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Polymeric Filomicelles and Nanoworms: Two Decades of Synthesis and

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Article in Polymer Chemistry · June 2016

DOI: 10.1039/C6PY00639F

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Polymeric filomicelles and nanoworms:

Cite this: DOI: 10.1039/c6py00639f
two decades of synthesis and application
Published on 02 June 2016. Downloaded by Monash University on 09/06/2016 05:35:49.

Nghia P. Truong,*a John F. Quinn,a Michael R. Whittakera and Thomas P. Davis*a,b

Received 12th April 2016,
Accepted 2nd June 2016
DOI: 10.1039/c6py00639f
www.rsc.org/polymers
Filomicelles and nanoworms are an emerging subclass of nanomaterials with a special elongated shape.
The physical properties of a filomicelle are distinct from a traditional spherical micelle, and as such have
attracted tremendous interest in a variety of research areas. In this review, we highlight the substantial
progress in the synthesis and application of polymeric nanoworms over the past two decades. Synthetic
techniques summarized in this review are particle replication in nonwetting templates (PRINT), film
stretching, self-assembly (SA), crystallization-driven self-assembly (CDSA), polymerization-induced self-
assembly (PISA), and temperature-induced morphological transformation (TIMT). The applications of
filomicelles as (i) templates for inorganic nanoparticles, (ii) building blocks for superstructures, (iii) syn-
thetic dendritic cells for immunotherapy, (iv) constituents of thermoresponsive gels for biomedical appli-
cations, and (v) nanocarriers for cancer drug delivery are subsequently discussed. In the conclusion, we
describe the current trajectory of research in the field and identify areas where further developments are
of urgent need.

a
ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash
1. Introduction
Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne,
Filomicelles and nanoworms are an emerging subclass of poly-
Victoria 3052, Australia. E-mail: nghia.truong@monash.edu,
thomas.p.davis@monash.edu meric nanoparticles that have recently attracted considerable
b
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK interest in a variety of different fields including catalysis,

Dr Nghia P. Truong completed Dr John Quinn completed his

his bachelor and master degrees
in Chemistry from Vietnam
National University – HoChi-
Minh City (VNU-HCM) and
received his Ph.D. in Polymer
Chemistry from the University of
Queensland, Australia. He was
an assistant lecturer, and then a
lecturer at VNU-HCM for four
years. Since 2014, he has been a
Research Fellow working along-
Nghia P. Truong side Prof. Thomas P. Davis at
Monash University. His current
research interests include engineering sequence-controlled, func-
tional, and smart polymers for applications in nanomedicine (e.g.,
drug and gene delivery, diagnostics, antibacterial materials, etc.)
by using a variety of synthetic techniques including radical
polymerization (RAFT, ATRP, SET-LRP, and CCTP), emulsion
polymerization, self-assembly, polymerization-induced self-assem-
bly, temperature-induced morphological transformation, and click
chemistry.
PhD at UNSW in 2002 under the
joint supervision of Professor
Tom Davis and Dr Ezio Rizzardo
(CSIRO). His PhD thesis exam-
ined the application of ionizing
radiation as an initiation source
in reversible addition fragmenta-
tion chain transfer (RAFT)
polymerization. He continued to
postdoctoral work at the Univer-
sity of Melbourne in the labora-
John F. Quinn tory of Professor Frank Caruso
(2003–2004), and was an ARC
Australian Postdoctoral Fellow in the same group from
2005–2007. After a number of years away from academic research,
Dr Quinn returned to scientific research in 2014 and is currently a
Senior Research Fellow at Monash Institute of Pharmaceutical
Sciences. His research explores the application of advanced poly-
meric materials in drug delivery applications.

This journal is © The Royal Society of Chemistry 2016 Polym. Chem.


Review
material science, immunology, tissue engineering, and drug
delivery.1–5 Filomicelles have a nonspherical morphology
similar to the shape of worms or fibers found in Nature
(Fig. 1).6 Various terms such as filomicelle, filament, nano-
worm, worm-like nanoparticle or micelle, cylindrical nano-
particle or micelle, nanofiber, and nanorod are currently used
in the literature when describing these nanomaterials. The
majority of these terms clearly aim to define the fiber- or
worm- or rod-like shape of filomicelles. Aside from being a dis-
tinct morphology, the elongated shape of a filomicelle also
leads to a number of beneficial physical properties such as
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high surface area and aspect ratio. In this review, we mainly
Fig. 1 (A) A three-dimensional cartoon of a nanoworm and (B) a trans-
mission electron microscopy image of a synthetic nanoworm. Adapted
with permission. Copyright 2016 by Royal Society of Chemistry.6
Dr Michael Whittaker completed
his PhD at the University of
Queensland under the joint
supervision of Prof. Andrew
Whittaker and Dr David
J. T. Hill. In 2001 he joined Poly-
merat Pty Ltd as a senior
research scientist, and from 2004
to 2008 was a Senior Research
Officer in the Department of
Chemistry at the University of
Queensland. During this time he
Michael R. Whittaker was awarded a UQ Postdoctoral
Fellowship to conduct research
in the Australian Institute of Bioengineering and Nanotechnology.
From 2008–2012, Dr Whittaker was Research Manager at the
Centre for Advanced Macromolecular Design (CAMD) at UNSW,
and since May 2013 has been a Senior Research Fellow at the
Monash Institute of Pharmaceutical Sciences (MIPS). His current
research explores the use of stimuli-responsive materials in
pharmaceutical applications.
Polym. Chem.
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Polymer Chemistry
employ the terms “filomicelle” and “nanoworm” though all
other terms will also be mentioned with regard to their orig-
inal reports. It should be noted that nanoobjects with a
similar filamentous shape can also be found in Nature (e.g.,
rod-shape bacteria, viruses, fungi), or be synthesized from in-
organic constituents (e.g., gold nanorods, carbon nanotubes,
rod-like nanocapsules etc.), peptides and polymer brushes (i.e.,
cylindrical polymer brushes), although these materials are
outside the scope of this review. In addition, theoretical studies
regarding the formation of filomicelles have been reviewed
elsewhere;7–10 and we do not aim to exhaustively account for
every paper in synthesis and application of polymeric nano-
worms in this succinct review. Therefore, we aim to highlight
only works of particular significance, thereby tracing the inter-
esting development of both synthesis methods and applications
for this polymeric nanomaterial. In particular, we will discuss
the progress of synthetic techniques including particle replica-
tion in nonwetting templates, film stretching, self-assembly,
crystallization-driven self-assembly, polymerization-induced
self-assembly, and temperature-induced morphological trans-
formation. Next, we will describe some recent applications
where filomicelles offer distinct advantages over spherical nano-
particles such as templates for inorganic nanoparticles, build-
ing blocks for superstructures, synthetic dendritic cells for
immunotherapy, thermoresponsive gels for biomedical appli-
cations, and nanocarriers for drug delivery. Finally, areas
where further developments are imminent will also be identi-
fied and discussed.
Prof. Thomas P. Davis is the
Monash-Warwick Professor of
Medical Nanotechnology at
Monash University in Mel-
bourne, Australia. Additionally,
he holds an appointment as Pro-
fessor of Polymer Nanotechno-
logy at the Department of
Chemistry at Warwick University,
U.K. Prof. Davis is currently the
Director of the Australian
Research Council (ARC) Centre
of Excellence in Convergent Bio-
Thomas P. Davis
Nano Science and Technology
and holds a prestigious Australian Laureate Fellowship from the
ARC. Prior to his appointment at Monash he spent 21 years as a
senior academic at the University of New South Wales in Sydney,
where he founded and directed two research centres: the Centre
for Advanced Macromolecular Design (CAMD) and the Australian
Centre for Nanomedicine (ACN). Prof. Davis’ research focuses on
the application of polymer science and nanotechnology to thera-
peutic applications, and enhancing the fundamental understand-
ing of how nanomaterials interact with biological systems. He is
an author on 430+ peer-reviewed papers, and his work has been
cited in excess of 25 000 times.
This journal is © The Royal Society of Chemistry 2016

Polymer Chemistry
2. State of the art of synthetic
techniques
2.1 PRINT and film stretching
Particle Replication In Nonwetting Templates (PRINT) is a con-
tinuous, roll-to-roll, high-resolution technology that allows the
molding of solid polymers into cylindrical nanoparticles using
a porous template (a top-down approach, see Fig. 2).11 Poly-
mers suitable for PRINT include poly(ethylene glycol) (PEG),
and poly(lactic acid) (PLA) (see Chart 1).12 The first step in the
PRINT methodology is to fabricate a silicon wafer with nano-
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scale patterns by photolithography.13 The wafer is then used to
cast a mold using a photocurable fluoropolymer (e.g.,
perfluoropolyether (PFPE)) having a low modulus, high
gas permeability, and excellent resistance to swelling by low-
molecular-weight organic molecules.14 By ensuring that the
mold was capable of mechanical elongation and had excellent
nonwetting properties, the first production of discrete nano-
rods using the PRINT process was reported in 2005.13–15 By
combining with other techniques (such as layer-by-layer (LbL)
Fig. 2 The formation of filomicelles via Particle Replication In Non-
wetting Templates (PRINT). Adapted with permission. Copyright 2009 by
John Wiley and Sons.11
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Chart 1 Chemical structures of some polymer blocks used for the for-
mation of nanoworms. Adapted with permission. Copyright 2010 by
Elsevier.20 Notation: PEO: poly(ethylene oxide); PPO: poly( propylene
oxide); PI: polyisoprene; PB: polybutadiene; PE: polyethylene; PS: poly-
styrene; PMA: poly(methyl acrylate); PAA: poly(acrylic acid); PMMA: poly
(methyl methacrylate); PLA: poly(lactic acid); P4VP: poly(4-vinyl pyri-
dine); P2VP: poly(2-vinyl pyridine); PAN: polyacrylonitrile; PCL: poly(ε-
caprolactone); PMCL: poly(4-methyl caprolactone); PDMS: polydi-
methylsiloxane; PFS: poly(ferrocenyl dimethylsilane); PFG: poly(ferroce-
nyl dimethylgermane); PMVS: poly(methyl vinyl siloxane); PBLG: poly-
(γ-benzyl l-glutamate); PtBA: poly(t-butyl acrylate); PGMA: poly(glycerol
methacrylate); PCEMA: poly(cinnamoylethyl methacrylate); OPV: oligo
( phenylene vinylene) R1 = C6H13, R2 = H, R1 = R2 = OC8H17; OOF: oligo
(9,9’-dioctyl-2,7-fluorene); P3HT: poly(3-hexyl thiophene).
film assembly), the PRINT technology has been extended to
prepare protein-coated nanorods.16–18 Interestingly, a modified
version of the PRINT process has been applied to produce rod-
like nanoparticles from amphiphilic block copolymers, which
represents a significant departure from the standard nanorods
composed of only homopolymers.19
Film stretching uses a mechanical force to elongate spheri-
cal nanoparticles into solid nanorods (see Fig. 3).21 In the first
step, spherical polystyrene (PS) nanoparticles are cast onto a
poly(vinyl alcohol) (PVA) film. The film is then heated to
200 °C (well above the glass transition temperature of PS), and
then stretched.22 At high temperature and under mechanical
stress, the spherical shape of the PS nanoparticles deforms to
cylindrical morphology. Upon cooling to room temperature,
the cylindrical shape of the nanoparticles becomes effectively
frozen. The PVA film can then be dissolved in isopropanol to
obtain a suspension of PS nanorods, after which the iso-
propanol is evaporated to produce solid rod-like nano-
Polym. Chem.

