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Nanostructured polymer assemblies formed at interfaces: applications fromimmobilization and encapsulation to stimuli-responsive release

Wang, Yajun; Rigau, Leticia Hosta; Lomas, Hannah; Caruso, Frank

Published in:Physical Chemistry Chemical Physics

Link to article, DOI:10.1039/c0cp02287j

Publication date:2011

Document VersionPublisher's PDF, also known as Version of record

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Citation (APA):Wang, Y., Rigau, L. H., Lomas, H., & Caruso, F. (2011). Nanostructured polymer assemblies formed atinterfaces: applications from immobilization and encapsulation to stimuli-responsive release. Physical ChemistryChemical Physics, 13(11), 4782-4801. https://doi.org/10.1039/c0cp02287j

https://doi.org/10.1039/c0cp02287j

https://orbit.dtu.dk/en/publications/c49fea04-7d0c-4fae-9242-ad6446d5961d

https://doi.org/10.1039/c0cp02287j

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Physical Chemistry Chemical Physics

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www.rsc.org/pccp Volume 13 | Number 11 | 21 March 2011 | Pages 4761–5188

Includes articles on the theme of materials innovation through interfacial physics and chemistry

1463-9076(2011)13:11;1-1

COVER ARTICLECaruso et al.Nanostructured polymer assemblies formed at interfaces: applications from immobilization and encapsulation to stimuli-responsive release

HOT ARTICLEVollhardt et al.Nanoaggregate shapes at the air/water interface

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Showcasing work on pyrazinacene nanotube

self-assembly from the Ariga group at WPI Center

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Title: Self-assembled pyrazinacene nanotubes

Hierarchical self-assembly of nitrogen-containing pentacene

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to high aspect ratio multiwalled pyrazinacene nanotubes with large

internal tubular cavities suitable for guest material encapsulation.

As featured in:

See Hill et al.,

Phys. Chem. Chem. Phys., 2011, 13, 4868.

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4782 Phys. Chem. Chem. Phys., 2011, 13, 4782–4801 This journal is c the Owner Societies 2011

Cite this: Phys. Chem. Chem. Phys., 2011, 13, 4782–4801

Nanostructured polymer assemblies formed at interfaces: applications

from immobilization and encapsulation to stimuli-responsive release

Yajun Wang, Leticia Hosta-Rigau, Hannah Lomas and Frank Caruso*

Received 27th October 2010, Accepted 11th January 2011

DOI: 10.1039/c0cp02287j

In recent years, interfacial properties have been tailored with nanostructured polymer assemblies

to generate materials with specific properties and functions for application in diverse fields,

including biomaterials, drug delivery, catalysis, sensing, optics and corrosion. This perspective

begins with a brief introduction of the assembly techniques that are commonly employed for

the synthesis of nanostructured polymer materials, followed by discussions on how the interfaces

influence the properties and thus the functionalities of the polymer materials prepared.

Applications of the interfacial polymer nanostructures, particularly for the immobilization and

encapsulation of cargo, are then reviewed, focusing on stimuli-responsive cargo release from the

polymer nanostructured assemblies for controlled delivery applications. Finally, future research

directions in these areas are briefly discussed.

1.0. Introduction

Controlling interfacial properties with polymers at the nano-

scale offers exciting possibilities for the preparation of advanced

materials with specific and tailored functions that could find

applications in fields as diverse as optics, biomaterials and

corrosion.

This perspective begins with a brief description of the

different techniques that can be used for the preparation of

nanostructured polymer materials (in section 2). Two distinct

categories of precursors, small molecules and macromolecules,

are widely used in the preparation of such materials. Examples

of techniques used to form nanostructured polymer materials

at interfaces from small molecules will be detailed; these

include surface-initiated polymerization, chemical vapor

deposition and interfacial self-polymerization. The assembly

of macromolecules using various driving forces has also been

widely examined and applied: self-assembly is one of the key

driving forces, which may be the result of hydrophobic inter-

actions. Electrostatic, covalent (including ‘click’ reactions),

and hydrogen bonding interactions also play important roles

in the assembly of a variety of polymer materials.

Department of Chemical and Biomolecular Engineering,The University of Melbourne, Parkville, Victoria 3010, Australia.E-mail: [email protected]

Yajun Wang

Dr Yajun Wang received hisBS (1996) and MS (1999)in Chemistry from NankaiUniversity. He obtained hisPhD in 2002 from FudanUniversity, China. Since then,he has been working as aresearch fellow in the Nano-structured Interfaces andMaterials Group in theDepartment of Chemical andBiomolecular Engineering atThe University of Melbourne.His main research interestsinclude the synthesis of nano-porous materials, the bio-orientated applications ofporous materials, and polymerself-assembly.

Leticia Hosta-Rigau

DrLeticiaHosta-Rigau receivedher PhD in Chemistry fromthe University of Barcelona(Spain) in 2009 under thesupervision of Prof. FernandoAlbericio. Her research wasfocused on the synthesis ofpeptides with antitumorproperties by Solid PhasePeptide Synthesis (SPPS).She is currently working as apostdoctoral researcher at theDepartment of Chemical andBiomolecular Engineering atThe University of Melbourne.Her main interest is the

development of capsosomes (polymer carrier capsules containingliposomal subcompartments) as a functional biomedical platformand as mimics for cells.

PCCP Dynamic Article Links

www.rsc.org/pccp PERSPECTIVE

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This journal is c the Owner Societies 2011 Phys. Chem. Chem. Phys., 2011, 13, 4782–4801 4783

Compared with bulk polymer materials, the nature of the

interfaces applied in polymer assembly can often add new

levels of control over the functionality of the obtained polymer

materials. In section 3, we illustrate how the interfaces

influence the properties and thus the functionalities of the

polymer assemblies. Both flexible (deformable) (e.g. emulsion

droplets, liquid crystals, liposomes, and gas bubbles) and rigid

(non-deformable) (e.g. planar, solid particulate, and spatially-

confined substrate) interfaces can be created that have different

functions, such as wettability and protein interactions.

Applications of the interfacial polymer nanostructures,

particularly for the immobilization and encapsulation of

distinct cargo, will then be discussed in section 4. Focus will

be placed on stimuli-responsive cargo release, which may be

triggered by a change in the environmental conditions

(e.g. change in temperature, pH or ionic strength), by chemical

and enzyme stimuli, or be remotely controlled (e.g. application

of light or magnetic field). Different carriers for cargo

encapsulation, including capsosomes, liposomes, polymersomes,

and dendrimersomes, are described.

2.0. Techniques for the formation of interfacial

polymer films

In recent years, various techniques have been developed to

prepare nanostructured polymer assemblies at interfaces

with finely controlled properties. In this perspective, a brief

introduction will be provided on some of the important

techniques used.

2.1 Polymerization techniques

Surface-initiated (free-radical) polymerization (SIP) is an

emerging technique for the generation of polyelectrolyte shells

on particles.1,2 The process allows the formation of poly-

electrolyte films in various organic solvents, which simplifies

the inclusion of monomers with a variety of functional groups

and cross-linking agents. Imroz Ali and Mayes have used this

technique to generate thin polymer films on the surfaces of

sub-100 nm-sized polymer cores.1 Polymer layers with a wide

range of characteristics can be grafted onto the particle cores

via SIP, demonstrating the versatility of this technique. SIP

has also been exploited by Zhao and coworkers as a single-step

method for the preparation of dual hydrophilic-hydrophobic

Janus silica particles.2 A polar poly(sodium methacrylate)

brush was deposited on one side of each particle, whilst non-

polar polystyrene (PS) was deposited on the opposite surface

of each particle. This was achieved by placing silica particles

functionalized with a free-radical initiator in a styrene-water

solvent combination. The silica particles spontaneously

positioned themselves at the interface between the two com-

ponents of the solvent mixture, and SIP polymerization of the

two polymers commenced upon raising the temperature.

Chemical vapor deposition (CVD) involves the polymeriza-

tion of monomers that are deposited from the vapor phase

onto a particular surface, resulting in the generation of highly

conformal polymer films in a one-step process.3 This is in

contrast to conventional polymerization, where monomer

linkage takes place in the presence of a solvent, and film

formation occurs in an additional step which may involve

‘‘spin-casting, dip-coating, or spray-and-bake’’ methods.3

Since CVD polymer thin films can be generated in a solvent-

free method, the technique avoids potential biocompatibility

issues and the use of organic solvents that are harmful to the

environment. In addition to the ability to create conformal

films on a particular surface, this solvent-free method allows

preservation of monomer functional domains, which facilitates

facile functionalization with moieties that are biologically

responsive and/or responsive to a particular stimulus, whilst

retaining the surface characteristics, including ‘‘wettability and

adhesion’’.3 Furthermore, organic CVD polymerization can

be performed on a large and cost-effective scale using roll-

to-roll processing4 and can be applied to flexible substrates.5

Highly pure polymer films can be produced without the need

for additives that are usually required to create a conformal

film using spin-casting techniques. This is essential if the

CVD-obtained film is to be used as bioimplants or in applications

Hannah Lomas

Dr Hannah Lomas completedher M.Chem. in Chemistrywith Study in Europe at theUniversity of Sheffield, UK in2005. She received her PhD inthe research group of DrGiuseppe Battaglia at theUniversity of Sheffield in 2009,focusing on the self-assemblyof pH-sensitive polymersomesfor the encapsulation anddelivery of nucleic acids. Shebegan her postdoctoralposition in the research groupof Prof. Frank Caruso at TheUniversity of Melbourne,

Australia, in 2009. Her current research interests include thepreparation of polyelectrolyte layer-by-layer capsules for thedelivery of therapeutic agents.

