Self-Assembly Strategy for the Preparation of Polymer-Based Nanoparticles for Drug and Gene Delivery

Feature Article

576

Self-Assembly Strategy for the Preparation ofPolymer-Based Nanoparticles for Drug andGene Delivery

Si Chen, Si-Xue Cheng,* Ren-Xi Zhuo

Nanoparticulate drug-delivery systems have attained much importance because of theirinjectable property, the possibility to achieve passive targeting and active targeting, andunique advantages to realize stimuli tailored delivery. Molecular self-assembly is a powerfulmethod for fabricating polymer-based nanoparticles,which involves various driving forces, such as hydro-phobic interactions, electrostatic interactions, stereo-complexation, host/guest interactions and hydrogenbonding. By fine tuning one or many types of theseinteractions, self-assemblies with a wide range of struc-tures and functions could be fabricated. In this article,recent developments in different self-assembly strat-egies for the preparation of polymer-based nanoparticu-late delivery systems are discussed.

Introduction

Compared with conventional therapeutic systems, drug

delivery systems with the aim of achieving controlled,

systematic or site specific drug release over an extended

period of time offer numerous advantages, including

prolonged duration time, reduced side effects, improved

drug bioactivity and enhanced therapeutic efficiency.[1–3]

Among various formulations, nanoparticulate drug

delivery systems have attained much importance and

been extensively explored because of their injectable

property. In particular, for nanoparticulate drug delivery

systems with a hydrophobic core/hydrophilic shell struc-

ture, the hydrophilic shells could prevent the nanoparticles

S. Chen, S.-X. Cheng, R.-X. ZhuoKey Laboratory of Biomedical Polymers of Ministry of Education,Department of Chemistry, Wuhan University, Wuhan 430072,ChinaFax: þ86 27 6875 4509;E-mail: [email protected], [email protected]

Macromol. Biosci. 2011, 11, 576–589

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from aggregating and being trapped in the reticuloen-

dothelial system (RES) to ensure a long circulation period in

the blood. Thus the particles could be accumulated inmany

tumors via the enhanced permeability and retention (EPR)

effectwhen their sizes are inparticular ranges.[4–7] This is of

extreme importance in cancer treatment. In addition,

nanoparticles are of special interest for oral drug delivery

because their small size and large surface area favor their

absorption compared to larger carriers.

Molecular self-assembly is a rapid and powerful method

for fabricating nano-sized materials with various supramo-

lecular architectures, and self-assemblyhas been extensively

used to prepare polymer nanoparticles for drug and gene

delivery.A largenumberofpolymerswithdifferent chemical

structures have been reported for preparing self-assembled

delivery systems. The common hydrophilic shell-forming

segments include synthetic polymers such as poly(ethylene

glycol) (PEG)/poly(ethylene oxide) (PEO), poly[N-(2-hydro-

xypropyl)methacrylamide] (PHPMA), polyvinylpyrrolidone

(PVP), ionized pH-sensitive polymers, such as poly(acrylic

acid) (PAA), at particular pH ranges, thermosensitive

library.com DOI: 10.1002/mabi.201000427

Si Chen received his BS degree from WuhanUniversity in 2006. He is currently a PhD studentin the Department of Chemistry at Wuhan Uni-versity. His research is focused on functionalpolymers for drug and gene delivery.

Si-Xue Cheng received her BS degree from SouthChina University of Technology in 1992, an MSdegree from the University of Science and Tech-nology of China in 1995, and a PhD from theNational University of Singapore in 2000. In2001, she joined the Institute of MaterialsResearch and Engineering in Singapore as aresearch associate. From 2001 to 2003, shewas an associate professor in the Departmentof Chemistry at Wuhan University. Since 2003,she has been a professor at Wuhan University.Currently her main research interests arefocused on polymeric biomaterials, polymersand I/O hybrid materials for drug and genedelivery, and polymer self-assembly.

Ren-Xi Zhuo received his BS from Fudan Univer-sity in 1953. After graduation, he joined WuhanUniversity. He has been a professor since 1982.He was elected as an Fellow of the ChineseAcademy of Sciences in 1997. His research isfocused on biomedical polymers.

Self-Assembly Strategy for the Preparation of Polymer-Based . . .