Review
Fig. 3 The formation of filomicelles via film stretching. Copyright 2007 by the National Academy of Sciences of the USA.23
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particles. PS nanorods were first fabricated by this technique
in 2007.23 As an alternative to the use of high temperature,
plasticizers such as toluene can be employed to decrease PS
rigidity and facilitate the deformation of the spherical nano-
particles under mechanical stretching. Similar to the PRINT
technique described above, the film stretching method can be
applied for a limited number of materials (e.g., PS, poly(lactic-
co-glycolic acid) (PLGA), poly(methyl methacrylate) (PMMA),
and poly(caprolactone) (PCL)), and combined with the layer-
by-layer assembly technique to produce nanorods having
different surface coatings.24,25
PRINT and film stretching allow the synthesis of mor-
phologically uniform cylindrical nanoparticles in relatively
large quantities via industrially scalable processes. Although
the nanorods produced by these synthetic techniques are not
truly self-assembled core–shell micelles, the subsequent appli-
cation of coating techniques (such as LbL assembly) enables
the preparation of nanomaterials with varied properties
between core and shell. For example, coating with proteins or
biocompatible hydrophilic polymers enables the preparation
of nanomaterials that are similar to self-assembled filomicelles
prepared via synthetic techniques that will be described below.
2.2 Self-assembly
Self-assembly (SA) can be applied to prepare polymeric filo-
micelles from diblock copolymers by exploiting their amphiphilic
properties in certain solvents or their phase separation in
solid state.26–29 Specifically, nanoparticles can be assembled in
a given solvent using diblock copolymers when one block (the
solvophilic block) is soluble in that solvent while the other is
insoluble (the solvophobic block).30,31 When the amphiphilic
diblock copolymers are self-assembled at suitable conditions,
the solvophilic block forms the corona or the shell of worm-
like nanoparticles (WLN) while the solvophobic block becomes
the core of these nanofibers.32 Triblock copolymers with two
solvophobic blocks and one solvophilic block can also form
filomicelles with the two solvophobic blocks forming the core
of the WLN.33–35 There are two main procedures for preparing
filomicelles via SA: solvent mixing and film dispersing.26,27
In the first procedure (Fig. 4), a diblock copolymer is first
dissolved in a good solvent for both blocks.26 Subsequently,
a poor solvent that solubilizes only the solvophilic block is
slowly added to the solution to gradually change the quality of
Polym. Chem.
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Polymer Chemistry
the formed solvent mixture. At a certain ratio of poor to good
solvent, the solvophobic block becomes insoluble in the
solvent mixture leading to the aggregation of the solvophobic
blocks and the formation of filamentous micelles. In the film
dispersing procedure, the diblock copolymer is first dissolved
in a good solvent for both blocks, after which the polymer
solution is cast into a thin film by slowly evaporating the good
solvent.36 The film is then annealed at a suitable temperature.
During the annealing process, the diblock copolymer chains
segregate into an hexagonally-packed cylindrical phase due to
a solid-state microphase separation of the two chemically
incompatible blocks.37 These cylinders are then lifted from the
film by dispersing in a solvent that solubilizes only the solvo-
philic block or the matrix phase, thereby obtaining separated
nanofibers.
The first self-assembled filomicelles were reported in 1995
by Eisenberg and coworkers using the solvent mixing pro-
cedure.38 In this pioneering report, polystyrene-b-poly(acrylic
acid) (PS-b-PAA) was dissolved in dimethylformamide (DMF, a
good solvent for both blocks) at a concentration of 2 wt%.
Water, a poor solvent for the PS block but a good solvent for
the PAA block, was slowly added to the DMF solution under
vigorous stirring. As the addition of water progressed, the
quality of the solvent mixture for the PS block worsened, with
aggregation of the PS-b-PAA occurring when the aqueous
content reached 5%. The addition of water was continued
until the aqueous content of the solution was 25%, yielding
so-called crew-cut nanoaggregates with stable morphology.
The solution was then dialysed against water to completely
remove the DMF. Worm-like morphology of crew-cut nano-
aggregates was observed, for the first time, by transmission
electron microscopy (TEM) when the diblock copolymer used
had 200 units of styrene and 15 units of acrylic acid. By slightly
changing the degree of polymerization (DP) of acrylic acid
(to either 21 or 8 units) while maintaining the same DP of
styrene, sphere and vesicle morphology, respectively, could
be obtained. In a subsequent report, the same group demon-
strated the formation of rod-like nanoaggregates with a neutral
surface via the SA of polystyrene-b-poly(ethylene oxide) (PS240-
b-PEO80).39 Following these initial reports, many subsequent
investigations have optimised the SA conditions (e.g., solvent,
water addition rate, polymer concentration, salt concentration,
etc.) to produce WLN.40,41 Interestingly, in 2015, 20 years after
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Polymer Chemistry
Fig. 4 (A) The formation of filomicelles via the self-assembly of diblock copolymer using the solvent mixing procedure. (B) A typical experimental
setup for the self-assembly.
the first negatively-charged filomicelles were reported, Davis
and coworkers have just extended the collection of PS filo-
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micelles with differently-charged surfaces by reporting the posi-
tively-charged WLN self-assembled from polystyrene-b-poly(2-
dimethylaminoethyl methacrylate)) (PS215-b-PDMAEMA22).42 In
addition to the PS cores, biodegradable polymers (e.g., aceta-
lated dextran) and biosynthesized molecules (e.g., cholesterol)
have also been successfully used as hydrophobic components
to form the cores of nanoworms, offering the opportunity
to use these worm-like nanomaterials in biomedical
applications.43,44
The first self-assembled nanofibers prepared by film disper-
sing were reported in 1996 by Liu and co-workers (Fig. 5).45
In this work, polystyrene-b-poly(2-cinnamoyloxyethyl metha-
crylate) (PS-b-PCEMA) incorporating 26% volume fraction of
PCEMA was dissolved in toluene and then cast into a thin film
by slowly evaporating the solvent. The film was then annealed
at 90 °C for 4 days to obtain complete microphase separation.
The cylindrical phase of PCEMA was then crosslinked by ultra-
violet (UV) light; and the dispersed nanofibers were thereafter
obtained by stirring the UV-irradiated film with THF. Sub-
sequently, other groups have used polystyrene-b-polyisoprene
(PS-b-PI) diblock copolymers with or without chemically cross-
linking PI to conduct detailed studies of the diblock copolymer
phase separation in the solid state as well as to produce nano-
particles with multiple morphologies.20,46–49 These phase
separation studies demonstrated that worm-like morphology,
Fig. 5 The formation of filomicelles via the self-assembly of triblock
copolymer using the film dispersing procedure. Adapted with per-
mission. Copyright 2008 by Springer.37
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along with other shapes, can be obtained by judicious selec-
tion of the constitutional units in both the solvophobic and
solvophilic blocks.
To date, SA remains the most widely used technique for the
preparation of filomicelles, as well as nanoparticles with other
morphologies. Of the two SA procedures, the solvent mixing
method is more widely used due to its compatibility with
many types of polymers. In contrast, the film dispersing
procedure has fewer parameters that affect the formation of
worm-like morphology (e.g., type of polymers, and degree of
polymerization). Over the last two decades, the synthesis of
filomicelles with various compositions and properties via the
solvent mixing procedure has undergone explosive growth.
Many SA conditions for the formation of WLN using a broad
range of diblock polymers have now been reported.50 More-
over, SA provides the fundamental concept to prepare WLN for
later approaches discussed below.
2.3 Crystallization-driven self-assembly
Crystallization-driven self-assembly (CDSA) exploits the crystal-
lization of semicrystalline diblock copolymers as the driving
force to form filomicelles or nanofibers (Fig. 6).51 Similarly to
the SA technique described above, one block of the copolymer
is soluble in a selective solvent (the solvophilic block which
ultimately constitutes the nanofiber corona) while the other
block can crystallize in that solvent (the crystalline block even-
tually forming the filomicelle core). During the CDSA process,
the crystalline blocks drive the SA or aggregation of the copoly-
mers, while the solvophilic blocks provide stability to the
formed aggregates. The crystallization process can be induced
and controlled by slowly changing the solvent quality or temp-
erature.52 There are a limited number of semicrystalline poly-
mers that have been employed as the crystalline cores,
including polyethylene, poly(ferrocenylsilanes) (PFS), poly-
(ethylene oxide) (PEO), PLA, PCL, polyacrylonitrile (PAN), and
polythiophene.53–58 Of these materials, organometallic PFS
was the first and has been the most extensively studied.
In 1998, Winnik, Manners, and coworkers reported the first
filomicelles based on the crystallization of organometallic
PFS.60 In this report, the solvophilic block, poly(dimethyl-
siloxane) (PDMS) was 6 times longer than the crystalline PFS
block (∼300 units of PDMS compared to 50 units of PFS). This
is in stark contrast to the typical SA of PS diblock copolymers
in water via the solvent mixing procedure, in which the solvo-
phobic PS block is typically much longer than the solvophilic
block (∼200 units of styrene compared to ∼20 units of hydro-
philic monomer). The use of longer solvophilic blocks dis-
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Fig. 6 The formation of filomicelles via crystallization-driven self-assembly (CDSA) from small, uniform, stub-like crystallites as initiators for the
crystallization-driven living self-assembly of PFS block copolymers with a crystallizable, core-forming block. The polymers used in this study are
shown in orange (PFS), red (PDMS) and blue (PI). Adapted with permission. Copyright 2010 by Nature Publishing Group.59