Frank Caruso

Professor Frank Caruso headsthe Nanostructured Interfaces& Materials (NIMS) Groupin the Department of Chemicaland Biomolecular Engineeringat The University ofMelbourne,and is an Australian ResearchCouncil Federation Fellow. Hereceived his PhD degree in1994 from The University ofMelbourne, and then moved tothe CSIRO Division ofChemicals and Polymers inMelbourne. He was anAlexander von HumboldtResearch Fellow and then

group leader at the Max Planck Institute of Colloids andInterfaces (Berlin, Germany) from 1997–2002. His researchfocuses on polymers at interfaces, colloidal systems, biomaterialsand nanocomposite thin films.

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such as ‘‘electrical conductivity’’.3 Furthermore, the grafting

of the film to the solid substrate can be carried out in situ.3

Examples of the application of CVD include the creation of air

channels in microfluidic devices for gas or liquid flow, which

can be achieved through the incorporation of polymers

that can be etched, e.g. by thermal means.6 Other potential

applications include drug delivery, diagnostics, scaffolds for

tissue engineering, and industrial applications such as water

and gas purification.3

Another interesting technique to assemble polymer thin films

with small molecules is via the interfacial self-polymerization

of melanin.7 A family of melanin film materials has been

reported through the oxidation polymerization of monomers

(e.g. dopamine,8 tyrosine, 5-S-cysteinyldopa) onto various

surfaces (e.g. electrodes, polyelectrolyte multilayers, carbon

nanotubes) using a single dip-coating procedure that allows

control over the film thickness via immersion time.7 It has been

reported that poly(dopamine) (PDA) thin films can also

be formed on colloids via the oxidative polymerization of

dopamine onto sacrificial silica particles9 or oil droplets,10

and that robust single component PDA capsules are obtained

upon removal of the particle template.9,10 Biocompatibility

tests further demonstrated negligible toxicity of PDA capsules

to cells, making them an attractive platform for drug delivery.9

2.2 Self-assembly techniques

Self-assembly is an important driving force in the formation

of a variety of highly ordered structures for polymeric macro-

molecules that are useful for different applications. The

most commonly used interactions include electrostatic and

hydrogen bonding, and amphiphilic forces.

The alternate deposition of oppositely charged polymers to

create a film of multiple layers (Fig. 1) was first described by

Decher et al. in 199111 and since then it has been used in the

preparation of functional and highly tailored thin films. This

technique was termed layer-by-layer (LbL) and its applica-

tion was extended in 1998 for the formation of polymeric

capsules by the use of sub-micrometre and micrometre-sized

charged particle templates.12,13 Electrostatic binding remains

the main approach used in the multilayer formation. To date,

a variety of polyelectrolytes and charged species have been

electrostatically adsorbed sequentially onto a charged template

(either onto a flat surface or a particle). The most commonly

investigated and commercially available polyelectrolytes for

electrostatic assembly include, but are not limited to, poly-

(ethyleneimine) (PEI), poly(allylamine hydrochloride) (PAH),

poly(diallyldimethylammonium chloride) (PDADMAC), poly-

(sodium-4-styrenesulfonate) (PSS), poly(acrylic acid) (PAA),

and poly(methacrylic acid) (PMA). In addition, natural poly-

electrolytes, such as nucleic acids, proteins and polypeptides,

polysaccharides and viruses, have also been used for electrostatic

assembly.14

Other types of interactions, including hydrogen and covalent

bonding, have also emerged as driving forces in LbL assembly.15,16

The fact that, in addition to electrostatics, different driving

forces for multilayer assembly can be exploited is of paramount

importance since it enables the use of uncharged materials,

avoiding the use of potentially toxic polycations. Moreover,

uncharged polymers which previously were not able to be

assembled via the LbL technique can now be incorporated into

films. LbL assembly driven by hydrogen bonding interaction

was discovered about a decade ago, and can occur when one of

the polymers in a polymer pair acts as a hydrogen-bond

acceptor, while the other acts as a hydrogen-bond donor.

Although this assembly can be performed in both organic

and aqueous solvents, the use of aqueous solutions is of

relevance for biomedical applications. The first demonstrations

in aqueous solution of LbL polymer processing driven by

hydrogen bonding interactions were reported by Zhang et al.15

and Rubner et al.16 in 1997. Zhang and coworkers formed a

multilayer film via the alternate deposition of poly(4-vinyl-

pyridine) and PAA,15 whilst Rubner and colleagues assembled

polyaniline (PAn) with poly(vinyl pyrrolidone) (PVPON),

poly(vinyl alcohol) (PVA), poly(acrylamide) (PAAM) and

poly(ethylene oxide) (PEO).16 Each of these polymers contains

functional groups that are capable of forming hydrogen bonds

with PAn. Since the hydrogen bonds are created at low pH

where the hydrogen donor polymer is protonated, the hydrogen-

bonded multilayers disassemble at higher pH (i.e. physiological

conditions).17 Therefore, in order to use such films for biome-

dical applications, there is a need to stabilize the

multilayers. Stabilization can be achieved by introducing

chemical cross-links which prevent dissolution of the multi-

layers under pH conditions that ionize the functional groups

of the weak polyelectrolyte.18,19

LbL assembly can also be used for the formation of covalent

bonds between polymers using sequential chemical reactions.

The advantage of using covalent bonding is that the obtained

multilayers possess high stability because of the formation of a

cross-linked network structure, and are therefore less prone

to disassemble. Reviewing the covalent multilayer designs

mentioned in the literature is beyond the scope of this work;

we therefore highlight several pertinent examples. The formation

of covalent bonds within different films has been performed

either by heat20–23 or photochemical treatment after polymer

assembly.24 Stabilization of the polymer assemblies via metal

coordination,25–27 as well as chemical cross-linking with

carbodiimide,28,29 glutaraldehyde chemistry,23,30,31 or click

chemistry,32,33 have also been reported. More information

about the LbL technique and LbL materials can be found in

a number of recent review articles.34–40

Van Tassel and co-workers reported an electric potential

mediated adsorption approach to continuously assemble

polymer films.41,42 Under an applied anodic potential, certain

amine side chain containing polycations were able to adsorb

onto indium tin oxide substrates in a continuous asymptotically

linear fashion. X-ray photoelectron spectra indicate a

suppressed polymer charge within the continuously deposited

polymer layers, but no electrochemical reactions were

evidenced. This approach provides a single-step film formation

process and good control over the film thickness, although it is

limited by the necessity for a conductive substrate. Also using

an electrochemical approach, Rydzek et al. reported the

construction of multilayered ‘‘click’’ films on gold electrodes

by the application of a mild potential, which can reduce Cu(II)

to Cu(I) in the absence of a reducing agent or ligand.43

Electrochemical tuning of the stability of PLL/DNA films

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was studied under different potentials on indium tin oxide

(ITO) electrodes.44

Amphiphilic macromolecules, i.e. those that contain a

hydrophilic part that is chemically attached to a hydrophobic

part, are one example of a species that displays self-assembling

properties. Amphiphiles can minimize the interfacial energy in

a mixture of two immiscible solvents, for example oil and

water, by forming a monolayer between the two solvents,

thereby producing microemulsions.45 They can also self-

assemble into an array of highly organized structures in the

presence of a solvent that is selective for just one part of the

molecule; this is as a consequence of the net system attempting

to decrease the total entropy upon addition of a foreign

molecule (for example, the addition of an amphiphile into

water) in a process known as the ‘hydrophobic effect’.45

Block copolymers are a typical class of amphiphilic macro-

molecules; they can self-assemble into nanometre-sized

particles (such as micelles and vesicles) in dilute solution.

The driving forces behind the generation of these structures

are (i) the immiscibility of the hydrophobic polymer block

with the solvent, and (ii) the immiscibility of the hydrophilic

and hydrophobic blocks of the copolymer.46 The rise in the net

free energy of the system as a result of forcing the copolymer

chains into a more ordered structure (i.e. reducing the

copolymer entropy) is offset by the reduction in the net free

energy as a result of lowering the interfacial energy between

the solvent and the immiscible polymer block. The exact

nature of the morphology that is generated depends on factors

such as the block copolymer packing parameter, which

takes the relative molecular weights of the hydrophilic and

hydrophobic blocks into consideration, as well as geometric

factors.47–50

Self-assembled hydrogels have also been prepared from

block copolymers using a system where it is not necessary to

cross-link the block copolymer chains in order to obtain a

stable, functional nanostructured material.51–55 Swann et al.

have recently prepared poly(methyl methacrylate)-block-

poly(2-(diethylamino)ethyl methacrylate)-block-poly(methyl

methacrylate) (PMMA-PDEA-PMMA) triblock copolymer

hydrogels.56 The individual block copolymer chains respond

to changes in pH by undergoing a coil to globular

transformation which is observed on a macroscopic scale via

a volume change of the hydrogel that the block copolymer

chains comprise. The magnitude of the response depends on

the nature of the Hofmeister anions present in solution, i.e. the

size and viscosity coefficient of the anion, and also the

‘chaotropic’ character of the ion, that is, its propensity to alter

the local structural network of water.

Macromolecules of homopolymers, block copolymers

and mixed copolymers can be grafted onto planar thin film

surfaces.57 If the density of grafted chains exceeds a certain

threshold, the chains are in their stretched form as a result of

‘‘excluded volume repulsions’’, thereby creating polymer

‘brushes’. If the polymer is responsive to a particular stimulus,

the brush conformation can be altered, for example poly-

(N-isopropylacrylamide) (PNIPAAM) undergoes a phase

transition at its lower critical solution temperature (LCST)

and alters its morphology from a random coil to a globular

conformation when the temperature is raised above its LCST.

Certain polymer materials can also respond reversibly to

modifications to the ionic strength and/or pH of the surrounding

media. In the case of block copolymers and mixed copolymer

brushes, the conjugation of various polymer blocks can be

used to tune brush characteristics.

