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Polymer Vesicles

Ionel Adrian Dinu, Christoph Edlinger, Evgeniia Konishcheva, Cornelia G. Palivan* and Wolfgang Meier*Department of Chemistry, University of Basel, Basel, Switzerland

Synonyms

Artificial vesicles; Nanocompartments; Polymer hollow spheres; Polymersomes

Definition

Polymer vesicles, called polymersomes, are hollow spherical supramolecular assemblies composedof an aqueous cavity surrounded by a polymer membrane. Polymersomes are generated by self-assembly of amphiphilic copolymers in dilute solutions.

Introduction

In nature, compartmentalization plays a fundamental role in supporting life processes, such asmetabolic reactions, transfer in/out of compounds, and signaling. In this respect cells representessential compartments both in terms of complex processes taking place in situ and for exchange ofcompounds through their lipidic membrane with embedded membrane proteins. The simplest modelto mimic the cell membrane and its compartment topology is with lipid vesicles, liposomes. Favoredfor their structural analogy to cell membranes, biocompatibility, and biodegradability, liposomeswere extensively studied as carriers for therapeutic or diagnostic purposes. However, the presence ofmembrane defects which induce mechanic instability of liposomes and undesired release of encap-sulated compounds required new solutions for more stable compartments. Because the limitations ofliposomes are not entirely solved by covering them with a polymer shell (e.g., using poly(ethyleneglycol), PEG, in so-called PEGylation), synthetic analogues of liposomes were introduced. Com-pared to liposomes, polymersomes have higher mechanic stability, based on a thicker membrane(3–5 nm compared to 7–20 nm, respectively). In addition, their stability can be improved by cross-linking the polymer membrane [1]. Polymersomes can simultaneously encapsulate hydrophilicmolecules in the aqueous cavity and hydrophobic molecules within the membrane (Fig. 1). Inaddition, specific molecules can be conjugated to the exterior surface to target the vesicles or toimmobilize them on solid support [2].

Properties of polymer vesicles, such as size, stability, membrane thickness, flexibility, andpermeability, are significantly influenced by the chemical nature of the copolymers. By an appro-priate selection of the copolymer’s chemical composition, molecular weight, polydispersity, blocklength, and hydrophilic-to-hydrophobic ratio, the characteristics of the self-assembled assemblies,and in particular vesicles, can be individually tuned for each individual application. A particularlyinteresting strategy is to design vesicle membranes based on stimuli-responsive block copolymers

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Encyclopedia of Polymeric NanomaterialsDOI 10.1007/978-3-642-36199-9_266-1# Springer-Verlag Berlin Heidelberg 2014

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because they induce dramatic changes of properties in the presence of the specific stimulus. Stimuli-responsive copolymers support development of vesicles able to change “on demand,” with prom-ising applications in nanomedicine. Polymersomes serve for encapsulation/entrapment of activemolecules resulting in a variety of hybrid assemblies, such as drug delivery systems, carriers forcontrast agents, nanoreactors, and artificial organelles [2].

Synthesis of Amphiphilic Block Copolymers

Amphiphilic block copolymers (AmBPs) consist of at least one hydrophilic and one hydrophobicblock sequentially connected by covalent bonds. The resulting copolymer is composed of domainswith opposite affinities for an aqueous solution. They self-assemble in solvents, which are selectiveonly for one of the constituent blocks and can generate supramolecular assemblies with a widevariety of architectures, such as micelles, worms, tubes, or vesicles [3]. Depending on the compo-sition, molecular weight, and relative length of the hydrophilic and hydrophobic blocks, it is possibleto favor the formation of assemblies with a specific architecture or properties.

AmBPs are synthesized from a large variety of monomers following several synthetic routes: (i) asequential controlled or living polymerization [4], (ii) a simple coupling reaction of homopolymers(by click chemistry) [5], and (iii) two consecutive polymerizations reactions, the first reactionserving to produce a preformed polymer used as macroinitiator for the second polymer reactionwith a different mechanism than the first one [4].