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polymers based on poly(N-isopropylacrylamide) (PNI-

PAAm/PNIPAM) and polyphosphoesters (PPEs) at tempera-

tures lower than their lower critical solution temperatures

(LCSTs), and natural polymers such as polysaccharides

and their derivatives. The common hydrophobic core-

forming segments include poly(propylene oxide) (PPO),

poly(butylene oxide) (PBO), polystyrene (PS/PSt), polylactide

(PLA) including poly(D,L-lactide) (PDLLA), poly(D-lactide)

(PDLA) and poly(L-lactide) (PLLA), poly(lactide-co-glycolide)

(PLGA), poly(e-caprolactone) (PCL), poly(b-benzyl-L-aspartate)(PBLA), poly(g-benzyl-L-glutamate) (PBLG), poly(undecenoic

acid), polycarbonates such as poly(trimethylene carbonate)

(PTMC), deionized pH-sensitive polymers, such as poly-

(aspartic acid) (PAsp), poly(L-glutamic acid) (PGlu), poly-

(L-histidine) (PHis), and poly[4-(2-vinylbenzyloxy-N-

picolylnicotinamide)] [P(2-VBOPNA)] at particular pH

ranges, and thermosensitive polymers based on

PNIPAAm and PPEs at temperatures higher than their

LCSTs.[8–20]

To enhance the bioavailability of therapeutics and to

deliver therapeutic agents to particular tissues and cells,

ideal drug carriers should have stimuli responsibility

combined with target ability. Due to the small size and

the relatively large surface area, which facilitates the

functionalization of nanoparticles, nanoparticulate drug

delivery systems have unique advantages to realize stimuli

tailored drug delivery and to achieve active targeting

comparedwith other drug formulations. To endow the self-

assemblies with stimuli responsibility and target ability,

stimuli-responsive segments or motifs and targeting

ligands need to be introduced to the polymer chains. The

extensively investigated stimuli responsibilities of nano-

particles include pH, temperature, redox potential, glucose

level, light andmagnetic sensitivities. To achieve enhanced

synergy effects, double/multiple stimuli-responsive sys-

tems, which could achieve more functionalities and could

bemodulated throughdifferent parameters, have attracted

more and more research interest in recent years.[21–25] To

endow thenanoparticleswith an active targeting property,

numerous studies have been carried out on the incorpora-

tion of various targeting ligands to self-assemblies, mainly

through covalent bonds and the biotin/avidin interaction.

Frequently reported targeting ligands include monoclonal

antibodies,[26] peptides,[27] carbohydrates such as galactose

for hepatocyte targeting[28,29] and vitamins such as

folate.[30]

During the preparation of polymer-based self-assembled

nanoparticles, variousdriving forces for self-assembly, such

as hydrophobic interactions, electrostatic interactions,

stereocomplexation, host/guest interactions and hydrogen

bondingmaybe involved. Byfine tuning oneormany types

of these interactions, self-assemblies with a wide range of

structures and functions can be produced (Table 1). In this

article, we focus our discussion on recent developments in

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Macromol. Biosci. 201

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different self-assembly strategies and methods for the

preparation of polymer-based nanoparticle delivery sys-

tems, with highlights of their properties in drug and gene

delivery.

Self-Assembly of Polymer Nanoparticlesthrough Hydrophobic Interactions

Hydrophobic interactions are the most important

noncovalent interactions leading to the self-assembly

of polymers to form nanoparticulate drug and gene

delivery systems. Many types of self-assembled drug

formulations have been developed based on polymer

amphiphiles possessing both hydrophilic and hydrophobic

parts. It should be noted that, in some polymer self-

assembled systems formed through hydrophobic interac-

tions, other noncovalent interactions such as hydrogen

bonding and electrostatic interactions may also exist. For

the examples discussed in this section, the hydrophobic

interactions are the dominant driving force for the

self-assembly.

Self-Assembly of Polymers with Different Topologies

Amphiphilic polymers for preparing drug-loaded self-

assemblies mainly fall into one of five categorized

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Table 1. Properties of polymer-based nanoparticle self-assemblies with various noncovalent forces for drug and gene delivery.