3.0 Interfaces applied in polymer assembly

Polymer assemblies self-organize at interfaces due to balanced

interactions between the substrate and polymer (or its

precursor) in certain media. In addition to the assembly

technique, the nature of the interfaces also plays a crucial role

in such self-assembly. The substrate may exist in a permanent

form, which can provide extra mechanical stability to the

polymer structures assembled at the interface (Fig. 2). Alter-

natively, the substrate can be removed after providing an

interface (scaffold) for polymer assembly; hence flexible,

soft materials are obtained. This is often termed ‘‘template

synthesis’’.36 The interfaces may be divided into two

categories: rigid interfaces (e.g. solid/liquid interface, solid/gas

interface) and flexible interfaces (e.g. liquid/liquid interface,

liquid/gas interface) based on the different mechanical properties

of the substrate materials.

3.1 Rigid interfaces

Rigid interfaces, provided by solid substrates, generally have

good mechanical stability, and these interfaces can exist in a

broad range of geometries and morphologies (e.g. planar

substrates, porous membranes, rods, fibers, tubes, particles,

and porous particles). These properties make rigid interfaces

widely used in fundamental research and applications.

3.1.1 Planar interfaces. In basic polymer assembly, planar

substrates, such as quartz, silicon wafers, mica, and gold

surfaces are the materials used most frequently. In this section

we discuss some of the emerging areas of polymer assemblies

formed on planar substrates, including tailoring surface

properties, biomedical implant modification, nanopatterned

films, nanoporous films, high-flux membranes and template

synthesis.

Fig. 1 Layer-by-layer (LbL) assembly of polyelectrolytes on planar

substrates. A substrate with inherent charge is first exposed to an

oppositely charged polyelectrolyte solution, followed by thorough

rinsing. Reversal of the surface charge then facilitates further polymer

adsorption. The process is continued until the desired number of

polymer layers is achieved. (Reprinted from J. F. Quinn et al., Chem.

Soc. Rev., 2007, 36, 707).39

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Tailoring the surface properties, such as wettability and

adsorption behavior, of ultrathin polymer films is important

for a wide variety of applications, including immobilization,

anti-fouling,58 anti-microbial activity,59 anti-reflection,60 fuel

cells, and sensing.61 McCarthy and coworkers reported that

the wettability of PAH and PSS multilayer films is controlled

almost entirely by the outermost polyelectrolyte (PE) layer.62

Rubner et al. demonstrated that the wettability of weak PE

multilayers comprising of PAA and PAH could be varied

dramatically by controlling the pH of the dipping solutions.63

The same group constructed stable superhydrophobic coatings

based on PAH/PAAmultilayers coated with silica nanoparticles

and a semifluorinated silane.64,65 As with the wettability of

polymer multilayer films, protein interactions depend strongly

on the type and charge of the outermost layer of the films.66,67

Controlling the surface properties of a biomaterial is

essential for the regulation of cell behavior, such as cell

adhesion, migration and differentiation. Emerging applica-

tions include medical implants, cell supports, and materials

that can be used as instructive three-dimensional (3D) environ-

ments for tissue regeneration.68 Polymer films can improve the

biocompatibility of implants,69–71 or the localized administration

of therapeutics in a controlled manner.69,72,73 Assembly of

multilayered films, such as PLL/PGA,73 gelatin/chitosan,70

hyaluronic acid/chitosan/RGD69 and chitosan/pDNA,71 on

the surface of titanium has been used to improve the inter-

action of the titanium implant with the surrounding tissues.

The therapeutic effect of stents can be improved by coating

the stent with a drug (paclitaxel)/therapeutic reservoir that can

be slowly released.72–74

Nanopatterned films can also be created using various

lithographic techniques to alter film topology. By using these

patterns as a ‘resist’, patterning of the layers immediately

beneath them can be achieved or specific species can

be immobilized.75–77 For example, oxidative CVD (oCVD)

(a technique commonly used to create CVD polymers with

conductive properties3) was exploited to chemically conjugate

silver nanoparticles to poly(pyrrole-co-thiophene-3-acetic acid)

films, thereby creating a composite material which displayed

much higher conductivity than the non-modified polymer

film.78 Recently, the Gleason group have incorporated quantum

dots into oCVD films, thereby creating ‘‘hybrid light-emitting

diodes’’.3,79 They have also recently combined the oCVD

technique with colloidal lithography to form poly(3,4-ethylene-

dioxythiophene) (PEDOT) nanopatterned conducting

polymer films functionalized with amine groups.80 Due to

the nanopatterning of these functional groups, conjugation

to biologically active species at specific sites on the film surface

can take place. These films, characterized by nanoscale

features, may find application as a sensory device or in tissue

engineering. The same group have also combined colloidal

lithography with initiated chemical vapor deposition (iCVD)

for obtaining highly organized, nanopatterned polyelectrolyte

films with a thickness of up to 500 nm and a topography that

mimicked the shape of the colloidal template (Fig. 3).81

Polymer film materials containing well-organized nanopores

have diverse applications in separations,82 antireflection coatings,83

sensing,84 and biomaterials engineering.85 Methods for

preparing nanoporous polymer films include phase separation

of block copolymers, selective degradation of block copolymer

domains, selective dissolution of polymer blends, surfactant

Fig. 2 Schematic representations of different polymer assemblies

(lower layer) at interfaces with various morphologies (top layer).

Lower layer, from left to right: LbL polymer assemblies, block

copolymer (membrane) assemblies and polymer brushes. Top layer

(left-hand side): polymer assembly onto planar substrates, porous

membranes, nonporous particles, nanoporous particles, and self-

assembled polymersomes. Right-hand side: Corresponding nano-

stuctured polymer assemblies formed at the interfaces shown on the

left-hand side after template removal: polymer replica particles,

capsules, polymer nanotubes and free-standing films.

Fig. 3 Scanning electron microscopy images of nanopatterned

polyelectrolyte films comprising ‘‘nanobowls’’ which were obtained

using a 1 mm-sized colloidal template. The polymers used to create the

patterns were poly(butylacrylate) (pBA) (a), poly(pentafluorophenyl

methacrylate) (pPFM) (b), poly(hydroxyethyl methacrylate) (pHEMA)

(c), and poly(perfluorodecyl acrylate) (pPFDA) (d). (Reprinted from

N. J. Trujillo et al., Chem. Mater., 2009, 21, 742).81

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templating, and CO2 foaming.83,86 Methods for introducing

porosity in LbL thin films have also been reported in recent

years. Rubner and coworkers prepared porous thin films

by inducing polymer rearrangement in weak polyelectrolyte

multilayers (PEMs) of PAA/PAH by exposing the assembled

films to a low pH solution.60,87 Porous PAA/PAH films were

also obtained by exposing PEMs prepared from salt-containing

polyelectrolyte solutions to pure water.88 The selective etching

technique has also been applied to introduce porosity into LbL

films.89,90 Films comprising three different components were

assembled on non-porous planar templates, after which two of

the components were stabilized via cross-linking, and the third

(sacrificial) component was selectively removed to produce

nanopores within the films.89,90 It was recently reported that

the response time of a fiber optic pH sensor deposited with a

nanoporous multilayer film was only one tenth of that with the

non-porous multilayer film.91

Membrane flux and selectivity are the two most important

factors that influence membrane-based separations. The

synthesis of high-flux composite membranes requires methods

for the deposition of ultrathin, defect-free films on highly

permeable supports. Ultrathin polyelectrolyte (PAH/PSS)

multilayers have been assembled on porous supporting

membranes of Celgard92 and alumina93 with pore sizes of

B20 nm for selective ion transport. Electron microscope

characterization indicates that as few as five bilayers (o25 nm)

of polyelectrolyte effectively cover the surface without filling

the underlying pores.93 These membranes possess selective

permeability for mono- and divalent ions due to the rejection

of the divalent ions by Donnan exclusion. The ion selective

permeability is affected by the concentration of excess charges

in the individual polyelectrolyte layers, which can vary

with the polymer assembly conditions (e.g. solution pH, salt)

used during membrane preparation,94 or can be tailored by

using the partially derivatized polyanion22 or polycation95 as

the building block, respectively.

Freestanding polymer and hybrid films can be prepared

by assembly of polymers on planar substrates followed by

selective etching of the substrate surface (Fig. 2).96–98 For

instance, artificial nacre has been synthesized by assembling

PDADMAC/montmorillonite clay multilayers on silicon

wafers coated with a silica layer, which was selectively

dissolved with hydrofluoric acid (HF) to release the LbL

films.96 The same group has deposited alternating layers of

magnetite nanoparticles and polyelectrolytes (PEs) onto glass

slides coated with cellulose acetate (CA).97 Freestanding films

were subsequently obtained by dissolving the initial CA layer

with acetone. Hammond and coworkers have introduced a

method to isolate LbL films using low-energy surfaces that

facilitate the removal of a substantial mass and area of

the film.98

3.1.2 Particulate interfaces. There is growing interest in

using nanoparticles (NPs, e.g. gold NPs, quantum dots, super-

paramagnetic NPs) in biomedical applications, such as bio-

labeling, encoding, bioassaying and as contrast agents, because

of the extremely small size (several to tens of nanometres), and

specific optic, electronic and magnetic properties of these

materials.99–101 However, the NPs typically need to be further

modified to overcome the inherent limitations of these materials,

such as low solubility in aqueous media, lack of stability,

and concerns regarding their biocompatibility.100,102,103 The

assembly of polymer shells on the NPs is a widely used

technique to address some of these issues; for example, the

NPs can be functionalized to exhibit specific properties for drug

loading and stimuli-responsive delivery applications.104–106

LbL assembly provides a versatile method to assemble

polymer multilayered films on various particles with different

components, dimensions, and geometries. The assembled

core–shell particles have been utilized in catalytic107 and

photonic108 applications, as confined environments for chemical

reactions within the shell coatings,109 and as building blocks to

create nanostructured functional thin films for biosensing.110

After removal of the core, hollow polymeric capsules can be

prepared (Fig. 2). This method permits unprecedented control

over capsule properties (e.g. size, composition, thickness,

permeability, function) through the choice of the sacrificial

particles and film components. Such capsules in the nanometre

to micrometre regime are important for a range of different

applications, including the encapsulation and controlled release

of substances, catalysis, and sensing. Further information can

be found in review articles on this topic.34–40

3.1.3 Spatially confined interfaces. Materials with uniform

pore structures are of interest in different applications, including

catalysis, adsorption, and separation.111,112 The pores in the

materials are able to host guest species and provide a pathway

for molecule transportation. The high surface area of the pore

walls provides an ‘‘active’’ and/or ‘‘affinity’’ interface to

associate with guest molecules.