(i) Living polymerization reactions (anionic and cationic) are frequently used to synthesizeAmBPs [4], in which the reactions proceed in the absence of an irreversible chain transfer andchain termination. However, both living polymerization methods are significantly affected by thesolvent nature and the presence of water and impurities and have limited applications for thesynthesis of copolymers with functional groups as side chains. Therefore, in order to synthesizeAmBPs with hydrophilic blocks having acidic or hydroxylic functional groups as side chains,protected monomers must be employed, which require deprotection after polymerization.Recent developments in controlled radical polymerization (CRP) methods provide a functionalgroup side chain compatible route to synthesize AmBPs. These methods are less affected by thepresence of impurities and provide conditions for a chain growth based on a rapid and dynamicequilibrium between dormant chains and propagating radicals [4]. Poly(N-(3-aminopropyl)

Fig. 1 Schematic representation of a polymersome (A) which can insert channel proteins or biopores within themembrane (B); can encapsulate proteins, enzymes, or mimics in the aqueous cavity (C); or can be functionalized onits surface (D)


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methacrylamide hydrochloride)-b-poly(N-isopropylacrylamide) (PAMPA-b-PNIPAM), poly(styrene)-b-poly(L-isocyanoalanine (2-thiophen-3-yl-ethyl)amide) (PS-b-PIAT), and poly(acrylic acid)-b-polystyrene-b-poly(4-vinyl pyridine) (PAA-b-PS-b-P4VP) are examples ofAmBPs synthesized by CRP methods [6–8]. When these synthetic methods are used to poly-merize acidic monomers such as acrylic acid, protected monomers are necessary.

(ii) Click chemistry methods allow the synthesis of well-defined block copolymers with a widevariety of functional groups as side chains or end groups. The functional groups of AmBPs canbe quantitatively and selectively modified by using relatively mild conditions without any sidereactions. Avariety of homopolymers can be coupled by click chemoselective reactions betweentheir functional end groups such as (a) thiol-ene/thiol-yne additions; (b) thiol–disulfideexchange; (c) modification of epoxides, anhydrides, oxazolines, and isocyanates by reactionwith amines/alcohols/thiols; (d) Michael-type addition; (e) copper-catalyzed azide alkynecycloaddition; (f) reaction of active esters with amines; (g) modification of ketones andaldehydes with amines/alkoxyamines/hydrazines; and (h) Diels–Alder reactions [5]. Clickchemistry methods represent relatively safe and easy synthetic routes to create new AmBPs,to improve their interaction with specific molecules, and to bind specific molecules (proteins,enzymes, DNA) [2]. However, the use of click chemistry for synthesis of AmBPs is limitedwhen the homopolymers have a different solubility in the selected solvent and does not allow forprecise control of their molecular weight.

(iii) Polymerization method based on two different consecutive polymerizations reactions, wherethe first serves to produce a preformed polymer used as macroinitiator for the second reaction, isanother method to design vesicle-forming AmBPs [4]. The end-group functionality of themacroinitiator can be achieved by in situ modification or by pretreatment of the prepolymerafter the first polymerization. This method is used to produce symmetric triblock copolymers,such as poly(2-methyloxazoline)-b-poly(dimethylsiloxane)-b-poly(2-methyloxazoline)(PMOXA-b-PDMS-b-PMOXA) copolymers by starting from bifunctional macroinitiators [7].

Examples of AmBPs

There are a large variety of vesicle-forming AmBPs with linear, branch, graft, star, or dendriticstructure, relevant examples are included in Table 1 [6–8]. For example, polystyrene–poly(propyl-ene imine) dendrimer is able to self-assemble and generate vesicles in aqueous solutions [6]. Byselecting the nature of the constituent blocks, the resulting copolymer can possess special properties,such as biodegradability, biocompatibility, or stimuli responsiveness. Stimuli-responsive AmBPsgenerate “smart” vesicles, which release the encapsulated molecules “on demand,” when thestimulus is present [6, 8]. Poly(butadiene)-b-poly(g-L-glutamic acid) (PB-b-PGA) vesicles undergoreversible coil–helix transition in response to pH changes [6], while those based on PAMPA-b-PNIPAM are temperature responsive, and those based on poly(ethylene glycol)-SS-poly(-propylene sulfide) (PEG-SS-PPS) are sensitive to reducing environments [8]. An interesting strategyto improve properties is achieved when synthetic blocks are coupled with natural ones, such aspolypeptides, nucleic acids, or polysaccharides [9]. In this respect, poly(L-lysine)-b-poly(L-tyrosine)and poly(L-glutamic acid)-b-poly(propylene oxide)-b-poly(L-glutamic acid) are polypeptide-basedcopolymers, which form polymersomes [9].