Fig. 7 The growth of monodisperse cylindrical micelles grown from short (a) to (b, c, d) longer lengths. (e) Histograms of the contour lengths of
samples a–d. Adapted with permission. Scale bars = 500 nm. Copyright 2010 by Nature Publishing Group.59

tinguishes CDSA from the SA technique reported earlier. Two
years after the initial report, the same authors confirmed the
essential role of PFS crystallization in the formation of cylind-
rical micelles.61 In particular, the authors reported that only
spherical morphology was observed when an amorphous ana-
logue of PFS was used. The most remarkable feature of the PFS
nanofibers is that shorter PFS fibers can be uniformly
extended in length with increased crystallization (Fig. 7). Due
to the nature of the CDSA process, the further addition of crys-
talline diblock copolymers results in additional crystallization
and, as a result, lengthening of the formed nanofibers.62 This
is clearly evident in Fig. 7, which shows that PFS fibers became
longer when aliquots of PFS53-b-PI320 in THF were added. This
result demonstrates the so-called “living” characteristic of the
CDSA process, which is analogous to “living” polymerization.
The seeds serve as “initiators”, with the PFS-b-PDMS playing a
similar role to the monomer in extending the length of the
construct.59 Although CDSA is restricted to a limited choice of
polymers and the crystallization process may be time-consum-
ing (a couple of days), it remains the only technique that can
prepare filomicelles of uniform length, and produce multi-
dimensional complex nanostructures from filomicelle building
blocks (see 3.2).63
2.4 Polymerization-induced self-assembly
Polymerization-induced self-assembly (PISA) is based on the
synthesis of amphiphilic diblock copolymers by reversible-
deactivation radical polymerization (RDRP), and the in situ
formation of filomicelles (and other morphologies) during the
RDRP (Fig. 8).64–66 In the first step, a macromolecular chain
transfer agent (macro-CTA) or a macromolecular initiator
(macro-initiator) which will ultimately form the filomicelle
corona is synthesized by using one of the popular RDRP
techniques.67–71 After purification, the macro-CTA is dissolved
in a selective solvent (water or organic solvent) in the presence
of a second monomer and a radical initiator in order to
perform the chain extension reaction. During the chain exten-
sion polymerization, the formed second block (the solvo-