The assembly of polymers in macroporous membranes

(e.g. anodic aluminium oxide (AAO) membranes,113 poly-

carbonate membranes,112,114 CA membranes,115 hierarchical

porous metal oxides,116,117 three-dimensionally ordered

macroporous (3DOM) inorganic materials,118 and hydrogel

membranes119) has been widely studied, as this allows control

of the hierarchical structure of the polymer assemblies.

Alem et al. have studied the LbL deposition of a pair of

strong polyelectrolytes within the macropores (50–850 nm) of

track-etched membranes.120 It was found that the increments

of thickness per cycle of deposition was much larger than on

non-porous planar surfaces, indicating that the polyelectrolyte

complexation occurs within a dense gel. Hollman and

Bhattacharyya have immobilized polyelectrolyte multilayers

within the inner pore structures (pore diameter B200 nm) of

polycarbonate membranes.114 The ion selective permeability

of the resulting membrane was found to depend highly on the

ionic strength of the solvent used for LbL adsorption.114

A hybrid micro-/nanofluidic device which contains an

array of parallel nanochannels has been employed to study

polyelectrolyte multilayer deposition in confined geometries.

LbL assembly of PAH and PSS at pH 4 and salt concentra-

tions ranging from 0.1 to 1 M were used to conformally coat

the nanochannel walls, systematically narrowing the channel

width from 222 to 11 nm in the wet state. The ability to

conformally coat the walls of the nanochannels with functional

PEMs opens up new possibilities in the design of active

nanochannel devices.121 The use of porous membranes with

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cylindrical pores for polymer assembly also permits the

preparation of freestanding polymer tubes after removal of

the porous membrane (Fig. 2). The outer diameter, length,

composition, and thickness of the tubes are controlled by the

pore diameter, membrane thickness, type of species deposited,

and number of layers assembled, respectively. So far, a broad

range of macromolecules have been assembled within the

cylindrical nanopores of membranes. Following membrane

template removal, nanotubes with various components, such

as DNAmultilayers,113 polymer multilayers,122 protein/polymer

multilayers,112 protein/lipid multilayers123 and protein/protein

multilayers,123,124 have been obtained.

Nanoporous particles have attracted significant interest in

recent years and have opened up new possibilities in many

areas of applications, such as catalysis, adsorption, imaging,

and drug delivery.125 The surface, geometry, and size of

the pores may be tailored to selectively store and release

(at controlled rates) the molecule of interest, which is particularly

attractive for controlled drug delivery applications. The assembly

of enzymes in nanoporous particles leads to the generation

of inorganic/organic hybrid materials for biocatalysis. The

restricted pore space may inhibit protein denaturation by harsh

solvents, denaturants, and extremes in pH and temperature.126,127

In addition to enzymes, the loading of various small

molecule compounds and other biomacromolecules, such as

proteins and DNA, inside nanoporous particles was

demonstrated.128,129 The cargo-loaded nanoporous particles

can be further coated with various polymers/other materials to

control the release of molecules from the pores. Materials and

macromolecules used as coatings include polypseudorotaxanes,130

antibodies,131 dendrimers,106 LbL-assembled polymer films,126,132

and in situ polymerized polymers.133

The assembly of polymer nanostructures in nanoporous

inorganic particles also provides a facile means to generate

nanoporous polymer particles (NPPs) after removal of the

inorganic template (Fig. 4).125 This can be achieved by an

in situ polymerization process or infiltration of preformed

macromolecules. The benefit of the former strategy is that

the pore size can be small since small-sized monomers are

used. In a typical in situ polymerization synthesis strategy, the

monomers are infiltrated into the mesopores. Polymerization

reactions are then performed to obtain an interconnected

network and the silica template is removed by dissolution

(Fig. 2).134–136 For instance, Kageyama et al. reported the

production of crystalline polyethylene fibers with a diameter of

30 to 50 nm by the polymerization of ethylene with catalysts

supported by a fibrous mesoporous silica with honeycomb-like

pores arranged in a parallel direction to the fiber axis.134

Spherical molecularly imprinted polymer (MIP) beads that

mirrored the silica particles in size, shape and pore structure

following removal of the silica matrix from the silica-MIP

composites were prepared.136 The synthesis of conjugated

polymer mesoporous particles and the self-assembly of

such particles into crystalline arrays has been investigated

for the construction of photonic crystals with novel band

gap properties.137

A versatile method to prepare NPPs through the assembly

of preformed polymers into mesoporous silica (MS) particles

was also reported.138 Size matching between the nanopores

and macromolecules must be considered for infiltration of the

macromolecules into the confined pores, as small pore sizes

will exclude larger molecules.139–141 Studies have shown that

polymer loading increases with particle pore size and that the

influence is more pronounced with increasing polymer size,

indicating that the larger nanopores are more accessible to the

macromolecules.140 In addition, the solution conditions, such

as pH and ionic strength, also play pivotal roles, as these

parameters not only determine the charge density at the

interface but also the charge density and hence the conforma-

tion of the infiltrating macromolecules.140,141 Stabilization of

the infiltrated macromolecule network is required to obtain a

replica after removal of the MS template. This can be achieved

by adsorbing a second complementary macromolecule to the

first, or cross-linking the network of a singular polymer.138,142

The general applicability of this technique facilitates the design

of polymer particles with tunable properties by varying the macro-

molecules used, which can include synthetic polyelectrolytes,138,143

proteins,144 polypeptides,145 polyesters,146 and polymer-drug

conjugates.142 Due to the nanoporosity and the large number

of functional groups in the polymer networks, the NPPs

exhibit excellent adsorption capacities, which may find applica-

tion in enzyme immobilization,138,143 drug delivery,142,144,145

and imaging.146

3.2 Flexible interfaces

Compared with rigid interfaces, flexible interfaces typically

have a much narrower range of geometries and simpler

morphologies. Flexible interfaces include emulsion droplets,

liquid crystals (LCs), liposomes, and gas bubbles.

Fig. 4 SEM images (a, c, e) and ultramicrotomed TEM images

(b, d, f) of the template-synthesized nanoporous polymer particles

(a–d) and capsules (e–f). The images show nanoporous polyelectrolyte

particles prepared via sequential deposition of PAA and PAH within

mesoporous silica (MS) particles, followed by removal of the MS

template (a and b); nanoporous protein particles prepared via sequential

deposition of lysozyme and PAA (8000 Da) within MS particles,

followed by removal of the MS template (c and d); and thick-walled

PAH capsules prepared via infiltration of PAH in 420 nm silica

particles with a mesoporous shell, followed by cross-linking with

glutaraldehyde and removal of the silica template (e and f). (Adapted

from Y. Wang et al., Angew. Chem., Int. Ed., 2005, 44, 2888; Adv.

Mater., 2006, 18, 795; Nano Lett., 2008, 8, 1741.)138,142,144

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Weitz and coworkers have prepared ‘colloidosomes’, which

are formed using double emulsions as templates for the

assembly of colloidal particles at the interfaces between the

immiscible liquids, followed by removal of the template.147

The use of a microcapillary device to form colloidosomes can

result in the generation of a highly monodisperse population.148

An example of a colloidosome formed from polymer materials

is a capsule shell comprising a PNIPAAM microgel cross-

linked using a glutaraldehyde linker.147 The PNIPAAM is

thermally-responsive, triggering reversible capsule shrinkage if

the temperature is raised above its phase-transition temperature.147

Such capsule shells contain pores in between the individual

colloidal particles that comprise the shell, for the diffusion of

molecules in and out of the colloidosome interior, which

can be controlled via the reversible temperature-controlled

expansion and shrinkage of the gel. The same group have also

prepared PNIPAAM microgel particles cross-linked with a

UV light-sensitive linker. Thus the degree of cross-linking

(and thereby the degree of permeability) can be finely tuned

by controlling the photon flux over a set time period.149 This

work has recently been extended to form core–shell particles

comprising ‘‘miscible yet distinct layers’’ of PNIPAAM and

polyacrylamide.150 Fig. 5a shows the ability of these capsules

to rapidly release an encapsulated payload on lowering the

temperature below the PNIPAAM phase transition tempera-

ture. This initial work on thermally-responsive capsules

is envisaged to be extended to the fabrication of systems

responsive to different stimuli, including pH, ionic strength

and various environmental stimuli for the controlled release of

encapsulated cargo and for use in sensory devices. Further-

more, functional groups can be introduced at precise locations

(on the nanometre-length scale) by controlling the position of

the monomers in the precursor polymer chain.149

The flexibility of the ‘‘microfluidic approach’’ is shown by

the ability to form PNIPAAM microgels incorporating both

microparticles (e.g. polystyrene spheres) and nanoparticles,

including quantum dots and magnetic nanoparticles.151 It is

also possible to generate non-spherical particles of consistent

morphology.152 Combining the fundamental properties of

such nanoparticles with the ability to precisely control the

morphology of their assembled structures via assembly at the

interface between two immiscible liquid phases provides

opportunities for a variety of applications, including con-

trolled drug delivery and release.

Emrick, Russell and colleagues have prepared PEGylated

gold nanoparticles that can self-assemble at the interface

between two immiscible liquids due to their amphiphilic

nature153 (see Fig. 5b). This self-assembly process results

in the formation of colloidosomes with ‘oily’ cores, for the

encapsulation of hydrophobic substances, using water as the

continuous phase153 (Fig. 5b).