Noncovalent force

involved in self-assembly

Typical self-assembly formed Drug and gene delivery properties

hydrophobic interaction micelles and vesicles composed of one or

various types of amphiphilic copolymers

with different architectures (linear, graft,

star, and hyperbranched structures)

hydrophobic drugs could be loaded in the

hydrophobic cores of micelles and the

lamellar bilayers of vesicles

hydrophilic drugs, peptides, proteins and

genes could be entrapped in the water-filled

cores of vesicles

DNA and RNA could be complexed with

cationic segments

self-assemblies with hyperbranched

structures exhibit improved drug loading

capacity and enhanced thermodynamic

and kinetic stabilities

mixed micelles and vesicles could achieve

multifunctionality (targeting ability,

stimuli-responsibility, etc.) and modulated

drug loading and release properties con-

veniently

electrostatic interaction micelles and vesicles composed of

polymers with oppositely charged

segments, or charged polymers and

oppositely charged compounds and ions

self-assemblies exhibit stimuli (pH- and

ionic strength-) responsivity

nanoparticles composed of oppositely

charged polyelectrolytes

nanoparticles composed of oppositely

charged cores (vector/gene complexes,

drugs, polymers and other templates)

and coating layers

drug release rate could be controlled by

adjusting the assembling multilayers

introduction of oppositely charged com-

ponents to vector/gene complexes could

reduce toxicity and incorporate target

ligands conveniently

stereocomplexation micelles composed of copolymers with

chiral segments with opposite chirality

stereocomplexation could improve

drug loading capacity and enhance

thermodynamic and kinetic stabilities

host/guest interaction micelles formed by polyrotaxanes Self-assemblies exhibit stimuli

(temperature, pH, and shearing) responsivity

nanoparticles formed by inclusion of

various compounds in cyclodextrins

free cyclodextrin cavities could further be

used to entrap drugs

hydrogen bonding micelles and vesicles with hydrogen

bonded parts

self-assemblies exhibit stimuli (pH)

responsivity

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S. Chen, S.-X. Cheng, R.-X. Zhuo

Figure 1. Polymer self-assemblies based on amphiphilic polymers with different archi-tectures: (a) diblock copolymer, (b) triblock copolymer, (c) graft copolymer, (d) starcopolymer, and (e) hyperbranched copolymer.

Figure 2. Polymer self-assemblies for delivery of different thera-peutics: (a) micelle for hydrophobic drug delivery, (b) vesicle forhydrophobic drug, hydrophilic drug and gene delivery, (c) cationicmicelle for gene delivery, and (d) cationicmicelle for co-delivery ofdrug and gene.


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architectures: linear, graft, star, hyperbranched and den-

dritic topologies.[8,9] Among these copolymers, the diblock

[Figure 1(a)] and triblock copolymers [Figure 1(b)] are the

most intensively studied copolymers for self-assembly.

Compared with linear block copolymers, amphiphilic

graft copolymers[31,32] [Figure 1(c)] most commonly can

easily form micelles and form smaller micelles because of

the possibility of forming micelles within several polymer

chains.Moreover, themicelleproperties canbeeasilyvaried

by simply adjusting the graft frequency and length of the

branches. However, in general, the micelles formed by

amphiphilic graft copolymers are more likely to form

aggregates since hydrophobic chains in such micelles are

less mobile and more loosely packed compared with those

in micelles formed by block copolymers.[8]

To improve the drug loading capacity, star amphiphilic

copolymers[33–35] have been developed because the multi-

hydrophobic block architecture could increase the drug

loading for hydrophobic drugs.[33,34] For example, the

analysis of intermolecular interactions indicated that a

star copolymer containing 3 PCL blocks and 1 PEG block,

designated as PEO-b-3PCL [Figure 1(d)], exhibited much

stronger interactions with the drug compared with the

linear PEG-b-PCL copolymer.[35]

For clinical applications, the stability ofmicelles is one of

themajor concerns, since themicelles tend todisassemble if

the polymer concentration is below the critical micelle

concentration (CMC). With the potential for achieving

enhanced stability in dilute solution and in vivo, hyper-

branched and dendritic copolymers have received increas-

ing interest [Figure 1(e)].[36–39] Because of the hyper-

branched structure, the hyperbranched copolymers



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generally have much lower CMC values

when compared with the linear block

copolymers. For instance, the polymer

which contains a polar hyperbranched

polyphosphate head group and many

aliphatic tails has a CMC of 19 to

3.9mg � L�1 when the grafting ratio of

alkyl tails is from 0.63 to 0.90.[36]

Polymeric Self-Assemblies forDelivery of Different Therapeutics

Developments inpharmaceuticshave led

to the discovery of more and more new

therapeutics. To satisfy the delivery

requirements of various therapeutic

agents with a wide range of properties,

different polymer self-assemblies with

different structureshavebeendeveloped.