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Fig. 8 The formation of filomicelles via polymerization-induced self-
assembly (PISA).
phobic block) becomes insoluble in the reaction solvent while
the first macro-CTA block (i.e., the solvophilic block) remains
soluble. This leads to the in situ self-assembly of the formed
amphiphilic block copolymer chains into core–shell micelles
during the chain extension reaction. As such, this method
is referred to as polymerization-induced micellization or
polymerization-induced self-assembly (“PISA”).72,73 Moreover,
as polymerization of the solvophobic block continues the
micelles change their shape from sphere to cylinder and then
to vesicle in order to retain the optimum free energy of the
formed nanoparticles. Although most RDRP methods are suit-
able for PISA, reversible addition fragmentation chain transfer
(RAFT) polymerization has been the most practical technique
due to its compatibility with a wide variety of monomers and
solvents, as well as lower polymerization temperatures.74,75 By
choosing suitable conditions for the chain extension reaction
(e.g., solvent, feed ratio of the second monomer to macro-CTA,
pH, ionic strength, stirring speed, etc.), WLNs can be readily
synthesized by PISA at high solids content and without any
subsequent SA process.76–81
In 2009, Pan and co-workers reported the first preparation
of filomicelles by PISA using RAFT-mediated dispersed
polymerization in an alcoholic solvent.82 In this work, poly(4-
vinylpyridine) (P4VP), styrene (S), methanol, and azobisiso-
butyronitrile (AIBN) were used as the macro-CTA, monomer,
solvent, and radical initiator, respectively. After about 24 h of
polymerization, the P4VP-b-PS diblock copolymers self-
assembled into stable nanoworms even at very high concen-
tration (∼500 mg mL−1). Interestingly, the nanoworms could
be dried and then redispersed in methanol without altering
the morphology. Subsequently, this synthesis technique was
successfully applied to prepare WLN with a PS core and
different coronas (i.e., PEO, PDMAEMA, and PAA).83–85 Aside
from styrene, methacrylates such as benzyl methacrylate
(BzMA) and 2-phenylethyl methacrylate (PEMA) have also been
used to form filomicelles in organic solvents such as metha-
nol, ethanol, and heptane.86–93 Recently, visible light and
microwave radiation have been applied in the RAFT-mediated
dispersion polymerizations of BzMA and PEMA in ethanol,
providing temporal control over the formation of worm-like
morphology in organic solvents.94,95
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In 2010, Charleux and co-workers developed a special
macro-CTA that allowed, for the first time, the formation of
filomicelles directly in water via RAFT-mediated emulsion
polymerization.79 This macro-CTA comprised acrylic acid (AA)
and poly(ethylene glycol) methyl ether acrylate (PEGA) units.
Under specific conditions (e.g., pH = 6, [NaHCO3] = 8.8 mM),
WLNs with a PS core and P(AA-co-PEGA) corona were formed.
It is worth noting that only sphere morphology was observed
when either a PEGA or PAA homopolymer was used as
the macro-CTA. Subsequently, a methacrylate version of this
macro-CTA, P(MAA-co-PEGMA), was utilized to obtain high
chain extension efficiency with styrene.96 Using a P(MAA-co-
PEGMA) copolymer with a 1 : 1 mole ratio of MAA to PEGMA,
uniform worm-like morphology was obtained at a suitable
diblock copolymer molecular weight and pH value ( pH =
5).97,98 To date, when P(AA-co-PEGA) or P(MAA-co-PEGMA)
has been used as the hydrophilic macro-CTA, no other hydro-
phobic monomer aside from styrene has been successfully
employed to form filomicelles in water.
In 2011, Armes and co-workers reported the first production
of WLN with a polymethacrylate core via aqueous RAFT-
mediated dispersion polymerization. By using 2-hydroxypropyl
methacrylate (HPMA) as the monomer for the chain extension
polymerizations in water, filomicelles with various coronas
( poly(glycerolmono-methacrylate), poly(galactose methacryl-
ate), poly(ethylene glycol) and poly(2-(methacryloyloxy)ethyl
phosphorylcholine)) were synthesized directly in concentrated
aqueous solution.99–102 Interestingly, these polymerizations
reached very high conversion (>99%) in very short reaction
times (<2 h). In addition, the filomicelle morphology could
be targeted by simply changing the final solids content
(the weight percentage of formed diblock copolymers in
water).100 The HPMA WLNs could be freeze-dried and reconsti-
tuted in cell growth media to obtain sterile gels without
variation to the worm-like morphology.103–106
In 2015, Sumerlin and co-workers described a new
version of PISA in water designated as polymerization-induced
thermal self-assembly (PITSA).107 In PITSA, the solvophobic
block is a thermoresponsive polymer (i.e., poly(N-isopropyl
acrylamide) – PNIPAM), which is insoluble in water at a temp-
erature above its cloud point temperature (Tcp, the temperature
at which there is a solubility transition from soluble chains to
aggregates). The solvophilic block used in this work was com-
prised of N,N-dimethylacrylamide (DMA) and AA units. During
the chain extension reaction in water, the diblock copolymers
self-assembled into micelles and then nanoworms after
reaching certain chain lengths of PNIPAM (DP 11 and 101,
respectively). This SA is induced by both the polymerization
and thermal energy, and as such this technique has been
designated as PITSA. Importantly, the PNIPAM cores
become water-soluble at a temperature below the Tcp (∼32 °C),
which means that without crosslinking, the WLN synthesized
by this technique will not be stable in water at room tempera-
ture. That said, the PITSA process represents the only method
for the preparation of filomicelles with thermoresponsive
cores.
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In summary, PISA is a technique that can produce filo-
micelles in situ during synthesis of amphiphilic copolymers.
The approach abrogates the need for a subsequent SA step,
and can rapidly produce WLN directly in an organic solvent or
water, and at relatively high solids content. Given these advan-
tages, PISA has been receiving widespread interest as a con-
venient method for making filomicelles. That said, until now
only three polymers (PS, PHPMA, and PNIPAM) have been
successfully used for the formation of nanoworms in water via
PISA.
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2.5 Temperature-induced morphological transformation
Temperature-induced morphological transformation (TIMT) is
a technique for preparing filomicelles from spherical nano-
particle seeds or intermediates (from either nanospheres or
nanovesicles). In TIMT, as the name suggests, a change in
temperature is used to trigger the morphological transform-
ation. Specifically, when the temperature is changed, the
solvent quality for the different blocks is altered, leading to a
change in amphiphilicity and transformation of the spherical
nanoparticles into worm-like nanoaggregates (to retain the
optimum free energy of the nanoparticles).108 In 2006, Sheiko
and coworkers reported the first morphological transformation
of PS-b-PI nanoparticles from sphere to cylinder when cooling
Fig. 9 The formation of filomicelles via the temperature-induced mor-
phological transformation (TIMT).
Fig. 10 The transformation of the spherical polystyrene aggregates into filomicelles and the formation of a gel-like solution of stable filomicelles in
hot water. Adapted with permission. Copyright 2016 by Royal Society of Chemistry.6
Polym. Chem.
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from 35 °C to 25 °C, and from vesicle to cylinder when heating
from 25 °C to 40 °C.109 A year later, Cheng and coworkers
reported a similar reversible morphological transformation
for PS962-b-PEO227 nanoparticles.110 In this work, heating
these PS962-b-PEO227 nanoparticles from room temperature to
50 °C, instigated a transformation from vesicles into cylinders.
The morphological changes triggered by heating were found
to be generally faster than the reverse process. Importantly,
these morphological transformations were predictable and
reversible.
TIMT can also be used to produce stable filomicelles with
fixed morphology (i.e., insensitive to subsequent changes in
temperature). This irreversible morphological transformation
can be achieved by using a thermoresponsive polymer as the
macro-CTA for the synthesis of an amphiphilic diblock copoly-
mer, and subsequent TIMT (Fig. 9). Similarly to PISA, the
macro-CTA in the irreversible TIMT is often synthesized by an
RDRP method before use in in situ morphological transform-
ation. For example, thermoresponsive poly((di(ethylene glycol)
methyl ether methacrylate)-co-N-(2-hydroxypropyl) methacryl-
amide) P(DEGMA-co-HPMA) with a Tcp of 40 °C was success-
fully used for chain extension with styrene via RAFT-mediated
emulsion polymerization (a RDRP).6 After the chain extension
reaction, spherical nanoaggregates of PS diblock copolymer
were formed at 70 °C (the temperature of the polymerization).
The suspension of spherical nanoaggregates was then cooled
from 70 °C to ambient temperature (23 °C) in the presence of
a suitable amount of plasticizer (e.g., 40 µL of toluene), result-
ing in the transformation of the spherical PS aggregates into
filomicelles (Fig. 10). This transformation is induced by the
change in amphiphilicity of the thermoresponsive block from
solvophobic to solvophilic when the temperature was changed
from above to below the Tcp of the thermoresponsive polymer.
The plasticizer (i.e., toluene) was then removed by dialysis or
lyophilization. In contrast to the aforementioned reversible
morphological transformation, when no plasticizer is present
in the core, the filamentous morphology of the thermo-
responsive WLN becomes kinetically trapped (due to the glassy
nature of the PS), leading to stable WLN in water or buffer
(even upon reheating). Interestingly, when the stable filo-
micelle suspension was reheated to 50 °C (a temperature higher
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than the Tcp of P(DEGMA-co-HPMA)), a gel-like state is
obtained due to topological interactions between the long,
stable nanofibers (Fig. 10).111 After cooling back to ambient
temperature, the gels revert to a relatively low-viscosity suspen-
sion without changes to the worm-like morphology. Clearly,
the temperature-stable filamentous morphology allows the for-
mation of reversible thermoresponsive gels from filomicelle
suspensions, and this is particularly promising for a number
of biomedical applications (see 3.4). Moreover, at human body
temperature (37 °C, a temperature lower than Tcp of P(DEGMA-
co-HPMA)), the filomicelle suspension does not form a gel,
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thereby demonstrating the possible application of these filo-
micelles in nanomedicines as nanocarriers (see 3.5).
As noted above, one limitation of TIMT as initially
described was that only filomicelles with PS cores could be
synthesized. However, this drawback has recently been over-
come, with an extensive library of filomicelles with different
polymethacrylate cores being successfully prepared directly
in water by using thermoresponsive P(DEGMA-co-HPMA)
(Fig. 11).112 Specifically, a polymethacrylate that forms cores of
only spherical nanoparticles in water via PISA (i.e., poly(benzyl
methacrylate) PBzMA), and a number of other polymethacry-
lates (e.g., poly(ethyl methacrylate)) that have not previously
been used for the synthesis of filomicelles, have been success-
fully used to prepare WLN using TIMT.113 Significantly, all
filomicelles prepared by TIMT were morphologically uniform,
highly stable in water or buffer, and able to form useful
thermoresponsive gels. In addition to the tuneable cores, the
Fig. 11 Facile access to thermoresponsive filomicelles with tuneable
cores via temperature-induced morphological transformation (TIMT).
Adapted with permission. Copyright 2016 by Royal Society of
Chemistry.112
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surfaces of filomicelles prepared by TIMT can also be modified
by coupling different polymers (e.g. PEG) or bio-active
molecules (e.g. biotin) via copper catalyzed alkyne–azide cyclo-
addition click chemistry (CuAAC).114
In short, TIMT is a powerful technique for rapidly preparing
uniform filomicelles directly in water, at relatively high solids
content, and with a variety of different cores and surfaces. The
irreversible morphological transformation of WLN prepared by
TIMT offers a useful gelling property ( provided the corona-
forming block exhibits a phase transition behavior in a usable
temperature range), along with stable morphology at human
body temperature, thus enabling the potential application of
these nanomaterials in a number of fields. Considering these
advantages, TIMT is arguably the most facile and versatile
technique in the preparation of filomicelles directly in water
and with tunable properties.
3. Emerging applications
3.1 Templates for inorganic nanoparticles
Novel hybrid nanomaterials comprising inorganic nano-
particles and organic filomicelles have been successfully syn-
thesized since 2009. For example, PFS cylindrical micelles
prepared via CDSA have been used as a template for the
formation of silica- and titania-nanowires.115 By simply mixing
metal alkoxide precursors with cylindrical micelles in a
mixture of isopropanol and water, continuous, smooth layers
of inorganic nanoparticles were coated onto the surfaces of
filomicelles. In this case, electrostatic interactions between the
hydrolysed metal anions and cationic cylinders promoted the
surface-specific deposition of metal oxides onto the cylindrical
micelles. These hybrid nanomaterials have potential to exhibit
both the shape anisotropy and mechanical properties of filo-
micelles as well as the conductive, magnetic, and photo-
catalytic properties of inorganic nanoparticles. In 2010,
Winnik and coworkers reported the synthesis of PS-b-P4VP
wormlike micelles with CdSe quantum dots bound to the
worm corona.116 The quantum dot coated nanoworms were
prepared by simply stirring a suspension of spherical hybrid
micelles of PS-b-P4VP diblock copolymer and CdSe quantum
dots at 1250 rpm for 50 h in mixed solvents of isopropanol
and chloroform. In 2014, by using PISA (see 2.4), Davis and co-
workers have successfully prepared PS nanoworms with gold
nanoparticles complexed within a poly(oligo(ethylene glycol)
methacrylate) corona.117 The amount of gold nanoparticles in
the nanoworm-gold composites varied from 8% to 20%,
depending on the amount of chloroauric acid added. While
these pioneering works reported the synthesis of hybrid in-
organic and filomicelle nanomaterials, they did not clearly
demonstrate the benefits of using these materials in specific
applications. In 2014, Tang and coworkers demonstrated, for
the first time, the advantages of functional hybrid nanoworm
materials for photocatalytic applications.1 In particular,
poly(N,N′-methylenebisacrylamide-4-vinylpyridine) nanofibers
have been loaded with silver nanoparticles and subsequently
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Fig. 12 (A) A transmission electron microscopy image of PMBA-b-P4VP
nanofibers loaded with silver nanoparticles. (B) Absorption spectra of
methylene blue during photodegradation catalyzed by PMBA-b-P4VP
loaded silver nanoparticles. Adapted with permission. Copyright 2014 by
John Wiley and Sons.1
used for the degradation of methylene blue under ultraviolet
irradiation (Fig. 12). The hybrid nanofibers exhibited high
photostability and degradation efficiency (e.g., 93% after
30 min), confirming the benefits of using hybrid inorganic-
coated filomicelles for photocatalytic applications.
3.2 Building blocks for superstructures
Filomicelles have been used successfully as building blocks for
the formation of one and/or three-dimensional (1D or 3D)
superstructures. In 2004, Liu and coworkers reported the syn-
thesis of 1D multiblock nanotubes (so-called CONATUBLOCs)
by joining asymmetrically functional nanorods prepared via
the film dispersing procedure head to tail.118 Specifically,
amino and carboxyl groups were incorporated at the head and
tail of nanorods respectively, with amidation then used to
form multiblock nanotubes. Like an amphiphilic block copoly-
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mer, the multiblock nanotubes with different nanotube pro-
perties were capable of segregating in selective solvents and
solid state to produce 1D superstructures. In 2015, Winnik,
Manners and coworkers extended this principle to build the
first 3D superstructures using monodisperse cylindrical tri-
block comicelles prepared via CDSA (Fig. 13).2 By exploiting
the unique feature of CDSA (the living CDSA process), cylindri-
cal triblock comicelles with two different block sequences
(hydrophobic–polar–hydrophobic (H–P–H) and polar–hydro-
phobic–polar (P–H–P)) were first produced without using any
chemical reactions (Fig. 13D).119 The triblock cylinders were
shown to stack into 1D or 3D superstructures depending on
their individual block lengths and solvent choices (Fig. 13B
and C), similarly to the SA of block copolymers via the solvent
mixing procedure. For example, when isopropanol was used,
H105 nm–P160 nm–H105 nm triblock comicelles formed a 3D
superstructure (Fig. 13A and B) while H410 nm–P160 nm–H410 nm
triblock cylinders formed a 1D superlatice (Fig. 13C). More-
over, the coronal blocks were able to be crosslinked or functio-
nalised with fluorescent dyes (Fig. 13E and F), offering great
opportunities to develop functional and robust micrometre-
scale assemblies similar to those found in nature.
3.3 Synthetic dendritic cells for immunotherapy
Filomicelles hold some promise for applications in immuno-
therapy. In 2013, Rowan and coworkers functionalised filo-
micelle surfaces with antibodies for a potential application as
synthetic dendritic cells.3 The authors found that biocompati-
ble filomicelles decorated with anti-CD3 antibodies not only
activated T cells at significantly lower concentrations than
either free antibodies or their spherical counterparts but also
induced a more sustained T cell response, paving the way to a
new generation of highly efficient and cost-effective vaccines.
The enhanced activity of antibody-decorated filomicelles is
attributed to the unique multivalent and flexible properties of
these worm-like nanomaterials, which facilitate attachment of
antibodies to multiple recognition sites of the T cells and clus-
tering of these recognition sites during formation of immune
synapse (Fig. 14). The results obtained suggest that the mul-
tiple chemical functionalities and flexibility of filomicelles are
important for modulating T cell response, or cellular function
more broadly. In 2015, Mitragotri and coworkers provided
further evidence of immune response when using PS nanorods
conjugated with ovalbumin for in vivo immunization study.120
Interestingly, rod-shaped nanoparticles produced a Th2-biased
response while spherical PS coated with ovalbumin produced
a Th1-biased response, suggesting that shape of nanoparticles
may be useful in the design of next-generation vaccines
against a wide range of pathogens. Taken together, these pio-
neering studies clearly demonstrate the benefits of using filo-
micelles for immunotherapy.
3.4 Thermoresponsive gels for biomedical applications
Nanoworms prepared via PISA have recently been used as
thermoresponsive gels for biomedical applications. In 2015,
Armes and coworkers demonstrated, for the first time, that
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Fig. 13 1D and 3D superstructures prepared through end-to-end stacking of H–P–H triblock copolymers. (A) P–H–P triblock comicelles with a
nonpolar, hydrophobic central segment (H) and two polar terminal segments (P) formed by the addition of PFS48-b-P2VP414 unimers to a solution
of monodisperse cylindrical seed micelles of PFS49-b-PDMS504. (B) H–P–H triblock comicelles with an inverse sequence of the hydrophobic and
polar segments formed by the addition of PFS49-b-PDMS504 unimers to a solution of monodisperse cylindrical seed micelles of PFS48-b-P2VP414.
PDMS corona regions are not visible in the TEM image because of insufficient electron density contrast. The widths of the PFS cores are different for
the H and P segments, which is often a feature of living CDSA processes that involve compositionally different block copolymer structures. The PFS
core-forming block and the PDMS and P2VP corona-forming blocks are indicated by orange, red, and green colors, respectively. Adapted with per-
mission. Copyright 2015 by American Association for the Advancement of Science.2