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Table 1 Examples of vesicle-forming AmBPs

Copolymer Structure Properties References

PMOXA-b-PDMS-b-PMOXA

SiO

Si ON

O

ON

Oxy y

Selectivepermeabilityand ability toincorporatemembraneproteins

[3, 7]

PS-b-PIAT

HNH

O

N

N

tBu

O

NH

m n

S

Selectivepermeability

[3, 7]

PAA-b-PS-b-P4VP O

O

N

m

n o

pH-responsive [6]

PB-b-PGA

NH

NH2

O

OH

O

n m p

pH-responsive [6, 8]

PAMPA-b-PNIPAM

HN

NH3 Cl

O

HN

O

n m

Temperatureresponsive

[8]

PEG-SS-PPS MeO

OO S S

SS

m n

Sensitive toreducingenvironments

[6, 8]


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Preparation of Polymer Vesicles

The driving force of the self-assembly process is the amphiphilic nature of the copolymers: thehydrophobic domain aggregates, to minimize its contact with water, while the hydrophilic domainsbecome hydrated and stabilize the supramolecular assembly in solution.

In order to form vesicles (Fig. 2), an AmBP has to adapt to a conical shape supporting theformation of a curved membrane [10]. An appropriate balance of the hydrophobic and hydrophilicforces, resulting from a hydrophobic fraction of 10–35 wt% of the AmBP, favors polymersomeformation, while other hydrophobic-to-hydrophilic ratios induce the formation of micelles, worms,or mixtures [1]. In addition, the solubility properties of AmBPs in water impose a specific route togenerate supramolecular assemblies, in particular vesicles. For example, poor water soluble AmBPsare used to generate vesicles in aqueous media, in the presence of detergents, which stabilize thecopolymers.

There are two main routes for vesicle formation: (i) dissolution of the AmBPs in water and(ii) dissolution of the AmBPs in a solvent and subsequent mixture with an excess of water.

(i) Dissolution of AmBPs in water serves as basis for three methods of polymersome preparation:direct dissolution method, film rehydration method, and electroformation method.

The easiest method for polymersome formation is the direct dissolution method, in which thepolymer is directly mixed with an aqueous solution, and agitated (shaking, stirring, vortexing, orsonication) at a desired temperature, 3D assemblies are formed indicated by opaqueness in thesolution. Film rehydration method for polymersome formation is based on a temporarily dissolu-tion of the AmBPs in a solvent to produce a thin polymer film upon evaporation, followed by thehydration of the film. This method generates high polymer surface area for fast rehydration andmorecontrolled conditions for vesicle formation than the direct dissolutionmethod [10].Electroformationmethod consists of hydration of the polymer film in the presence of an oscillating electric field,resulting in the formation of vesicles with sizes in the mm range (giant vesicles).

(ii) Solvent-assisted preparation methods for polymersome formation are kinetic trapping, ther-modynamic trapping, and double emulsion. They require a solvent capable of dissolving thepolymer and which is miscible with water. These methods allow the use of a large variety ofAmBPs but have drawbacks of the organic solvent being difficult to remove completely,interacting with the formed membrane, and denaturation of sensitive molecules such as proteins,enzymes, or siRNA [10, 11].

Fig. 2 Schematic representation of a polymersome generated by a triblock AmBP


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Kinetic trapping is a preparation method in which a polymer solution is injected into anexcess of water, inducing a fast phase inversion. Thermodynamic trapping is a preparationmethod in which an excess of water is slowly added to the polymer solution, enabling the systemto equilibrate [10]. A slightly different approach is the formation of double emulsions in whichan aqueous solution containing the molecules intended to be encapsulated inside the vesicle isemulsified with a nonmiscible organic phase that contains the polymer. The oil phase isdispersed in a second aqueous medium by stirring or centrifugation, so that the solution isincluded into an oil drop, which serves for droplet formation, in a second aqueous phase. Thismethod is used to create giant vesicles and offers the advantage of a very high encapsulationefficiency [11]. The removal of the remaining organic solvents is achieved through reducedpressure or, more efficiently, through dialysis.