For hydrophobic drug delivery, the

classic self-assembled core/shell micelles

with hydrophobic cores and hydrophilic

shells can successfully enhance the water solubility of

poorly soluble drugs and thus increase their bioavailability

through encapsulating drugs in their hydrophobic cores

[Figure 2(a)].

For the delivery of drugswith different hydrophobicities,

polymersomes, which are self-assembled vesicles based on

amphiphilic copolymers, have a unique benefit because

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their water-filled cores allow for the encapsulation of

hydrophilic drugs,[40] peptides, proteins and genes,[41] in

addition to the entrapment of hydrophobic drugs in their

lamellar bilayers [Figure 2(b)]. For example, polymersomes

prepared from the diblock copolymer PEG-PTMBPEC with

an acid-labile poly(2,4,6-trimethoxybenzylidenepentaery-

thritol carbonate) (PTMBPEC) block were used to co-deliver

the hydrophobic drug paclitaxel (PTX) and the hydrophilic

drug doxorubicin hydrochloride (DOX �HCl) simulta-

neously. Polymersomes with average sizes of 100–

200nm were stable at pH¼ 7.4, and underwent fast

hydrolysis at a mildly acidic pH of 4.0–5.0. As a result,

the drug releasewas significantly faster atmildly acidic pH

compared to physiological pH. This property endowed the

polymersomeswithgreatpromise for combination therapy

for cancers.[42] Through conjugating the strong hydropho-

bic anti-cancer drug camptothecin (CPT) to a short oligomer

chain of ethylene glycol, an amphiphilic phospholipid-

mimicking prodrug was synthesized, which could form

stable liposome-like nanocapsules with the capability to

load water soluble drugs such as DOX �HCl with a high

loading efficiency. The obtained nanocapsules could

produce a synergistic cytotoxicity to cancer cells through

co-delivery of two anti-cancer drugs.[43]

For gene (pDNA, siRNA and shRNA) delivery, polymer

self-assemblies most commonly need to have cationic

segments to form complexes with DNA or RNA through

electrostatic interactions. It is well known that cationic

polymers are themost intensively studied polymer vectors

for gene delivery. Although many cationic polymers

provide high in vitro gene transfection efficiency, the

stability of the cationic polymer/DNA complexes is not

satisfactory for in vivo gene transfection. Through incor-

poration of hydrophilic polymer chains into various

cationic polymers, the stability of the polymer/DNA

complexes in the blood could be improved by preventing

protein absorption and the uptake of macrophages, mono-

nuclear phagocytes and RES. Recently, many amphiphilic

cationic polymer self-assemblies [Figure 2(c)] have been

designed and synthesized for gene delivery. For instance,

PEO-b-PCL based copolymers with various polyamine side

groups on the PCL block were synthesized for siRNA

delivery. The copolymers exhibited significant gene knock-

down activities through the effective release of siRNA in

HEK293 cells.[44] When compared with poly(L-lysine) (PLL)