Coating oil-in-water emulsions with polyelectrolytes by the

LbL technique is a promising way to avoid the use of

emulsifiers. LbL polymer-coated monodispersed LC emulsions

have been used as biosensors to distinguish between Gram

positive and Gram negative bacteria, and to also differentiate

between enveloped and non-enveloped viruses.154 The remarkable

ability of the presence of a surfactant to trigger configurational

switching of the LC droplets from a planar to radial con-

figuration has been demonstrated (Fig. 6).154,155 This pheno-

menon is the result of lipid transfer from the exterior of the

bacteria/viruses to the outside of the LC droplets.154 In order

Fig. 5 (a) PAAM-PNIPAAM core–shell cross-linked hydrogel microparticles encapsulating RITC-dextran. During the first 10 s, the temperature

is kept higher than the PNIPAAM phase transition temperature of 33 1C. After 10 s, the temperature is decreased below 33 1C triggering core–shell

particle swelling and subsequent release of the encapsulated dye into the surrounding medium. (b) On the left hand side is a drawing of PEGylated

gold nanoparticles and their self-assembly into colloidosomes upon the addition of oil to a continuous aqueous phase. On the right hand side are

oil-in-water droplets encapsulating courmarin 153 (a hydrophobic dye) in 1,2,4-trichlorobenzene, stabilized by the PEGylated gold nanoparticles,

which assemble at the interface between these two immiscible liquids. (Reprinted from S. Seiffert et al., J. Am. Chem. Soc., 2010, 132, 6606; and

E. Glogowski et al., Nano Lett., 2007, 7, 389)150,153

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to obtain a monodispersed distribution of the LC emulsion

droplets, multilayered polymer capsules can be employed as

templates which are backfilled with LCs before removal of the

capsule template.156,157 The aforementioned results demon-

strate the potential of these LC emulsion droplets as a fast

method for distinguishing between different types of micro-

organisms according to the composition of their cell wall/viral

envelope.154

Liposomes are formed spontaneously by the assembly

of phospholipids in an aqueous environment due to their

amphiphilic character and are widely used in various applica-

tions such as drug and cosmetic delivery, as well as for

biosensing.158 However, liposomes have some limitations as

they can easily degrade. Various structural modifications have

been attempted to make them physically more robust, such as

the addition of cholesterol to the lipid bilayer membrane,159

coating the liposome surface with inert, biocompatible, hydro-

philic polymers with a highly flexible main chain such as

poly(ethylene glycol) (PEG), poly-N-vinylpyrrolidone, poly-

[N-(2-hydroxypropyl)methacrylamide)] or polyvinyl alcohol,

to name a few.160,161 Liposomes with increased thermal and

detergent stability were also obtained when one layer of PAH

was adsorbed onto negatively charged DMPA liposomes.162

Another approach to enhance their mechanical strength is to

coat them with charged polyelectrolyte multilayers, such as

PAH/PSS163 or PGA/PAH164,165 using the LbL technique.

A different approach to combine liposomes using the LbL

technique are in the preparation of so-called capsosomes, a

new class of polyelectrolyte capsules containing multiple,

intact liposomes in the capsule interior (Fig. 7). This sub-

compartmentalized platform has been recently introduced, and

it is envisaged that it can be used as a synthetic microreactor

for the creation of therapeutic artificial cells or organelles.166–169

This combination of liposomes and polymeric capsules

preserves the advantages of both systems whilst eliminating

some of their shortcomings, endowing them with additional

functionality. Although liposomes provide effective encapsula-

tion for small and medium-sized cargo and divide the capsule

into thousands of subcompartments, they are structurally

unstable and highly impermeable to the external milieu. To

counteract these shortcomings, the polymeric capsule equips

the capsosomes with the desired structural stability and allows

communication within the interior and external milieu due to

its semi-permeable nature.

The De Smedt group has developed microbubbles for the

incorporation and delivery of drugs mediated by the application

of ultrasound.170 These microbubbles comprise a perfluoro-

carbon gaseous centre covered by a stabilizing shell, which

prolongs their blood circulation time.170 An example is

the electrostatic binding of DNA to a cationic PAH layer

surrounding microbubbles with an albumin-functionalized

surface.171 In addition to stabilizing the adhered DNA against

nuclease degradation, the PAH layer greatly increased the

blood half-life of the microbubbles, thereby enhancing their

in vivo applicability. Current challenges facing the develop-

ment of optimal microbubble carriers include overcoming

difficulties in obtaining monodisperse size-distributions, low

blood circulation times, and low drug inclusion capacities.

4.0. Applications of polymer assemblies

Polymer assemblies, including capsules, thin films, membranes,

and nanoporous particles, are useful for the immobilization

and encapsulation of different cargo for various applications.

4.1 Immobilization of cargo in polymer films

One method of achieving cargo immobilization is via

post-loading into the polymer assembly (Fig. 8A), which can

occur by altering the net charge and permeability of the

polymer assembly, for example, by modifying the pH or ionic

strength of the surrounding medium. Using this method,

various drugs, dyes, enzymes, metal ions and nanoparticles

can be immobilized.

An alternative method is to use the cargo as a building com-

ponent (Fig. 8B). This is widely used in LbL assembly, since

this technique permits the utilization of building blocks of various

functional species such as enzymes, DNA, liposomes,166–169,172

and nanoparticles (NPs) (e.g. Au NPs,173 Fe3O4 NPs,174

quantum dots,175 MnO2 NPs,176 zeolite nanocrystals,177 meso-

porous hollow spheres178,179). For instance, Kunitake and

coworkers developed multi-enzyme reactors containing glucose

oxidase (GOD) and glucoamylase (GA) prepared on ultrafilters.180

Bruening and coworkers used the LbL technique to immobilize

Fig. 6 Fluorescence image of the 40-pentyl-4-cyano-biphenyl

(5CB)-PSS emulsion coated with seven bilayers of PAH-fluorescein

isothiocyanate (FITC)/PSS (a); cross-polarized image of 5CB-PSS

emulsions coated with (PAH/PSS)7 after exposure to 5 mM sodium

dodecyl sulfate (SDS) (b). The scale bars are 10 mm. (Adapted from

E. Tjipto et al., Nano Lett., 2006, 6, 2243).155

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gold NPs within porous supports to form catalytic membranes.181

Membrane bioreactors were prepared through the LbL assembly

of PEs and catalase within 3DOM zeolite membranes.118 The

loading and activity of the enzyme were found to vary linearly

with the membrane thickness.118 Lee et al. proposed an

approach for preparing flash memory devices composed of

polyelectrolyte/gold nanoparticle multilayered films.182 The

reported approach offers new opportunities to prepare nano-

structured polyelectrolyte/gold nanoparticle-based memory

devices with tailored performance.182 The assembly of DNA

into multilayer films and capsules has been reported.183 DNA

hybridization has also been exploited to achieve high control

over the structure, properties and stability of both capsule

walls and thin films.183–187

Drug-conjugated polymers can be used as a building block

in the construction of LbL thin films and capsules. For

example, the anti-cancer drug doxorubicin (DOX) has been

conjugated to PGA to prepare single-component capsules,

either via mesoporous-shell templating synthesis142 or LbL

assembly coupled with click chemistry.188 In a more recent

study by Hammond and coworkers, the micelle-forming block

copolymer poly(ethylene oxide)-block-poly(2-hydroxylethyl-

methacrylate) (PEO-PHEMA) was conjugated to DOX and

incorporated into multilayered films via alternate deposition

with tannic acid (TA).189 TA acts as a hydrogen-bond donor

for the PEO chains comprising the micelles at physiological

pH. The same group also reported films comprising cationic

poly(b-amino ester) moieties that are alternately electrostatically

Fig. 7 Schematic illustration of capsosome formation. Percursor layers of PAH and PSS are alternately deposited on a sacrificial silica core

template. After depositing the required number of precursor layers, a layer of liposomes is deposited, followed by capping layers of PSS/PAH. This

is repeated until the required number of liposome layers is incorporated. The sacrificial core is then removed, creating hollow capsules known as

capsosomes. (Reprinted from B. Stadler et al., Langmuir, 2009, 25, 6725).168

Fig. 8 Two representative strategies used for the immobilization of cargo in polymer films: post-loading into the polymer films (A); the cargo

(or cargo-polymer conjugate) is used as a building block in LbL assembly (B).

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layered with poly(carboxymethyl-b-cyclodextrins).190 Cyclo-

dextrins are oligosaccharides and comprise a hydrophilic

surface and hydrophobic cup-shaped ‘‘interior’’ for ‘‘reversible

complexation’’ with non-polar molecules.190

4.2 Encapsulation of cargo in nanostructured polymeric

capsules

Polymeric capsules have provided a versatile platform to

encapsulate different types of cargo molecules, ranging from

small molecular drugs to macromolecules, and also to perform

chemical reactions inside their interior. So far, various

approaches have been proposed for incorporating different

types of substances within polymeric capsules.

The first method entails loading of cargo in a polymeric

capsule by changing the permeability of the capsule shell via

different solution environments (e.g. temperature, pH, and

ionic strength) (Fig. 9A).191–193 Cargo diffusion through the

capsule walls is driven by a concentration gradient between

the external medium and the hollow cores of the capsules.35

The encapsulation efficiency of this technique is typically low

due to the lack of affinity of the cargo for the capsule interior;

hence the concentration of cargo inside and outside the

capsule is nominally the same. Sequestration agents, such as

oleic acid194 and dextran sulfate,195 have been proposed to

enhance cargo loading and to retain the cargo inside the

capsules.

Fig. 9 Strategies applied to encapsulate various cargo: Post-loading of a hollow polymer capsule (A); polymer coating on a drug crystal (B);

pre-loading and polymer coating of a MS particle (C); pre-loading and polymer coating of an emulsion (D); capsosome assembly with loaded

liposomes (E); self-assembly of block copolymers to form loaded polymersomes (F).