The specificity of the preparation method influences the size of polymersomes and the encapsu-lation efficiency of the molecules in the aqueous cavity of the vesicles [2, 10]. Independent of thepreparation method, the solutions containing polymersomes require to be “purified” by removingsolvents, detergents, unencapsulated molecules, and other 3D assemblies, such as micelles, worms,or larger aggregates. The purification of the polymersome solution is usually achieved through sizeexclusion [10] or dialysis, the latter being better suited for solvent residues and detergents [12]. Thecontrol of the vesicle size and the removal of aggregates also represent an important step and areachieved by repeated extrusion through a filter [10] or by sonication [1].

Stability and Permeability of Polymer VesiclesAmBPs self-assemble and form membranes that are thicker (10–25 nm thickness) than lipidicmembranes (to 3–5 nm) [13] and are usually less permeable. The stability of polymersomes dependson the strength of the hydrophobic interactions between the hydrophobic segments inside themembrane. High temperature, the presence of solvents and detergents, or a broad size distributionof the AmBPs decreases the interactions, resulting in a lower mechanical stability of the membrane.A balance between the flexibility of the membrane, which allows an insertion of biomoleculeswithout denaturation, and the stability of the membrane must be achieved [3]. The gelation of theaqueous content of vesicles by in situ polymerization is a method to increase the stability of thevesicles but has to be carefully considered when biomolecules are intended to be encapsulated insidethe aqueous cavity in order to not affect their structure or biologic activity [13]. A more commonapproach for stabilization of vesicles is cross-linking of the membrane by polymerization ofhydrophobic monomers inserted in the membrane. However, addition of monomers can affect themembrane, and the radical polymerization used for cross-linking can induce aggregation of vesicles[10]. The best way to stabilize vesicles is direct cross-linking of AmBPs, by polymerization ofexisting molecular groups, alkene groups, for example.

The permeability of vesicle membranes is important when transportation of molecules throughthe membrane is required, such as when polymersomes serve as compartments for the design ofnanoreactors and artificial organelles. The vesicle membrane is rendered permeable by (i) usinga specific chemical composition of AmBPs, (ii) chemical modification of the membrane, or (iii)insertion of channel proteins. For example, PS-b-PIAT copolymers form porous membranes [13],while PMOXA-b-PDMS-b-PMOXA membranes, known as highly impermeable except to oxygenspecies, are permeabilized by an elegant method based on insertion of channel proteins [3]. Variouschannel proteins have been successfully inserted in PMOXA-b-PDMS-b-PMOXA membranes andsupported a rapid transport of substrates into the membrane or products involved in in situ enzymaticreactions out of the membrane.


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An alternative method to create defects in an impermeable membrane is based on the insertion ofspecific molecular groups that are degraded in particular conditions. Inserted hydrophilic photosen-sitizers on the surface of the vesicles disrupt the membrane upon irradiation [13]. The effect can betuned by adjusting the concentration of the photosensitizer. Larger defects can be produced in themembrane of polymersomes by washing out domains of “sacrificial” AmBPs [10] or lipids [13],which are specially inserted for permeabilization of the membrane. These defects destabilize themembrane, and by carefully controlling the conditions, the vesicles preserve their overall sphericalarchitecture. Also, the insertion of pH-sensitive groups (e.g., 2-(diethylamino)ethyl methacrylate) inthe hydrophobic domain of the membrane induces a pH-dependent swelling, which destabilize themembrane and increase its permeability [13]. The pH responsiveness of one of the polymer domainscan be used to completely disintegrate the membrane when an “on demand” release of theencapsulated compound is intended. Stimuli responsiveness of polymersome membrane representsa smart approach to release the encapsulated compounds in desired conditions provided by thepresence of a specific, or combination of, stimulus (physical, chemical, enzymatic).