and PLL-PEG, PLL-PEG-dimethylmaleic anhydride modified

mellitin (PLL-PEG-DMMAn-Mel) exhibited a significantly

improved performance in mediating gene knock down in

serum containing media due to the enhanced stability of

PLL-PEG-DMMAn-Mel/siRNA complexes.[45] Other reported

amphiphilic cationic block copolymers include triblock

copolymer mPEG-b-PCL-b-PPEEA, consisting of mono-

methoxy PEG, PCL and cationic poly(2-aminoethylethylene

phosphate) (PPEEA) blocks for siRNA delivery,[46] a RGD-



modified triblock copolymer PEG-b-PLLA-b-PLL containing a

cationic PLL block for targeting gene delivery,[47] and

PEGylated poly{(N-methyldietheneamine sebacate)-co-

[chloesteryloxocarbonylamidoethylmethylbis(ethylene)-

ammonium bromide] sebacate} [PEG-P(MDS-co-CES)] for

pDNA delivery.[48] It was found that the PEGylation could

decrease the cytotoxicity of the gene vector and the

hydrophobic moiety, such as cholesterol, on the polymer

chain led to an enhanced gene expression level.[48] Besides

block copolymers, amphiphilic cationic graft copolymers

havealsobeenreported forgenedelivery.A typical example

is the fluorine-containing amphiphilic graft copolymer

poly(HFMA-St-MOTAC)-graft-PEG with a backbone based

on poly(hexafluorobutyl methacrylate) (PHFMA), PSt and

poly(methacryl oxyethyl trimethylammonium chloride)

(PMOTAC) for pDNA delivery.[49]

A unique advantage of amphiphilic cationic copolymers

is the ability to co-deliver drug and gene [Figure 2(d)]. For

example, a PDMAEMA-PCL-PDMAEMA triblock copolymer

containing cationic poly(2-dimethylaminoethyl methacry-

late) (PDMAEMA) blocks could form micelles for the

combinatorial delivery of siRNA and lipophilic anti-cancer

drugs.[50] An amphiphilic graft polymer PEI-g-PCL with

cationic polyethylenimine (PEI) chains could assemble into

micelles for the co-delivery of DOX and pDNA.[51] An

oligopeptide amphiphile containing three blocks of amino

acids, Ac-(AF)6-H5-K15-NH2 (FA32), which could self-

assemble into cationic micelles with an average size of

102nm,wasused as a carrier for the co-delivery ofDOXand

p53genewithasynergy in cytotoxic effect, i.e., an increased

gene expression level as well as an enhanced inhibition

effect for HepG2 cells.[52]

Except for binding genes through electrostatic interac-

tions, genes can also be physically encapsulatedwithin the

inner water phase of polymer vesicles.[53] For example,

poly[2-(methacryloyloxy)ethylphosphorylcholine]-block-

poly[2-(diisopropylamino)ethyl methacrylate] (PMPC-

PDPA) diblock copolymer can form vesicles with sizes of

200–400nm. The PDPA block was pH-sensitive, which

switched from being hydrophobic at physiological pH to

hydrophilic in mildly acidic conditions. DNA could be

encapsulated within vesicles at neutral pH, whereas

lowering the pH led to the formation of DNA/copolymer

complexes.[53]

Mixed Micelles and Mixed Polymersomes Self-Assembled through Hydrophobic Interactions

To improve the drug loading and release property and to

realizemulti-functionality in drug delivery, a large number

of studies have been focused on mixed polymeric micelles

to take on the advantages of different types of copolymers.

For example, core/shellmicelles constituted fromtwoblock

copolymers, PHis-b-PEG and PLLA-b-PEG-b-PHis-biotin,

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Figure 3. Mixed micelles and mixed vesicles: (a) pH sensitive mixed micelle withtargeting ligands, (b) multifunctional mixed micelle, and (c) mixed vesicles.


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could realize pH-sensitive ligand exposure for tumor

targeting, i.e., the cell interacting ligand (biotin) was

exposed on the micelle surface under the slightly acidic

environmental conditions of various solid tumors. Besides,

the micelles also showed pH-dependent dissociation,

causing the enhanced release of DOX at early

endosomal pH [Figure 3(a)].[54] Mixed micelles formed

from AP peptide (CRKRLDRN) conjugated PEG-b-PLA block

copolymer (AP-PEG-PLA) (10 wt.-%) and the pH-responsive

block copolymer methyl ether poly(ethylene glycol)-block-

poly(b-amino ester) (MPEG-PAE) showed a sharp pH-

dependent micellization/demicellization transition at the

tumoral acid pH. The mixed micelles presented a higher

tumor specific targeting ability in vitro and in vivo.[55]

Mixedmicelles composed ofmPEG-b-PLAand temperature-

sensitive methoxypoly(ethylene glycol)-block-poly(N-pro-

pylacrylamide-co-vinylimidazole) [mPEG-b-P(NnPAAm-co-

VIm)] were stable during storage and could disintegrate in

the body because the body temperature exceeded the cloud

point of mPEG-b-P(NnPAAm-co-VIm).[56] Mixed micelles

fabricated from PLGA-PEG-folate and D-a-tocopherylpo-

ly(ethylene glycol) succinate (TPGS) synthesized by the

esterification of vitamin E succinate with PEG achieved

a high drug encapsulation efficiency (EE) for DOX since




TPGS has a high emulsification effi-

ciency.[57] Mixed micelles prepared from

MPEG-b-PLA and Pluronic triblock poly-

mer exhibited enhanced stability com-

pared with the Pluronic micelles.[58]