Fig. 14 The proposed mechanism of filomicelle binding and T cell activation. (a) The mobility of the filomicelles assists in locating the T cell; (b) the
filomicelle docks onto the T cell; (c) attachment of the filomicelle to multiple recognition sites; (d) the filomicelle clustering at the recognition sites.
Adapted with permission. Copyright 2015 by Royal Society of Chemistry.3

a poly(glycerol monomethacrylate)-b-poly(2-hydroxypropyl
methacrylate) (PGMA-b-PHPMA) worm gel is suitable as a bio-
inert 3D matrix for pluripotent stem cells (PSC) and human
embryos (Fig. 15).4 Specifically, after the formation of the
nanoworms by PISA, the worm suspension was purified by one
of three protocols: dialysis against PBS for 2 days ( protocol 1)
or 7 days ( protocol 2) or dialysis against PBS for 2 days fol-
lowed by freeze-drying overnight ( protocol 3). The worm gel
purified by protocol 3 showed lower toxicity to PSC than that
purified by either protocol 1 or 2, while still exhibiting similar

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Fig. 15 The application of PGMA-b-PHPMA worm gel for human stem cells and embryos. Copyright 2016 by American Chemical Society.4
gelation behaviour. These toxicity and gelation results
suggested that dialysis followed by freeze-drying is a suitable
protocol for preparing nanoworms for biomedical appli-
cations. After purifying the nanoworms, human embryos cul-
tured to zona-free blastocyst at day 5 were immersed in PGMA-
b-PHPMA worm gel containing Nutristem medium (6% w/v of
nanoworms in medium). Significantly, within 24 h incubation
at 37 °C, PSC colonies immersed in such worm gels entered
cellular stasis and then maintained cell viability for up to two
weeks with little to no differentiation. As such, the use of
PGMA-b-PHPMA worm gel offers a novel method for storage of
either PSC or human embryos without cryopreservation. In
2016, Gibson, Armes and coworkers further extended the use
of biocompatible PGMA-b-PHPMA worm gel for another useful
biomedical application (cryopreservation of red blood cells).121
In this work, PGMA-b-PHPMA worm gel combined with poly-
(vinyl alcohol) was employed as an effective cryopreservative
for red-blood-cells without the need for any toxic organic
solvents. Moreover, the morphology of the red blood cells was
normal; and there was no hemagglutination. Interestingly, the
cryopreservation mixture could directly form standing gels
upon cooling to room temperature, suggesting an attractive
one-pot solution for future whole blood cryopreservation and
tissue-engineering applications.
3.5 Nanocarriers for drug delivery
Filomicelles have recently emerged as highly efficient nano-
carriers for drug delivery applications.122–125 Compared to
their spherical counterparts, the unique physical properties of
filomicelles (e.g., long length, reptation behaviour, high
surface area, flexibility etc.) provide several advantages when
these materials are used in in vivo drug delivery applications
(i.e., long circulation time, high accumulation into tumor,
deep penetration into tumor, and enhanced active target
delivery).124–129 Importantly, these advantages lead to higher
efficacy and fewer side effects for drugs encapsulated within
the filomicelles. As such, filomicelle nanomaterials are prom-
ising candidates for the possible replacement of traditional
nanospheres currently used in drug and gene delivery.130–134
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The key advantages of using filomicelles in drug delivery appli-
cations will be discussed in more detail below.
Long circulation. Therapeutic agents (e.g., anticancer drugs,
small interfering RNA, etc.) usually have a short circulation
time following administration because of their low molecular
weight, hydrophobicity and degradability.135 One strategy
for increasing circulation time is to load these therapeutic
compounds inside nanoparticles having poly(ethylene glycol)
surfaces (PEGylated nanoparticles).135,136 In 2007, the pioneer-
ing work of Discher and coworkers showed that PEGylated filo-
micelles had even longer circulation times than PEGylated
spherical nanoparticles.5 In particular, PEGylated filomicelles
circulated in rat for more than a week while their PEGylated
spherical counterparts were cleared within two days. In
addition, it has been found that longer filomicelles display
higher circulation times than their short fragmented versions.
However, no relationship between the filomicelle diameter and
their pharmacokinetics has been established. The prolonged
circulation of long filomicelles may be related to the ability
of filomicelles to stretch out under flow conditions
within blood vessels and during spleen filtration (where νflow >
5 µm s−1).5,137,138 The stretched filomicelles can avoid uptake
and subsequent elimination by phagocytic systematic clear-
ance (e.g. macrophages), and as a result, can remain in circula-
tion for longer (Fig. 16).138–140 In addition, PEGylated rod-
shaped tobacco mosaic virus, PEGylated inorganic nanorods
and other types of PEGylated filomicelles also exhibit
enhanced circulation behavior similar to that observed for
PEGylated filomicelles.141–144 These results confirm the long-
circulating behaviour of worm-like nanomaterials which may
offer significant advantages compared to traditional spherical
nanoparticles in drug delivery applications.
High accumulation in tumor. The reduced clearance and
concomitant prolonged circulation time of filomicelles in vivo
allow these nanomaterials greater opportunity to reach
targeted disease sites (e.g. tumors) compared to their spherical
counterparts.17 Further, due to their small diameter (from
10 nm to 50 nm), filomicelles can extravasate through leaky
vascular networks via the enhanced permeability and retention
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a carrier for Docetaxel resulted in higher accumulation of drug

in SKOV-3 human ovarian carcinoma xenograft tumor than did
the administration (at same dose) of Taxotere (a formulation of
Docetaxel currently used in the clinic). These results, together
with similar observations with inorganic nanorods and carbon
nanotubes, suggest that cylindrical nanomaterials have high
potential for improving efficacy and reducing side effects of
anti-cancer drugs, due to their ability to accumulate to high
concentrations in tumor.147,148
Deep penetration in tumor. In addition to accumulating in
tumor to high concentrations, worm-like nanomaterials can
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also penetrate deeper in tumor when compared to spherical

nanoparticles. To examine this property, Discher and

Fig. 16 Stretched filomicelles flow past macrophages and avoid phago-

cytic uptake. Adapted with permission. Copyright 2007 by Nature Pub-
lishing Group.5

(EPR) effect without the need for deformation (as is necessary

for their spherical counterparts having the same volume).124
These unique features can lead to higher accumulation of filo-
micelles and, as a result, anti-cancer drugs, in tumor tissue.
For example, in 2009, Discher and coworkers injected filo-
micelles labeled with near infrared fluorophore (NIF) into xeno-
graft tumor-bearing mice.145 Ten minutes after intravenous
administration (via tail vein) of these NIF-labelled nano-
materials, the authors found a strongly luminescent tumor in
contrast to a relatively weak systemic fluorescent signal (see
Fig. 17). The strong luminescence correlated to an abnormally
high concentration of filamentous micelles found in the mouse
xenograft tumor. In 2013, DeSimone and coworkers also found
a similar passive accumulation in tumor of cylindrical nano-
particles prepared via PRINT.146 The use of PRINT nanorods as

Fig. 17 Bioluminescent images of a mouse bearing tumor xenograft

showing high accumulation of NIF-labelled filomicelles in tumor. Fig. 18 Gel permeation of vesicles and worm-like micelles through 2%
Adapted with permission. Copyright 2009 by American Chemical agarose gel having 100 nm effective pore size. Adapted with permission.
Society.145 Copyright 2005 by IOP Publishing.149