Functionalization of the Surface of Polymer VesiclesWhen the intended use of polymersomes includes targeting approaches or immobilization onsurfaces, it is necessary that their external surface contains specific molecular groups. Thefunctionalization of polymersomes with exposed functional groups can be achieved either prior tovesicle formation by using AmBPs with the corresponding functional groups or by modification ofthe polymersomes via click chemistry. The two main risks regarding polymersome functionalizationare unintended interactions of the functional groups and their deep insertion into the membrane dueto hydrophobicity making them inaccessible [10, 14]. There are a large variety of possible functionalgroups and related reactions, which can be used to decorate a polymersome surface for each desiredapplication. For example, a selective and robust reaction (in pH ranging from 4 to 12) isalkyne–azide cycloaddition, often regarded as the archetype of a click reaction. It has the advantagethat the terminal bromine groups can be directly substituted by azides for AmBPs synthesized byATRP [14].

Molecular recognition interactions, based on specific molecule pairs, as, for example, biotin/streptavidin or antigen–antibody, represent an elegant way to be used for targeting or immobilizationof polymersomes [2, 3]. In order to specifically interact with the target cell, polymer vesicles arefunctionalized with specific molecules, such as RGD-peptides (integrin binding), folic acid [14], orpolyguanylic acid [1].

Methods of Vesicle Characterization

3D supramolecular assemblies, and in particular polymersomes, are characterized by variousscattering methods combined with microscopy methods (Fig. 3).

By measuring scattering properties of supramolecular assemblies, it is possible to establish theirsize, size distribution, morphology, and critical aggregation concentration. Light scattering method(LS) is applied when the size of assemblies, in particular vesicles, ranges from 100 nm up to severalmm. In dynamic light scattering (DLS), fluctuations in the scattered light intensity on the microsec-ond time scale appear because of the diffusion of assemblies in a solution. Hydrodynamic radius ofassemblies (Rh) is obtained by using Stokes–Einstein equation with an angle-dependent apparentdiffusion coefficient (Dapp) and by extrapolation to zero concentration and zero momentum transfer[3]. Weight-average molecular weight (Mw), z-average radius of gyration (Rg), and the second viral


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coefficient (A2) are evaluated from static light scattering experiment (SLS). A2 gives informationabout particle–particle and particle–solvent interactions [3], while the ratio Rg/Rh, (r-parameter)indicates the morphology of the assembly. Theoretically, for thin vesicles r ¼ 1.0, for homogeneoushard balls r ¼ 0.779, and for polymers in extended conformations r > 1 [3]. The experimentalvalues obtained for r-parameter allow identifying the formation of vesicles in a solution upon theself-assembly process. LS is a fast and precise technique but present [3].

Light scattering method is used in combination with the electrophoretic mobility of assemblies toobtain the zeta potential of vesicles [15]. In addition, stopped-flow spectroscopy serves to study thepermeability of the vesicle membrane or the kinetics of vesicle formation [16].

If a solution contains assemblies with a size from few nm up to 100 nm, small-angle X-ray(SAXS), wide-angle X-ray (WAXS), or small-angle neutron (SANS) scattering methods can beapplied to characterize them. SAXS is applied to very dilute solutions, where the distances betweenparticles are much higher than their size, and allows the characterization of both polydisperse andmonodisperse assemblies. For monodisperse assemblies, SAXS provide information about theirshape, aggregation number, and inner structure. However, monodispersity of the assemblies has tobe proven by other methods [17]. SANS is a very useful tool for the investigation of the nativestructure of assemblies and interaction parameters. Unlike SAXS, SANS is very sensitive towardlight elements and allows a more detailed investigation based on isotope labeling [17].

For direct visualization of supramolecular assemblies generated by self-assembly, in particular theformation of vesicles, various microscopy methods are used and the appropriate method selectiondepends on the assembly size or the structural details to be evaluated. Microscopy methods allow theestimation of morphology, size, and homogeneity of the supramolecular assemblies and representa complementary proof of vesicle formation. In the case of giant vesicles with diameters above 1 mm,optical microscopy is a very simple and fast method that can be used to characterize them in solution.However, it has limited magnification, resolution, and contrast compared to electron microscopy[12, 15]. Polymersomes with sizes in the nanometer range are studied by electron microscopy.Transmission electron microscopy (TEM) provides a high-resolution (<1 nm) image of a specimen(Fig. 4). This technique is based on the interaction of a high-energy electron beam, which passesthrough the sample containing the assemblies. However, the high vacuum and the dried state of thesample, which are necessary for TEM, might affect the vesicles morphology in case of instablepolymer membranes. Cryogenic TEM (cryo-TEM) serves for the investigation of vesicles in theirnatural hydrated state and enables the study of micellar polymorphism, spontaneous formation ofvesicles, and their transition to lamellar or multilamellar structures [12].