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The second method entails encapsulating the therapeutic

agent through the assembly of polymer films on the particulate

substance, such as crystals and aggregated complexes

(Fig. 9B). After polymer assembly, a core–shell particle is

formed, which results in the cargo being surrounded by a

protective thin film. This technique has been used to encapsulate

crystallized small molecule dyes and drugs,196 protein crystals,197

condensed DNA,198 and protein aggregates.199 However, with

this method it is often difficult to tailor the capsule size, which is

determined by the template particles, and the type and quality of

the template formed.

The third approach for encapsulating drugs in polymeric

capsules is through nanoporous inorganic particle-mediated

drug loading and subsequent generation of a polymer multi-

layer shell, which is followed by removal of the sacrificial

inorganic particle (Fig. 9C).125 The salient feature of this

method is that it is applicable to the encapsulation of a wide

range of materials, such as proteins,200,201 DNA,202 and water-

insoluble compounds (e.g. thiocoraline, paclitaxel, dyes).203

The encapsulation of emulsions (and cargo-loaded emulsions)

into polymeric shells performed by the LbL technique can be

achieved in two main ways; by infiltrating the emulsion into

the polymeric shell or by coating oil emulsion droplets dispersed

in water by the alternate deposition of polymer layers

(Fig. 9D). The post-loading or infiltration approach was first

reported by Moya et al. and demonstrates how solvents

immiscible with water can be encapsulated into polymeric

shells by gradual solvent exchange.204 The post-loading method

has also proven to be a successful method for the preparation

of monodispersed emulsion droplets with a high degree of

control over the size of the droplets.157 The second method

involves coating an oil emulsion by the addition of poly-

electrolytes by adsorbing consecutive layers of charged polymers

to oppositely charged droplets. With this approach, the liquid

particles simultaneously play the role of template and con-

tainer. Monodisperse polymer PDA capsules were prepared

by one-step interfacial polymerization of dopamine onto

dimethyldiethoxysilane (DMDES) emulsion droplets and

removal of the DMDES templates with ethanol.10 Functional

substances, such as organically stabilized magnetic nanoparticles,

quantum dots, and hydrophobic drugs (thiocoraline), can be

preloaded in the emulsion droplets. Following PDA coating

and DMDES removal, these materials remain encapsulated in

the polymeric capsules.

The functionality of capsosomes was demonstrated by

encapsulating a model enzyme (b-lactamase) into the liposomal

subcompartments (Fig. 9E) and performing a quantitative

colorimetric assay by the conversion of nitrocefin into its

hydrolyzed product. The reaction does not occur until the

liposomes are disassembled by adding a surfactant. This

demonstrates that liposomes can efficiently encapsulate fragile

cargo such as enzymes and at the same time that they are able

to restrict the access of substrates (nitrocefin).172 Furthermore,

it was shown that capsosomes are able to encapsulate small

hydrophobic cargo by entrapping an anti-tumoral compound

into the membrane of the liposomal compartments. The

functionality of this small entrapped molecule was demon-

strated by performing a cell viability assay.166,205 Importantly,

pristine capsosomes do not exhibit any inherent cytotoxicity,

making them ideal candidates for biomedical applications.205

In one of the most recent studies on capsosomes, the upper

limit of the number of liposome multilayers that can be

deposited onto silica templates was identified, in order to

maximize the number of subcompartments and therefore the

amount of loaded cargo.206

Polymeric vesicles and micelles are particles that are formed

via the self-assembly of amphiphilic macromolecules in the

presence of a selective solvent and show much promise in the

field of biomedicine (Fig. 9F). Indeed, there are several

examples of polymeric micelle vectors reaching clinical

trials.207,208 However, some intriguing novel structures that

are also generated via the self-assembly of amphiphiles have

emerged as promising drug delivery candidates. Percec and

coworkers have recently discovered dendrimersomes that are

obtained by the self-assembly of Janus dendrimers,209 which

comprise a hydrophilic dendrimer block covalently bound to a

hydrophobic dendrimer block. This is in contrast to the

symmetrical character of typical dendrimers. Dendrimersomes

have shown mechanical toughness, colloidal stability and

payload retention comparable to polymersomes, and have

furthermore demonstrated stability in biological milieu. More-

over, dendrimersomes are more monodisperse than their lipid

and block copolymer counterparts, and fine control over

branch architecture can be exerted. One can envisage these

self-assembled structures finding application in areas such as

controlled drug delivery (through inclusion of stimuli-responsive

moieties) and artificial cell organelles (due to the ability to

readily incorporate protein channels within the dendrimersome

membrane).

4.3 Stimuli-responsive release of loaded substances

Designing and assembling polymer materials that can respond

to specific stimuli is critical for many applications. Triggering

the release of loaded substances can be achieved through a

number of different methods (summarized in Table 1) that can

be divided into two categories: internal stimuli-responsive

systems and external stimuli-responsive systems.

4.3.1 Solution environment stimuli. ‘Intelligent’ polymers

can recognize a stimulus as a signal and then significantly alter

(for instance) their chain conformation in response to changes

in the environment. The internal stimulus (e.g. pH, ionic

strength, temperature, presence of a chemical or enzyme) can

induce a change in the local environment.

One of the most widely exploited environmental triggers

that has been used to induce release in polymeric capsules is

pH. Changing the solution pH can induce a modification of

the charge density (and hence conformation) of the weak

polyelectrolyte chains that comprise the capsule shells. The

permeability changes allow molecules to pass through the

capsule walls.210

Hammond and coworkers have reported the release of DOX

from block copolymer micelles within a LbL film in mildly

acidic conditions via the hydrolysis of carbamate bonds used

to conjugate DOX to the block copolymer.189 Over a 24 h

period, more than 90% of the conjugated DOX was released

from the micelles, and subsequently from the LbL films at

pH 4. However, carbamate bond hydrolysis also occurred at

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pH 7.4, releasing around 20% of the encapsulated DOX

within 24 h.

The same group have also prepared similar multilayered

polyelectrolyte films for the delivery of drugs and vaccines to

the skin by using the films as a skin patch.211 In this example, a

cationic poly(b-amino ester) was electrostatically alternately

layered with either immunostimulatory DNA oligonucleotides

(e.g. CpG) or the antigen ovalbumin. Delivery of these two

therapeutics into ‘‘barrier-disrupted skin’’ was successfully

demonstrated through hydration of the film upon its contact

with the skin, triggering hydrolytic film deconstruction with a

different release kinetics profile for each therapeutic. It was

proven that the therapeutic agents retained their function and

were non-aggregated on release following their incorporation

into the films.

In a recent study by Addison and coworkers, a chrysoidin

dye was loaded into pH-sensitive micelles comprising poly-

[2-(dimethylamino)ethyl methacrylate-block-poly(2-(diethyl-

amino)ethyl methacrylate)] (PDMA-PDEA).212 The PDMA

block was partially quaternized to ensure its protonation

and thus hydrophilicity, even at very basic pH values.

The PDEA block becomes hydrophobic above its pKa of

B7–7.3, triggering self-assembly of the block copolymer into

micelles above this pH. These micelles were successfully

incorporated into LbL films and core–shell particles; the

latter obtained using polystyrene latex particles as the core

via their alternate deposition with anionic PSS. The micelles

retained their structural integrity and encapsulated payload

during preparation of the LbL assemblies, but lost their

structural integrity below the block copolymer pKa,

which is likely to trigger the release of an encapsulated payload

at physiological pH. However, since the micelles remain

bound to the anionic component of the film, this responsive-

ness to pH can act as an ‘‘open-close’’ mechanism for the

triggered release of therapeutic agents. Removal of the

core template by THF treatment compromised the morpho-

logical integrity of the micelle component; therefore, an

alternative sacrificial core template would be necessary to

Table 1 Nanostructured polymer materials for stimuli-responsive release of loaded cargo

Stimuli Materials Morphology Cargo Ref.

pH PAH/PAA Particle Lysozyme 143pH poly(NIPAAM)-co-AA Capsule GOD 244pH PAA/PAH Film Methylene blue 245pH PAH/hyaluronic acid Film Indoine blue, chromotrope 2R 246pH HSA and L-a-dimyristoylphosphatidic acid Capsule Dextran, 6-carboxyfluorescein 247pH PDADMA/PSS-gelatin/PSS Capsule Furosemide 248pH Plasmid DNA/hydrolytically degradable polyamine Film DNA 73pH PMPC-PDPA Vesicles DNA, quantum dots, antibodies,

propidium iodide, various dyes,doxorubicin

214–220

pH Insulin/(PVS, PAA, or dextran) Film Insulin 249pH PEI/PAA Capsule Dextran 250pH or salt PLL/PGA Capsule EnzymeTemperature PNIPAAM Core/shell

particleCarbazochrome sodiumsulfonate

251

Temperature poly(NIPAAM-co-AA) Film Insulin 252Temperature PNIPAAM-AAc microgels/PAH Film Doxorubicin 253Sugar Mannan/PAA grafted with phenylboronic acid Film BSA 254Glucose Glucose oxidase/catalase (cross-linked) Capsule Insulin 223Thiol-disulfideexchange

PEG/poly(aspartamide) Micelle Plasmid DNA 225

Thiol-disulfideexchange

PMASH Capsule BSA, DNA, DOX, vaccines,thiocoraline, paclitaxel

194, 203, 228,255, 256

Chitosanase Chitosan/dextran sulfate Capsule BSA 200Hydrolase PGA-Dox (crosslinked) Capsule Carboxypeptidase, protease 142, 188EcoRI DNA (with EcoRI cut-sites) Film, capsule BSA 184Proteases DEXS/pARG Capsule Ovalbumine 229NIR radiation PAH/PSS capsule (embedded with gold NPs) Capsule Lysozyme, dextran 192, 232IR radiation PDADMA/PSS (embedded with Ag NPs) Capsule Dextran 233, 257IR radiation PAH/PSS capsule (embedded with Ag NPs) Capsule IR-806 dye 257IR radiation PAH/PSS capsule (containing light absorbing

species)Capsule Porphyrine 258

UV irradiation photo-cross-linked NPs Emulsion Cyclodextrin 259UV irradiation PSS/diazoresin (with photo-cross-linking) Capsule Glucose oxidase 260UV irradiation PSS/PDADMA (decorated with TiO2) Capsule Dye (phenol red) 236Light PEO-PBD polymersomes Vesicle Ferritin, BSA, myoglobin 234Magnetic field PSS/PAH (Ferromagnetic gold-coated cobalt) Capsule Dextran 237Magnetic field PAH/PSS encapsulated with g-Fe2O3 NPs Capsule Doxorubicin 240Magnetic field PAH/PSS multilayer (embedded with Fe3O4 NPs) Capsule Dextran, doxorubicin 238Magnetic field PAH/PSS multilayer (embedded with Fe3O4 NPs) Capsule Calcein 239Ultrasound PAH/PSS multilayer (embedded with ZnO NPs) Capsule n.a. 243Ultrasound PAH/PSS multilayer (embedded with Fe3O4 NPs) Capsule Dextran 242Ultrasound PAH/PSS multilayer (embedded with Ag NPs) Capsule Dextran 241Ultrasound Microbubbles Bubble DNA 171

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obtain stable, hollow capsules incorporating structurally

intact micelles.