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coworkers employed 2% agarose gels with 100 nm effective
pore size as a model of tumor.149 The authors found that
spherical nanoparticles having a diameter of 100 nm stuck
to the periphery of the gel while filomicelles penetrated deeply
through the gel (see Fig. 18).
In another study, Steinmetz and coworkers used spheroid
as a model of the tumor microenvironment, and also observed
enhanced tumor penetration for rod-shaped nanoparticles
compared to nanospheres.150 These in vitro results were com-
bined with in vivo studies to show that filomicelles and nano-
rods penetrate xenograft tumor deeper than spherical
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nanoparticles.145,151 The improved tumor penetration of
worm-like nanomaterials may be related to the reptation
behaviour of filomicelles in dense environments, which
allows these nanomaterials to move around obstacles in the
tumor microenvironment more easily than spherical nano-
particles.124,151,152 These results suggest that worm-like nano-
particles may be more effective for cancer therapy than
traditional spherical nanoparticles currently used in the clinic.
Enhanced active target delivery. Aside from the higher
accumulation of filomicelles in tumor tissue via the EPR effect
( passive targeting), filomicelles decorated with suitable
ligands can also be used to actively target specific cells or
organs.153 The large surface area of the filomicelles allows
more ligands to be presented on the surface, enabling better
receptor binding than their spherical counterparts and thus
resulting in enhanced cellular uptake or higher retention in
specific organs (see Fig. 19).154 For example, when compared
to spherical analogues, biotinylated filomicelles were found to
have higher affinity to avidin-coated surfaces and to smooth
muscle cells, leading to improved internalization of these
materials into the targeted cells.155 For drug delivery in vivo,
the strong interaction between antibodies decorated on the
filomicelle surface was sufficient to overcome the effect
of blood flow and enable the retention of the filomicelles at
the targeted organs.156 By selecting suitable antibodies for
surface functionalization of the filomicelles (anti-intracellular
Fig. 19 Carrier shape modulates ligand-mediated anchoring on endo-
thelium. Copyright 2014 by American Chemical Society.153
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adhesion molecule 1 or anti-transferrin) these worm-like nano-
materials could be targeted to lung or brain endothelium,
while spherical nanoparticles with similar ligand functional-
ities exhibited much lower, nonspecific accumulations.157,158
The enhanced active targeting of ligand-presenting filomicelles
offers great promise for improving drug efficacy, and for allow-
ing potential treatment of diseases where using traditional
spherical nanoparticles has seen limitations (e.g., brain
cancers, dementia, etc.).
4. Conclusions
This review summarises the state of the art in the synthesis
of filomicelles and explores emerging applications for these
interesting materials. We have also highlighted the unique
properties of these elongated nanomaterials which offer many
advantages over spherical nanoparticles for certain appli-
cations (i.e., large surface area, high aspect ratio, flexibility,
different head and tail properties, topological interactions,
and reptation behaviour). Over the past two decades, innova-
tive synthetic techniques have been developed to provide more
uniform, complex, biocompatible, and functional worm-like
nanoparticles. The synthetic procedures for preparing filo-
micelles have become simpler, faster, involve fewer steps, and are
increasingly amenable to scale-up. While nanoworm synthesis
previously necessitated the use of organic solvent, direct prepa-
ration in water is now possible, from dilute suspensions to
highly concentrated latexes, with tunable core and surface pro-
perties. Polymer chemists, using the powerful methods of
RDRP, have recently made significant contributions to the
field by establishing facile and versatile synthetic techniques
such as PISA and TIMT. Although significant advances in syn-
thesis have been made, the complexity and functionality of
worm-like micelles are still a pale shadow of that achieved for
traditional spherical micelles. As such, further developments
in filomicelle synthesis are still urgently needed to enable
advances in many applications. As an example, nanoworms
that can respond to stimuli (e.g., temperature, pH, etc.) to
release cargo and/or switch on diagnostic signals similar to
spherical nanoparticles will be of great interest for nano-
medicine. Alongside advances in synthesis, we anticipate that
the current potential for these materials will be translated into
an increasingly wide array of practical applications. Moreover,
new applications for these interesting materials will continue
to emerge as further light is shed on their unique physical
properties and interactions with biological systems.
Acknowledgements
This work was carried out within the Australian Research
Council (ARC) Centre of Excellence in Convergent Bio-Nano
Science and Technology (Project No. CE140100036). T. P. D. is
grateful for the award of an Australian Laureate Fellowship
from the ARC. N. P. T. acknowledges the financial support
This journal is © The Royal Society of Chemistry 2016

Polymer Chemistry
from the Faculty of Pharmacy and Pharmaceutical Sciences,
Monash University.
References
1 X. Wen, L. M. Tang and B. T. Li, Chem. – Asian J., 2014, 9,
2975–2983.
2 H. B. Qiu, Z. M. Hudson, M. A. Winnik and I. Manners,
Science, 2015, 347, 1329–1332.
3 S. Mandal, Z. H. Eksteen-Akeroyd, M. J. Jacobs,
Published on 02 June 2016. Downloaded by Monash University on 09/06/2016 05:35:49.
R. Hammink, M. Koepf, A. J. A. Lambeck, J. C. M. van
Hest, C. J. Wilson, K. Blank, C. G. Figdor and A. E. Rowan,
Chem. Sci., 2013, 4, 4168–4174.
4 I. Canton, N. J. Warren, A. Chahal, K. Amps, A. Wood,
R. Weightman, E. Wang, H. Moore and S. P. Armes, ACS
Cent. Sci., 2016, 2, 65–74.
5 Y. Geng, P. Dalhaimer, S. Cai, R. Tsai, M. Tewari, T. Minko
and D. E. Discher, Nat. Nanotechnol., 2007, 2, 249–255.
6 N. P. Truong, M. R. Whittaker, A. Anastasaki,
D. M. Haddleton, J. F. Quinn and T. P. Davis, Polym.
Chem., 2016, 7, 430–440.
7 E. B. Zhulina and O. V. Borisov, Macromolecules, 2012, 45,
4429–4440.
8 Y. Termonia, J. Polym. Sci., Part B: Polym. Phys., 2002, 40,
890–895.
9 A. Blanazs, S. P. Armes and A. J. Ryan, Macromol. Rapid
Commun., 2009, 30, 267–277.
10 J. N. Israelachvili, Intermolecular and Surface Forces,
3rd edn, 2011, pp. 1–674.
11 D. A. Canelas, K. P. Herlihy and J. M. DeSimone, WIREs
Nanomed. Nanobiotechnol., 2009, 1, 391–404.
12 J. Xu, D. H. C. Wong, J. D. Byrne, K. Chen, C. Bowerman
and J. M. DeSimone, Angew. Chem., Int. Ed., 2013, 52,
6580–6589.
13 J. P. Rolland, B. W. Maynor, L. E. Euliss, A. E. Exner,
G. M. Denison and J. M. DeSimone, J. Am. Chem. Soc.,
2005, 127, 10096–10100.
14 P. Hunziker, WIREs Nanomed. Nanobiotechnol., 2015, 7,
169–188.
15 Y. P. Wang, T. J. Merkel, K. Chen, C. A. Fromen,
D. E. Betts and J. M. DeSimone, Langmuir, 2011, 27, 524–
528.
16 J. Y. Kelly and J. M. DeSimone, J. Am. Chem. Soc., 2008,
130, 5438–5439.
17 K. G. Reuter, J. L. Perry, D. Kim, J. C. Luft, R. Liu and
J. M. DeSimone, Nano Lett., 2015, 15, 6371–6378.
18 S. W. Morton, K. P. Herlihy, K. E. Shopsowitz, Z. J. Deng,
K. S. Chu, C. J. Bowerman, J. M. Desimone and
P. T. Hammond, Adv. Mater., 2013, 25, 4707–4713.
19 J. Y. Wang, Y. Wang, S. S. Sheiko, D. E. Betts and
J. M. DeSimone, J. Am. Chem. Soc., 2012, 134, 5801–5806.
20 J. S. Qian, M. Zhang, I. Manners and M. A. Winnik, Trends
Biotechnol., 2010, 28, 84–92.
21 C. C. Ho, A. Keller, J. A. Odell and R. H. Ottewill, Colloid
Polym. Sci., 1993, 271, 469–479.
This journal is © The Royal Society of Chemistry 2016
View Article Online
Review
22 C. C. Ho, A. Keller, J. A. Odell and R. H. Ottewill, Polym.
Int., 1993, 30, 207–211.
23 J. A. Champion, Y. K. Katare and S. Mitragotri, Proc. Natl.
Acad. Sci. U. S. A., 2007, 104, 11901–11904.
24 Z. M. Zhou, A. C. Anselmo and S. Mitragotri, Adv. Mater.,
2013, 25, 2723–2727.
25 J. W. Yoo and S. Mitragotri, Proc. Natl. Acad. Sci. U. S. A.,
2010, 107, 11205–11210.
26 N. S. Cameron, M. K. Corbierre and A. Eisenberg,
Can. J. Chem., 1999, 77, 1311–1326.
27 F. S. Bates and G. H. Fredrickson, Phys. Today, 1999, 52,
32–38.
28 S. G. Zhang, Nat. Biotechnol., 2003, 21, 1171–1178.
29 G. Rizis, T. G. M. van de Ven and A. Eisenberg, Angew.
Chem., Int. Ed., 2014, 53, 9000–9003.
30 M. W. Matsen and F. S. Bates, Macromolecules, 1996, 29,
7641–7644.
31 J. Rodriguez-Hernandez, F. Checot, Y. Gnanou and
S. Lecommandoux, Prog. Polym. Sci., 2005, 30, 691–
724.
32 T. P. Lodge, J. A. Bang, Z. B. Li, M. A. Hillmyer and
Y. Talmon, Faraday Discuss., 2005, 128, 1–12.
33 Z. Li, J. Ma, N. S. Lee and K. L. Wooley, J. Am. Chem. Soc.,
2011, 133, 1228–1231.
34 Z. B. Li, Z. Y. Chen, H. G. Cui, K. Hales, K. L. Wooley and
D. J. Pochan, Langmuir, 2007, 23, 4689–4694.
35 Q. G. Ma, E. E. Remsen, C. G. Clark, T. Kowalewski and
K. L. Wooley, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 5058–
5063.
36 A. Walther, M. Drechsler, S. Rosenfeldt, L. Harnau,
M. Ballauff, V. Abetz and A. H. E. Muller, J. Am. Chem.
Soc., 2009, 131, 4720–4728.
37 G. J. Liu, Adv. Polym. Sci., 2008, 220, 29–64.
38 L. Zhang and A. Eisenberg, Science, 1995, 268, 1728–1731.
39 L. F. Zhang, K. Yu and A. Eisenberg, Science, 1996, 272,
1777–1779.
40 Y. Mai and A. Eisenberg, Chem. Soc. Rev., 2012, 41, 5969–
5985.
41 J. H. Zhu, S. Y. Zhang, K. Zhang, X. J. Wang, J. W. Mays,
K. L. Wooley and D. J. Pochan, Nat. Commun., 2013, 4,
2297.
42 N. P. Truong, J. F. Quinn, M. V. Dussert, N. B. T. Sousa,
M. R. Whittaker and T. P. Davis, ACS Macro Lett., 2015, 4,
381–386.
43 J. T. Xu, L. Tao, C. Boyer, A. B. Lowe and T. P. Davis,
Macromolecules, 2011, 44, 299–312.
44 H. T. T. Duong, F. Hughes, S. Sagnella, M. Kavallaris,
A. Macmillan, R. Whan, J. Hook, T. P. Davis and C. Boyer,
Mol. Pharm., 2012, 9, 3046–3061.
45 G. J. Liu, L. J. Qiao and A. Guo, Macromolecules, 1996, 29,
5508–5510.
46 Y. Y. Won, H. T. Davis and F. S. Bates, Science, 1999, 283,
960–963.
47 M. Templin, A. Franck, A. DuChesne, H. Leist,
Y. M. Zhang, R. Ulrich, V. Schadler and U. Wiesner,
Science, 1997, 278, 1795–1798.
Polym. Chem.

