. Liu and J. Yuan, Chem.
Commun., 2014, 50, 8958–8961.
51 S. Davaran, A. Ghamkhari, E. Alizadeh, B. Massoumi and
M. Jaymand, J. Colloid Interface Sci., 2017, 488, 282–293.
52 M. Arotçaréna, B. Heise, S. Ishaya and A. Laschewsky,
J. Am. Chem. Soc., 2002, 124, 3787–3793.
53 Y. Maeda, H. Mochiduki and I. Ikeda, Macromol. Rapid
Commun., 2004, 25, 1330–1334.
54 J. Virtanen, M. Arotçaréna, B. Heise, S. Ishaya,
A. Laschewsky and H. Tenhu, Langmuir, 2002, 18, 5360–
5365.
55 A. Can, Q. Zhang, T. Rudolph, F. H. Schacher, J.-F. Gohy,
U. S. Schubert and R. Hoogenboom, Eur. Polym. J., 2015,
69, 460–471.
56 A. Ghamkhari, B. Massoumi and M. Jaymand, Des.
Monomers Polym., 2017, 20, 190–200.
57 V. Hildebrand, M. Heydenreich, A. Laschewsky,
H. M. Moeller, P. Mueller-Buschbaum, C. M. Papadakis,
D. Schanzenbach and E. Wischerhoff, Polymer, 2017, 122,
347–357.
58 N. S. Vishnevetskaya, V. Hildebrand, M. A. Dyakonova,
B.-J. Niebuur, K. Kyriakos, K. N. Raftopoulos, Z. Di,
P. Müller-Buschbaum, A. Laschewsky and C. M. Papadakis,
Macromolecules, 2018, 51, 2604–2614.
59 N. S. Vishnevetskaya, V. Hildebrand, N. M. Nizardo,
C.-H. Ko, Z. Di, A. Radulescu, L. C. Barnsley, P. Müller-
Buschbaum, A. Laschewsky and C. M. Papadakis,
Langmuir, 2019, 35, 6441–6452.
This journal is © The Royal Society of Chemistry 2020

Biomaterials Science
60 M. Ranka, H. Katepalli, D. Blankschtein and T. A. Hatton,
Langmuir, 2017, 33, 13326–13331.
61 X. Tang, Q. Zhang and M. Pei, RSC Adv., 2017, 7, 1567–
1571.
62 H. Sun, X. Chen, X. Han and H. Liu, Langmuir, 2017, 33,
2646–2654.
63 J. Rodríguez-Hernández and S. Lecommandoux, J. Am.
Published on 02 October 2020. Downloaded by Auckland University of Technology on 10/3/2020 4:48:21 PM.
Chem. Soc., 2005, 127, 2026–2027.
64 F. Chécot, J. Rodriguez-Hernandez, Y. Gnanou and
S. Lecommandoux, Biomol. Eng., 2007, 24, 81–85.
65 J. Du and R. K. O’Reilly, Macromol. Chem. Phys., 2010, 211,
1530–1537.
66 S. S. Naik, J. G. Ray and D. A. Savin, Langmuir, 2011, 27,
7231–7240.
67 B. P. Bastakoti, S. Guragain, K. Nakashima and
Y. Yamauchi, Macromol. Chem. Phys., 2015, 216, 287–291.
This journal is © The Royal Society of Chemistry 2020
View Article Online
Review
68 P. Sar, S. Ghosh, Y. D. Gordievskaya, K. G. Goswami,
E. Y. Kramarenko and P. De, Macromolecules, 2019, 52,
8346–8358.
69 F. A. Plamper and W. Richtering, Acc. Chem. Res., 2017, 50,
131–140.
70 F. Han, A. H. Soeriyadi and J. J. Gooding, Macromol. Rapid
Commun., 2018, 39, 1800451.
71 H. Guo, M. de Magalhaes Goncalves, G. Ducouret and
D. Hourdet, Biomacromolecules, 2018, 19, 576–587.
72 L. Lauber, J. Santarelli, O. Boyron, C. Chassenieux,
O. Colombani and T. Nicolai, Macromolecules, 2017, 50,
416–423.
73 X. Jiang, Z. Ge, J. Xu, H. Liu and S. Liu, Biomacromolecules,
2007, 8, 3184–3192.
74 C. M. Papadakis, P. Müller-Buschbaum and A. Laschewsky,
Langmuir, 2019, 35, 9660–9676.
Biomater. Sci.