Hammond and coworkers have exploited the ability of

poly(ethylene glycol)-block-poly(caprolactone) (PEO-PCL)

micelles to interact by hydrogen bonding with PAA under

acidic conditions.213 At physiological pH, this hydrogen bonding

interaction is disrupted and the LbL films rapidly disassemble,

releasing the incorporated micelles. The rate of film disassembly

can be controlled by cross-linking the carboxylic acid moieties

on the PAA. The PCL block imparts biodegradability to the

micelles, thus gradual release of a hydrophobic cargo can take

place. However, the PCL block undergoes gradual hydrolysis

upon storage, potentially lowering the suitability of the system

for long-term storage, especially at physiological pH.

Polymersomes can be designed so that they contain a

domain that is responsive to a change in pH. For instance,

Armes, Battaglia and coworkers have developed nanometre-

sized polymersomes comprising a poly(2-methacryloyloxy-

ethyl phosphorylcholine)-block-(2-(diisopropylamino)-ethyl

methacrylate) (PMPC-PDPA) copolymer.214,215 The PMPC

block imparts biocompatibility and forms the polymersome

corona, whilst the PDPA block is responsive to changes in

pH and is hydrophobic above its pKa of B6.4. This diblock

copolymer can electrostatically interact with nucleic acids such

as plasmid DNA215,216 under weakly acidic pH conditions, at

which the PDPA block is protonated, allowing a high DNA

encapsulation efficiency within polymersomes which can form

at physiological pH.217 DNA release is triggered by lowering

the pH from physiological pH to below pH 6.4, which causes

the polymersomes to dissociate. The disassembly of the

polymersomes into the thousands of single copolymer chains

that each polymersome comprises has been shown to trigger

lysis of the cellular endosomes through an osmotic pressure

shock, allowing release of the block copolymer carrier and its

payload into the cell cytosol,218 which is typically required

in order for a particular therapeutic to be effective. This

pH-responsive system has recently been further exploited for

the efficient loading and delivery of a variety of different payloads,

including antibodies and quantum dots, into cells.219,220

By using a temperature-responsive polymer, e.g. PNIPAAM,

release can occur as a result of a change in the polymer

conformation upon heating. Temperature-responsive polymeric

micelles have been layered with PMA at acidic pH, based on

hydrogen bonding interactions with the PVPON block of

PVPON-block-PNIPAAM micelles.221 These micelles form

above the LCST of the PNIPAAM block, and disassemble

releasing encapsulants at 20 1C. Once incorporated into LbL

films with PMA, micelle dissociation is no longer observed

upon decreasing the temperature below 34 1C; instead, reversible

swelling of the micelles was observed, indicating dissolution

of the formerly hydrophobic micelle core and thus escape

of any encapsulants. At physiological salt concentration

(0.15 M NaCl), the micelle core collapses and a pyrene dye

payload release of 50% is observed within 35 min. A system

that is more stable at physiological pH and salt concentration

would be more desirable, in addition to micelles that can

release their therapeutic payload just below physiological

temperature so release could be triggered, for example, by

the application of ice packs.

The contents inside the liposomes can be released by

increasing the temperature above the phase-transition tempera-

ture (Tm) due to an increase in the permeability of the

liposomal membrane. Moreover, by incorporating different

lipids with various Tm, the encapsulated compounds can be

released at different temperatures.222 As previously mentioned,

capsosomes are a new therapeutic platform, which consist of

polymer carrier capsules containing liposomes.167,168 Since

capsosomes are a promising new approach toward the con-

struction of artificial cells and organelles, it is highly desirable

that these systems are reusable so that the enzyme can be

recycled and therefore able to convert the substrate into the

therapeutic product in a continuous manner. Temperature was

recently used as a trigger to repeatedly initiate the enzymatic

reaction without destroying the liposomal compartments.206

By increasing the temperature above the liquid-gel transition

temperature (Tm) of the liposomes, the permeability of the

liposomal membrane increases, thus allowing the substrate to

repeatedly contact the enzyme.

4.3.2 Chemical and enzyme stimuli. Capsule permeability

can be engineered via an external stimulus, such as chemical

and enzyme stimuli. Li and coworkers have developed

a glucose-responsive capsule for the delivery of insulin.223

Glucose oxidase and catalase were alternately assembled on

insulin particles and then the enzymes were cross-linked using

glutaraldehyde. The coupled enzymatic reactions of glucose to

gluconic acid in the assembled capsules reduced the pH value

and led to an enhancement in the shell permeability. In

addition, the solubility of insulin increased with decreasing

solution pH, which also favors the release of the encapsulated

insulin. These systems are relevant for the treatment of

diseases such as diabetes, where the delivery of required insulin

is based on the concentration of glucose in the bloodstream.

In drug delivery, it is often desirable for the drug to be

released once the capsules are internalized by cells. This can be

achieved by exploiting the change in the redox potential

between the extracellular and intracellular environments.

Thiol-disulfide exchange can be applied to induce capsule

degradation, as disulfide bonds within the capsules are stable

in the oxidizing environment outside the cell, but are cleaved

in the reducing environment within the cell.19 The disulfide

bonds can be incorporated either into a polymer backbone or

as a cross-linker to conjugate the assembled polymer chains.

Disulfide bonds have been used to stabilize a variety of

polymeric capsules, including polymersomes,224 cross-linked

micelles225 and LbL capsules.19,226–228 For instance, cystamine

moieties have been covalently attached onto PMA, thus

creating PMASH (PMA backbone with pendant thiol

groups).226–228 Using an oxidative reagent the thiol groups

were converted into disulfide linkages resulting in multilayers

that remained intact when exposed to alkaline or neutral

solutions, resulting in single-component PMA films or capsules

cross-linked by disulfide linkages.19 A further advantage of

this system is that PMASH capsules can be degraded at

the physiological concentration of glutathione, a natural

thiol-containing peptide which is found in the intracellular

environment but not in the bloodstream and which is able to

reduce disulfide bonds. This promotes capsule disassembly

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once taken up by cells. Hence, these capsules are attractive

candidates for biomedical applications, particularly for intra-

cellular drug delivery.228

Polymer assemblies can be engineered with degradation

capabilities that can be triggered by the presence of an enzyme.

The enzyme stimuli-responsive properties of polymer films can

be achieved by using enzymatically degradable biopolymers,

such as oligonucleotides, polypeptides and polysaccharides, as

building blocks.200,229 The release system, in response to

specific enzymes present locally in the diseased organ of a

living body, would be interesting for local drug release.

Further, the release rate of this system can be tuned by altering

the thickness of the film200 and the degree of cross-linking.

Films assembled from naturally occurring polymers are

susceptible to non-specific degradation as a result of ubiquitous

peptidases and carbohydrases. In these cases, the entire bio-

polymer is degraded rather than having a specific sequence

recognized by the degradation enzyme. It has been demon-

strated that capsules and films assembled solely from DNA

can be engineered to contain restriction enzyme cut-sites,

which allow the DNA films to degrade only when that specific

enzyme (EcoRI) is present.184 It was shown that protein

(bovine serum albumin, (BSA)) can be encapsulated inside

the capsules and released specifically when EcoRI is present.

Rather than simply shedding material as the capsule is

degraded, the capsules shrink as the oligonucleotides in the

capsule wall are cleaved.

DOX-loaded PGA nanocapsules have been prepared via

templating silica particles with a solid core and mesoporous

shell.142 The potential of DOX-loaded PGA nanocapsules in

tumor therapy applications has been demonstrated by in vitro

degradation experiments.142 These studies showed a near-linear

release of the DOX in the presence of a lysosomal hydrolase.

The PGA-DOX capsules provide a unique drug delivery

system; they remain stable at physiological pH and are

amenable to degradation (by lysosomal hydrolases) in

response to enzyme stimuli within living cells, thereby delivering

DOX to tumor cells and causing tumor cell death. The

physiological pH of the bloodstream is 7.4, while subcellular

lysosomal compartments (endosomes and lysosomes) of tumor

cells have reducing environments and possess several hydro-

lytic enzymes at acidic pH (pH r 5.8). For a drug delivery

vehicle to be highly effective, it is desirable that it should not

degrade in the bloodstream; however, it should readily release

its cargo after reaching the lysosomal compartments.

4.3.3 Remotely controlled stimuli. Many smart materials

in bioengineering, nanotechnology and medicine allow the

storage and release of encapsulated drugs on demand at a

specific location by an external stimulus, by the action of

different external influences such as light, magnetic fields,

and ultrasonic radiation. Various reports suggest that these

external stimuli sources can penetrate the tissue well and can

deconstruct polymer assemblies to release cargo. A distinct

advantage of this technique is that cargo release can be

controlled remotely and on demand.