Review
48 K. Ishizu, T. Ikemoto and A. Ichimura, Polymer, 1999, 40,
3147–3151.
49 Y. F. Liu, V. Abetz and A. H. E. Muller, Macromolecules,
2003, 36, 7894–7898.
50 J. P. Patterson, M. P. Robin, C. Chassenieux,
O. Colombani and R. K. O’Reilly, Chem. Soc. Rev., 2014,
43, 2412–2425.
51 W. N. He and J. T. Xu, Prog. Polym. Sci., 2012, 37, 1350–
1400.
52 J. Schmelz, F. H. Schacher and H. Schmalz, Soft Matter,
2013, 9, 2101–2107.
Published on 02 June 2016. Downloaded by Monash University on 09/06/2016 05:35:49.
53 L. Sun, A. Pitto-Barry, N. Kirby, T. L. Schiller,
A. M. Sanchez, M. A. Dyson, J. Sloan, N. R. Wilson,
R. K. O’Reilly and A. P. Dove, Nat. Commun., 2014, 5,
5746.
54 Z. X. Du, J. T. Xu and Z. Q. Fan, Macromolecules, 2007, 40,
7633–7637.
55 D. Portinha, F. Boue, L. Bouteiller, G. Carrot,
C. Chassenieux, S. Pensec and G. Reiter, Macromolecules,
2007, 40, 4037–4042.
56 J. T. Xu, J. P. A. Fairclough, S. M. Mai and A. J. Ryan,
J. Mater. Chem., 2003, 13, 2740–2748.
57 D. Richter, D. Schneiders, M. Monkenbusch, L. Willner,
L. J. Fetters, J. S. Huang, M. Lin, K. Mortensen and
B. Farago, Macromolecules, 1997, 30, 1053–1068.
58 H. Schmalz, J. Schmelz, M. Drechsler, J. Yuan, A. Walther,
K. Schweimer and A. M. Mihut, Macromolecules, 2008, 41,
3235–3242.
59 J. B. Gilroy, T. Gadt, G. R. Whittell, L. Chabanne,
J. M. Mitchels, R. M. Richardson, M. A. Winnik and
I. Manners, Nat. Chem., 2010, 2, 566–570.
60 J. Massey, K. N. Power, I. Manners and M. A. Winnik,
J. Am. Chem. Soc., 1998, 120, 9533–9540.
61 J. A. Massey, K. Temple, L. Cao, Y. Rharbi, J. Raez,
M. A. Winnik and I. Manners, J. Am. Chem. Soc., 2000,
122, 11577–11584.
62 X. Wang, G. Guerin, H. Wang, Y. Wang, I. Manners and
M. A. Winnik, Science, 2007, 317, 644–647.
63 L. Sun, N. Petzetakis, A. Pitto-Barry, T. L. Schiller,
N. Kirby, D. J. Keddie, B. J. Boyd, R. K. O’Reilly and
A. P. Dove, Macromolecules, 2013, 46, 9074–9082.
64 N. J. Warren and S. P. Armes, J. Am. Chem. Soc., 2014, 136,
10174–10185.
65 B. Charleux, G. Delaittre, J. Rieger and F. D’Agosto, Macro-
molecules, 2012, 45, 6753–6765.
66 S. L. Canning, G. N. Smith and S. P. Armes, Macro-
molecules, 2016, 49, 1985–2001.
67 K. Matyjaszewski and N. V. Tsarevsky, Nat. Chem., 2009, 1,
276–288.
68 G. Moad, E. Rizzardo and S. H. Thang, Aust. J. Chem.,
2012, 65, 985–1076.
69 C. J. Hawker, A. W. Bosman and E. Harth, Chem. Rev.,
2001, 101, 3661–3688.
70 C. Waldron, A. Anastasaki, R. McHale, P. Wilson, Z. D. Li,
T. Smith and D. M. Haddleton, Polym. Chem., 2014, 5,
892–898.
Polym. Chem.
View Article Online
Polymer Chemistry
71 Y. Kitayama, H. Moribe, K. Kishida and M. Okubo, Polym.
Chem., 2012, 3, 1555–1559.
72 N. P. Truong, M. V. Dussert, M. R. Whittaker, J. F. Quinn
and T. P. Davis, Polym. Chem., 2015, 6, 3865–3874.
73 J. Rieger, Macromol. Rapid Commun., 2015, 36, 1458–
1471.
74 M. Semsarilar and S. Perrier, Nat. Chem., 2010, 2, 811–
820.
75 N. T. D. Tran, Z. F. Jia, N. P. Truong, M. A. Cooper and
M. J. Monteiro, Biomacromolecules, 2013, 14, 3463–3471.
76 X. W. Zhang, J. Rieger and B. Charleux, Polym. Chem.,
2012, 3, 1502–1509.
77 D. Zehm, L. P. D. Ratcliffe and S. P. Armes, Macro-
molecules, 2013, 46, 128–139.
78 J. R. Lovett, N. J. Warren, L. P. D. Ratcliffe, M. K. Kocik
and S. P. Armes, Angew. Chem., Int. Ed., 2015, 54, 1279–
1283.
79 S. Boisse, J. Rieger, K. Belal, A. Di-Cicco, P. Beaunier,
M. H. Li and B. Charleux, Chem. Commun., 2010, 46,
1950–1952.
80 S. Boisse, J. Rieger, G. Pembouong, P. Beaunier and
B. Charleux, J. Polym. Sci., Part A: Polym. Chem., 2011, 49,
3346–3354.
81 A. Blanazs, A. J. Ryan and S. P. Armes, Macromolecules,
2012, 45, 5099–5107.
82 W. M. Wan, C. Y. Hong and C. Y. Pan, Chem. Commun.,
2009, 5883–5885.
83 C. Q. Huang and C. Y. Pan, Polymer, 2010, 51, 5115–5121.
84 W. M. Cai, W. M. Wan, C. Y. Hong, C. Q. Huang and
C. Y. Pan, Soft Matter, 2010, 6, 5554–5561.
85 W. D. He, X. L. Sun, W. M. Wan and C. Y. Pan, Macro-
molecules, 2011, 44, 3358–3365.
86 Y. W. Pei and A. B. Lowe, Polym. Chem., 2014, 5, 2342–
2351.
87 E. R. Jones, M. Semsarilar, A. Blanazs and S. P. Armes,
Macromolecules, 2012, 45, 5091–5098.
88 Y. Pei, L. Thurairajah, O. R. Sugita and A. B. Lowe, Macro-
molecules, 2015, 48, 236–244.
89 M. Semsarilar, E. R. Jones, A. Blanazs and S. P. Armes,
Adv. Mater., 2012, 24, 3378–3382.
90 K. Bauri, A. Narayanan, U. Haldar and P. De, Polym.
Chem., 2015, 6, 6152–6162.
91 M. Semsarilar, V. Ladmiral, A. Blanazs and S. P. Armes,
Polym. Chem., 2014, 5, 3466–3475.
92 L. A. Fielding, M. J. Derry, V. Ladmiral, J. Rosselgong,
A. M. Rodrigues, L. P. D. Ratcliffe, S. Sugihara and
S. P. Armes, Chem. Sci., 2013, 4, 2081–2087.
93 Y. W. Pei, J. M. Noy, P. J. Roth and A. B. Lowe, Polym.
Chem., 2015, 6, 1928–1931.
94 E. T. Garrett, Y. Pei and A. B. Lowe, Polym. Chem., 2016, 7,
297–301.
95 J. Yeow, J. T. Xu and C. Boyer, ACS Macro Lett., 2015, 4,
984–990.
96 X. W. Zhang, S. Boisse, W. J. Zhang, P. Beaunier,
F. D’Agosto, J. Rieger and B. Charleux, Macromolecules,
2011, 44, 4149–4158.
This journal is © The Royal Society of Chemistry 2016