Fig. 3 The most commonly applied methods of characterization for polymer vesicles


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Direct visualization of polymer vesicles with sizes large enough to be visualized by opticalmicroscopy can be analyzed by fluorescence microscopy if the vesicle membrane is labeled witha fluorescent dye. This method has several advantages, such as high sensitivity, ability to distinguishspecific nonfluorescent regions which are appropriately labeled, and the possibility of multiplelabeling for visualization of individual molecules [12]. However, this technique has disadvantagesof limited resolution (>0.2 mm), a decrease of the fluorescent intensity of dyes due to photo-bleaching, and the possible generation of reactive chemical species under illumination whichpromote a phototoxic effect [3].

A particular type of fluorescence microscopy is laser scanning confocal microscopy (LSCM),which allows obtaining images with a high resolution and contrast due to the reduction of thebackground fluorescence and an improved signal-to-noise ratio [12].

Fluorescence correlation spectroscopy (FCS) is based on a special fluctuation correlationapproach, in which the laser-induced fluorescence of the excited fluorescent molecules that passthrough a very small probe volume is auto-correlated in time to give information about the diffusiontimes of the molecules. The diffusion times, which are proportional to the RH of the fluorescentmolecules, provide information about interactions of the fluorescent molecules with larger targetmolecules, including formation of vesicles or encapsulation inside their cavity [18]. Fluorescencecross-correlation spectroscopy (FCCS) expands the FCS method by introducing two differentlylabeled particles, which provide a positive cross-correlation readout when bound to each other orlocated in the same carrier, thus diffusing through the confocal volume in a synchronized way. Incontrast, the probability of simultaneous movement of freely diffusing fluorophores is so small that itcan be neglected. The method is used for simultaneous characterization of vesicles and encapsulatedcompounds or for dynamic co-localization of different molecular in vesicles [19].

Scanning tunneling microscopy (STM) can be performed on conducting substrates and atomicforce microscopy (AFM) on both conducting and nonconducting substrates to obtain images witha few Å resolution. These techniques have been applied to investigate polymer vesicles immobilizedon a solid support [12].

Pulse gradient spin-echo NMRmethod (PGSE NMR) has been proposed to establish the size andsize distribution of polymer vesicles and give information regarding the presence of interaction/aggregation phenomena [20].

Fig. 4 Microscopy images of polymer vesicles. (a) TEM and (b) cryo-TEM images of PDMS-PMOXA-OH polymervesicles, (c) LCSM micrograph of giant polymersomes of PEG-PLA in the presence of Nile red (Reprinted withpermission from reference [12], Copyright 2005 Elsevier)


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Conclusion and Outlook

Polymer vesicles, as robust and straightforward produced compartments, can be modulated andeasily control the sizes and assembly properties. Because of their diverse applications, polymervesicles represent ideal candidates for applications in medicine, catalysis, environmental sciences,or food sciences. The large variety of AmBP supports the generation of polymer vesicles witha desired size, permeability, or responsitivity. These assemblies can be advanced further through thecombination of polymersomes with active compounds, such as enzymes, proteins, DNA, andmimics, in order to design active systems, such as nanoreactors and artificial organelles.Polymersomes are necessary to shield the biomolecules and prevent their degradation by harmfulenvironmental conditions to maintain the active component’s specific activity, such the productionof drugs, the detoxification of reactive oxygen species, and sensing of a specific molecule. Thesesystems are gaining popularity today in various research fields and lead to the development newstrategies for delivery of assemblies at a nanometer scale.

Related Entries

▶Micelles and Vesicles▶Molecular Assemblies of Block Co-polymers in Solutions▶ Self-Assembly of Hyperbranched Polymers▶ Stimuli-responsive Polymers

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