Light. Near-infrared (NIR) radiation has been used

extensively as an external release trigger because this stimulus

can be applied in a focused area, allowing localized release

from individual capsules. The use of NIR light is particularly

interesting for biomedical applications, as tissue absorption is

negligible in the region between 800 and 1200 nm. Sershen and

coworkers have developed a photothermally responsive macro-

scopic hydrogel (i.e. a copolymer of N-isopropylacrylamide

and acrylamide incorporating gold-gold sulfide nanoshells),

which undergoes a dramatic volume collapse upon illumina-

tion with NIR light.230,231 A number of materials with tunable

absorption characteristics (e.g., gold,192,232 and silver233) can

effectively absorb NIR light, leading to significant localized

heating. To this end, the fabrication of optically addressable

nanostructured capsules comprising a polyelectrolyte multi-

layer shell doped with light-absorbing gold nanoparticles has

recently been reported.192,232 Light-responsive microcapsules,

comprising PSS/PAH multilayers infiltrated with gold nano-

particles, were prepared via the LbL colloid-templating

technique. It was shown that the enzyme lysozyme can be

encapsulated within the polyelectrolyte/gold nanoparticle shell

via LbL assembly on the surface of lysozyme crystals and that

the enzyme can be released on demand without significant loss

of bioactivity following irradiation with short pulses of laser

light in the NIR region. The laser-induced release is attributed

to gold nanoparticle-mediated heating of the capsule shell,

which ultimately causes it to rupture, but without significantly

affecting the capsule cargo or surrounding cells.

Robbins et al. have studied the release of model proteins,

such as ferritin, encapsulated within PEO-PBD polymersome

lumen by light stimuli.234 The mechanism of release was found

to be photoinduced when a light-sensitive porphyrin chromo-

phore was loaded within the polymersome membrane. Ferritins

can accumulate large numbers of iron atoms and are therefore

well suited to be employed as magnetic resonance imaging

contrast agents.235 The polymersome morphology was altered

in response to light, as a result of the porphyrin-protein system

utilizing energy from light to generate a local temperature

increase, which triggered membrane fission. Such membrane

budding is analogous to the fission of cell organelle membranes

to generate vesicles which are used to transport materials/

various solutes from one cell organelle to another.

UV irradiation has also been used to release encapsulated

materials from polymeric microcapsules. For instance,

UV-responsive microcapsules, comprising PSS/PDDAmultilayer-

coated SiO2–TiO2, were prepared via the LbL colloid-templating

technique and sol–gel chemistry.236 After UV irradiation, the

SiO2–TiO2-polymeric capsules disassembled. The encapsu-

lated dyes were released on demand by UV irradiation

(1–20 mW cm�2). The capsules without TiO2 were unaffected

by UV irradiation. Hence, the UV-induced release is

attributed to the photocatalytic activity of the TiO2 com-

ponent for the decomposition of the polyelectrolytes,

which causes the capsules to rupture. This system is likely to

be interesting for applications in cosmetics and agriculture,

where UV light from direct sunlight (ca. 3 mW cm�2) can

trigger the release of encapsulated low-molecular-weight

substances.

Magnetic field. Numerous studies have been conducted on

applying magnetic particles to treat diseases, including cancer. A

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new concept for targeted and controlled release of anti-cancer

drugs using magnetic nanoparticle-decorated capsules has been

recently proposed. Themagnetic NPs were generally incorporated

inside the polymer shells via embedding,237 PE and NP LbL

assembly,238 and in situ catalysis synthesis.239 It has been reported

that capsule permeability can be modulated by an external

magnetic field to control the release of an encapsulated thera-

peutic. It has been proposed that the presence of magnetic

nanoparticles produces heat due to magnetic energy dissipation

(as Brown and Neel relaxations), and mechanical vibrations and

motions that induce stress development in the thin shell. Both

mechanisms significantly accelerated the relaxation of the shell

structure, causing a microstructural evolution.

Hu et al. have systematically studied the release behavior

of fluorescent dyes and DOX from polymeric capsules with

LbL-assembled magnetic nanoparticles.238 It was found that

the presence of the magnetic nanoparticles in the shell struc-

ture allowed the shell structure to evolve from nanocavity

development to rupturing of the shell under a given magnetic

stimulus over different times. Such a microstructural evolution

of the magnetically sensitive shell structure was used to explain

a corresponding variation in the drug release profile, from

relatively slow release to burst-like behavior at different time

stages within which the stimulus was applied. A cell culture

study also indicated that the magnetically sensitive micro-

capsules displayed rapid uptake kinetics by the (cancerous)

A549 cell line, suggesting that the magnetic-sensitive micro-

capsules with controllable shell rupturing behavior offer a

potential and effective drug carrier for anti-cancer applications.

Magnetically-sensitive alginate-templated polyelectrolyte

multilayer microcapsules were prepared by a process combining

emulsification and LbL techniques.240 The as-synthesized

microcapsules were superparamagnetic with a saturation

magnetization of 14.2 emu g�1, which contained approximately

30 wt% magnetic nanoparticles. The in vitro release behavior

under a high-frequency magnetic field (HFMF) indicated that

the applied HFMF significantly accelerated the drug (DOX)

release from the microcapsules.240

Ultrasonic radiation. Ultrasound has the benefits of being

‘‘a non-invasive, cheap, portable technique that is applicable to

a (large) part of the body’’170 and has been widely used in

medicine. To prepare polymeric capsules with high ultrasound

sensitivity, inorganic nanoparticles (e.g. Ag,241 Fe3O4,242

ZnO243) are embedded in the capsule shell. Capsule shells with

an increased number of embedded nanoparticles can, in some

cases, lead to a decrease in Young’s modulus and shell elasticity,

which is accompanied by an increase in fragility. Changing the

amount, size, and/or concentration of inorganic nanoparticles,

as well as the amount of polyelectrolyte in the shell, enables the

stiffness of the microcapsules to be tailored whilst significantly

improving their sensitivity to ultrasound radiation.

5.0. Conclusions and outlook

We have described the various techniques and molecular

interactions used to prepare polymer nanostructures at inter-

faces, including the assembly of LbL films and capsules,

grafted polymer brushes, membranes, liposomes, polymersomes,

micelles, hydrogels, and nanoporous particles, and also

multicomponent systems, such as the recently developed

capsosomes. Various emerging nanopatterning techniques,

such as colloidal lithography combined with CVD, provide

new methods for obtaining functional surfaces with ordered

domains for different applications. Furthermore, new self-

assembled structures, such as dendrimersomes, have emerged,

which show potential as novel carriers for the delivery of

therapeutic agents. The continuing emergence of new techniques

for polymer assembly will lead to the design and generation of

novel polymer nanostructured materials and architectures,

resulting in broad impact in fields underpinned by polymer-

based materials.

The nature of the interfaces used in polymer assembly also

plays a pivotal role in controlling the functionality of the

polymer materials obtained. Nanostructured polymer materials

assembled on both flexible and rigid interfaces have demon-

strated a number of uses and applications in fields as diverse as

drug delivery, diagnostics, biosensing, catalysis and optics.

Rigid interfaces are most widely applied, not only because of

their high mechanical stability but also because of the broad

range of geometries and morphologies available for such

interfaces. Recent progress in the assembly of polymer nano-

structures at spatially confined interfaces has led to the

emergence of new applications. The high surface area provided

by porous materials and the large number of functional groups

provided by the assembled polymer nanostructured materials

endow the hybrid materials with excellent adsorption

capacities, which may find applications ranging from separa-

tions and immobilization to drug delivery. The category of

flexible interfaces includes the interface between two immiscible

liquids, leading to the self-assembly of, for example, colloidal

particles, at the interface. Microcapillary devices have led to

the formation of highly monodisperse colloidosomes, with

applications ranging from sensing to controlled drug delivery

and release. Flexible interfaces also include microbubbles,

liposomes and capsosomes, the latter of which have the

remarkable ability to incorporate liposomes within a LbL

structured polymeric capsule for applications as a microreactor,

as well as being potentially beneficial to the field of therapeutic

delivery. Different sacrificial templates are emerging for the

preparation of freestanding films and capsules, with the benefit

of retaining the integrity of multicomponent systems, e.g. LbL

capsules incorporating micelles, the micelle component of

which is sometimes morphologically disrupted through the

template etching process. Furthermore, the development of

alternative yet suitable sacrificial templates (e.g., emulsion

droplets, calcium carbonate particles) may avoid the use of

toxic etching agents, such as HF.

Applications for interfacial polymer assemblies as coatings,

e.g. for coating vascular stents or to direct cell proliferation, is

well established. Polymer assemblies (e.g., capsules, thin films,

membranes, nanoporous particles) are also useful for the

immobilization and encapsulation of different cargo for drug

delivery applications. Immobilization of cargo in polymer

nanostructured materials can be achieved either via post-

loading or by using the cargo as a building component,

depending on both the properties of the polymer and the

nature of the cargo. Polymeric capsules have provided a

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versatile platform to encapsulate different types of cargo

molecules, ranging from small molecular drugs, to nanoparticles

and macromolecules. Various approaches have been demon-

strated in the incorporation of different types of substances

within polymeric capsules.

Release of the immobilized and encapsulated cargo in

response to specific stimuli is critical to the use of the polymer

assemblies as drug delivery vehicles. The internal stimulus can

induce a change of the polymer nanostructure in the local

environment, and hence trigger loaded cargo release at the

desired sites. While the advantage of the external stimulus is

that cargo release can be controlled remotely, the polymer

nanostructured materials are required to be decorated with a

light- or electromagnetic field-sensitive substance.

Given the recent advances in the techniques of polymer

assembly, sophisticated interface preparation, cargo immobili-

zation and encapsulation, and triggered release, we anticipate

that the unique combination of these techniques will play an

important role in the design of the next generation of polymer

based nanostructures for a range of different applications.

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