Polymer Chemistry
97 I. Chaduc, A. Crepet, O. Boyron, B. Charleux, F. D’Agosto
and M. Lansalot, Macromolecules, 2013, 46, 6013–6023.
98 W. J. Zhang, F. D’Agosto, O. Boyron, J. Rieger and
B. Charleux, Macromolecules, 2012, 45, 4075–4084.
99 A. Blanazs, J. Madsen, G. Battaglia, A. J. Ryan and
S. P. Armes, J. Am. Chem. Soc., 2011, 133, 16581–16587.
100 S. Sugihara, A. Blanazs, S. P. Armes, A. J. Ryan and
A. L. Lewis, J. Am. Chem. Soc., 2011, 133, 15707–15713.
101 V. Ladmiral, M. Semsarilar, I. Canton and S. P. Armes,
J. Am. Chem. Soc., 2013, 135, 13574–13581.
102 N. J. Warren, O. O. Mykhaylyk, D. Mahmood, A. J. Ryan
Published on 02 June 2016. Downloaded by Monash University on 09/06/2016 05:35:49.
and S. P. Armes, J. Am. Chem. Soc., 2014, 136, 1023–1033.
103 M. K. Kocik, O. O. Mykhaylyk and S. P. Armes, Soft Matter,
2014, 10, 3984–3992.
104 A. Blanazs, R. Verber, O. O. Mykhaylyk, A. J. Ryan,
J. Z. Heath, C. W. I. Douglas and S. P. Armes, J. Am. Chem.
Soc., 2012, 134, 9741–9748.
105 L. A. Fielding, J. A. Lane, M. J. Derry, O. O. Mykhaylyk and
S. P. Armes, J. Am. Chem. Soc., 2014, 136, 5790–5798.
106 V. J. Cunningham, L. P. D. Ratcliffe, A. Blanazs,
N. J. Warren, A. J. Smith, O. O. Mykhaylyk and
S. P. Armes, Polym. Chem., 2014, 5, 6307–6317.
107 C. A. Figg, A. Simula, K. A. Gebre, B. S. Tucker,
D. M. Haddleton and B. S. Sumerlin, Chem. Sci., 2015, 6,
1230–1236.
108 E. B. Zhulina, M. Adam, I. LaRue, S. S. Sheiko and
M. Rubinstein, Macromolecules, 2005, 38, 5330–5351.
109 I. LaRue, M. Adam, M. Pitsikalis, N. Hadjichristidis,
M. Rubinstein and S. S. Sheiko, Macromolecules, 2006, 39,
309–314.
110 P. Bhargava, Y. F. Tu, J. X. Zheng, H. M. Xiong, R. P. Quirk
and S. Z. D. Cheng, J. Am. Chem. Soc., 2007, 129, 1113–
1121.
111 S. R. Raghavan and J. F. Douglas, Soft Matter, 2012, 8,
8539–8546.
112 N. P. Truong, J. F. Quinn, A. Anastasaki, D. M. Haddleton,
M. R. Whittaker and T. P. Davis, Chem. Commun., 2016,
52, 4497–4500.
113 E. R. Jones, M. Semsarilar, P. Wyman, M. Boerakker and
S. P. Armes, Polym. Chem., 2016, 7, 851–859.
114 Z. F. Jia, V. A. Bobrin, N. P. Truong, M. Gillard and
M. J. Monteiro, J. Am. Chem. Soc., 2014, 136, 5824–
5827.
115 H. Wang, A. J. Patil, K. Liu, S. Petrov, S. Mann,
M. A. Winnik and I. Manners, Adv. Mater., 2009, 21, 1805–
1808.
116 M. Zhang, M. F. Wang, S. He, J. S. Qian, A. Saffari, A. Lee,
S. Kumar, Y. Hassan, A. Guenther, G. Scholes and
M. A. Winnik, Macromolecules, 2010, 43, 5066–5074.
117 R. Bleach, B. Karagoz, S. M. Prakash, T. P. Davis and
C. Boyer, ACS Macro Lett., 2014, 3, 591–596.
118 X. H. Yan, G. J. Liu and Z. Li, J. Am. Chem. Soc., 2004, 126,
10059–10066.
119 O. E. C. Gould, H. B. Qiu, D. J. Lunn, J. Rowden,
R. L. Harniman, Z. M. Hudson, M. A. Winnik, M. J. Miles
and I. Manners, Nat. Commun., 2015, 6, 10009.
This journal is © The Royal Society of Chemistry 2016
View Article Online
Review
120 S. Kumar, A. C. Anselmo, A. Banerjee, M. Zakrewsky and
S. Mitragotri, J. Controlled Release, 2015, 220, 141–148.
121 D. E. Mitchell, J. R. Lovett, S. P. Armes and M. I. Gibson,
Angew. Chem., Int. Ed., 2016, 55, 2801–2804.
122 N. S. Oltra, P. Nair and D. E. Discher, Annu. Rev. Chem.
Biomol., 2014, 5, 281–299.
123 N. S. Oltra, J. Swift, A. Mahmud, K. Rajagopal,
S. M. Loverde and D. E. Discher, J. Mater. Chem. B, 2013,
1, 5177–5185.
124 N. P. Truong, M. R. Whittaker, C. W. Mak and T. P. Davis,
Expert Opin. Drug Delivery, 2015, 12, 129–142.
125 S. Venkataraman, J. L. Hedrick, Z. Y. Ong, C. Yang,
P. L. R. Ee, P. T. Hammond and Y. Y. Yang, Adv. Drug
Delivery Rev., 2011, 63, 1228–1246.
126 J. A. Champion, Y. K. Katare and S. Mitragotri, J. Con-
trolled Release, 2007, 121, 3–9.
127 N. P. Truong, W. Y. Gu, I. Prasadam, Z. F. Jia, R. Crawford,
Y. Xiao and M. J. Monteiro, Nat. Commun., 2013, 4,
1902.
128 P. Dalhaimer, H. Bermudez and D. E. Discher, J. Polym.
Sci., Part B: Polym. Phys., 2004, 42, 168–176.
129 B. Karagoz, L. Esser, H. T. Duong, J. S. Basuki, C. Boyer
and T. P. Davis, Polym. Chem., 2014, 5, 350–355.
130 S. S. Cai, K. Vijayan, D. Cheng, E. M. Lima and
D. E. Discher, Pharm. Res., 2007, 24, 2099–2109.
131 H. J. Yu, Z. A. Xu, D. G. Wang, X. Z. Chen, Z. W. Zhang,
Q. Yin and Y. P. Li, Polym. Chem., 2013, 4, 5052–5055.
132 B. Karagoz, C. Boyer and T. P. Davis, Macromol. Rapid
Commun., 2014, 35, 417–421.
133 M. Elsabahy, R. Shrestha, C. Clark, S. Taylor, J. Leonard
and K. L. Wooley, Nano Lett., 2013, 13, 2172–2181.
134 S. Barua and S. Mitragotri, ACS Nano, 2013, 7, 9558–9570.
135 S. E. Lee, S. F. Bairstow, J. O. Werling, M. V. Chaubal,
L. Lin, M. A. Murphy, J. P. DiOrio, J. Gass, B. Rabinow,
X. E. Wang, Y. Zhang, Z. J. Yang and R. M. Hoffman,
Pharm. Dev. Technol., 2014, 19, 438–453.
136 D. Vllasaliu, R. Fowler and S. Stolnik, Expert Opin. Drug
Delivery, 2014, 11, 139–154.
137 I. C. Macdonald, E. E. Schmidt and A. C. Groom, Micro-
vasc. Res., 1991, 42, 60–76.
138 P. Dalhaimer, F. S. Bates and D. E. Discher, Macro-
molecules, 2003, 36, 6873–6877.
139 J. A. Champion and S. Mitragotri, Pharm. Res., 2009, 26,
244–249.
140 G. Sharma, D. T. Valenta, Y. Altman, S. Harvey, H. Xie,
S. Mitragotri and J. W. Smith, J. Controlled Release, 2010,
147, 408–412.
141 M. A. Bruckman, L. N. Randolph, A. VanMeter, S. Hern,
A. J. Shoffstall, R. E. Taurog and N. F. Steinmetz, Virology,
2014, 449, 163–173.
142 Arnida, M. M. Janat-Amsbury, A. Ray, C. M. Peterson and
H. Ghandehari, Eur. J. Pharm. Biopharm., 2011, 77, 417–
423.
143 Z. X. Zhou, X. P. Ma, E. L. Jin, J. B. Tang, M. H. Sui,
Y. Q. Shen, E. A. Van Kirk, W. J. Murdoch and M. Radosz,
Biomaterials, 2013, 34, 5722–5735.
Polym. Chem.

Review
144 Y. J. Wang, D. Wang, Q. Fu, D. Liu, Y. Ma, K. Racette,
Z. G. He and F. Liu, Mol. Pharm., 2014, 11, 3766–
3771.
145 D. A. Christian, S. Cai, O. B. Garbuzenko, T. Harada,
L. Allison, T. Minko and D. E. Discher, Mol. Pharm., 2009,
6, 1343–1352.
146 K. S. Chu, W. Hasan, S. Rawal, M. D. Walsh, E. M. Enlow,
J. C. Luft, A. S. Bridges, J. L. Kuijer, M. E. Napier,
W. C. Zamboni and J. M. DeSimone, Nanomed. Nanotech-
nol., 2013, 9, 686–693.
147 Z. Liu, W. Cai, L. He, N. Nakayama, K. Chen,
Published on 02 June 2016. Downloaded by Monash University on 09/06/2016 05:35:49.
X. Sun, X. Chen and H. Dai, Nat. Nanotechnol., 2007, 2,
47–52.
148 K. C. L. Black, Y. C. Wang, H. P. Luehmann, X. Cai,
W. X. Xing, B. Pang, Y. F. Zhao, C. S. Cutler,
L. H. V. Wang, Y. J. Liu and Y. N. Xia, ACS Nano, 2014, 8,
4385–4394.
149 Y. Kim, P. Dalhaimer, D. A. Christian and D. E. Discher,
Nanotechnology, 2005, 16, S484–S491.
150 K. L. Lee, L. C. Hubbard, S. Hern, I. Yildiz, M. Gratzl and
N. F. Steinmetz, Biomater. Sci., 2013, 1, 581–588.
Polym. Chem.
View publication stats
View Article Online
Polymer Chemistry
151 V. P. Chauhan, Z. Popović, O. Chen, J. Cui, D. Fukumura,
M. G. Bawendi and R. K. Jain, Angew. Chem., Int. Ed.,
2011, 123, 11619–11622.
152 A. Pluen, P. A. Netti, R. K. Jain and D. A. Berk, Biophys. J.,
1999, 77, 542–552.
153 M. Howard, B. J. Zern, A. C. Anselmo, V. V. Shuvaev,
S. Mitragotri and V. Muzykantov, ACS Nano, 2014, 8, 4100–
4132.
154 J. D. Pillai, S. S. Dunn, M. E. Napier and J. M. DeSimone,
IUBMB Life, 2011, 63, 596–606.
155 P. Dalhaimer, A. J. Engler, R. Parthasarathy and
D. E. Discher, Biomacromolecules, 2004, 5, 1714–1719.
156 V. V. Shuvaev, M. A. Ilies, E. Simone, S. Zaitsev, Y. Kim,
S. S. Cai, A. Mahmud, T. Dziubla, S. Muro, D. E. Discher
and V. R. Muzykantov, ACS Nano, 2011, 5, 6991–6999.
157 P. Kolhar, A. C. Anselmo, V. Gupta, K. Pant,
B. Prabhakarpandian, E. Ruoslahti and S. Mitragotri, Proc.
Natl. Acad. Sci. U. S. A., 2013, 110, 10753–10758.
158 S. Muro, C. Garnacho, J. A. Champion, J. Leferovich,
C. Gajewski, E. H. Schuchman, S. Mitragotri and
V. R. Muzykantov, Mol. Ther., 2008, 16, 1450–1458.
This journal is © The Royal Society of Chemistry 2016