Mixed micelles self-assembled from

PEG-block-poly(aspartate-hydrazide)

modified with levulinic acid (LEV) con-

jugated with PTX [PEG-p(Asp-Hyd-LEV-

PTX)] and PEG-block-poly(aspartate-

hydrazide) modified with 4-acetyl ben-

zoic acid (4AB) conjugatedwithPTX [PEG-

p(Asp-Hyd-4AB-PTX)] could easily

achieve a controlled drug release rate

by simply adjusting the mixing ratio

of two copolymers.[59] Micelles self-

assembled from lactose-PEG-PLA and a

rhodamine-containing copolymer PEG-b-

poly[L-lactide-co-(2,2-dihydroxylmethyl-

propylene carbonate/rhodamine] [PEG-b-

P(LA-co-DHP/rhodamine)] with a size in

the range 60–100 nm were used for

targeted drug delivery to human liver

cancer cells.[60] Mixed micelles con-

structed from poly [(2-hydroxylethyl

methacrylate)-co-histidine]-graft-PLA

with a pH-sensitive main chain and

diblock copolymers PEG-b-PLA with dif-

ferent functional moieties (Cy5.5 for

biodistribution diagnosis and folate for

tumor cell targeting) [Figure3(b)] exhibitedapHstimulated

drug release property. An in vivo study revealed that the

mixed micelles exhibited cancer targeting properties.[61]

Beside the frequently reported core/shell micellar

structures, a mixture of copolymers may self-assemble

into membrane-enclosed vesicular structures [Figure 3(c)].

For example, mixed polymersomes comprising two block

copolymers poly 2-(methacryloyloxy)ethylphosphorylcho-

linepoly[2-(diisopropylamino)ethyl methacrylate] (PMPC-

PDPA) and PEO-PDPA formed at a pH higher than the pKa of

PDPAcoulddiffuse into full thickness tissueengineeredoral

mucosa in the in vitro model, indicating their clinical

potential for intra- and/or trans-epithelial delivery of

therapeutic agents.[62]

Polymer Nanoparticles Self-assembledthrough Electrostatic Interactions

Electrostatic interactions are another important class of

noncovalent interactions to induce the self-assembly of

polymers and to form nanoparticles for drug and gene

delivery. Most commonly, the electrically charged parts in

the self-assemblies are sensitive to the environment, such

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Figure 4. Polymer nanoparticles self-assembled through electrostatic interactions: (a) micelle formed by block copolymers with oppositelycharged segments, (b) vesicle formed by block copolymers with oppositely charged segments, (c) micelle formed by a block polymers and apolyelectrolyte with opposite charges, (d) nanoparticle formed by polyelectrolytes with opposite charges, (e) nanoparticle formed by apositively charged vector/DNA complex with a negatively charged coating layer (f) micelles formed by a charged polymer and an oppositelycharged compound, (g) polymeric micelle with crosslinked ionic core, and (h) nanoparticles formed by LbL assembly.

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as the pH of the media. As a result, the self-assemblies

formed through electrostatic interactions exhibit stimuli

responsivity.

Self-assemblies formed from block copolymers with

oppositely charged ionic segments, which are termed

‘‘polyion complex’’ (PIC) micelles [Figure 4(a)] or vesicles

[Figure 4(b)] are frequently reported systems self-

assembled through electrostatic interactions for drug and

gene delivery. For example, complex micelles could be

assembled fromPS-b-PNIPAM-b-PAAandPEG-block-poly(4-

vinylpyridine) (PEG-b-P4VP) block copolymers via the

strong electrostatic interaction between PAA and P4VP

blocks. The micelles consisted of a core of PS blocks and a

shell composed of PAA/P4VP complex and PEG segments.

Between the core and the shell, the fluid-filled space, which

was formed with the thermo-responsive PNIPAM seg-

ments, could pump the drug out of the micelles when the

temperature increased.[63] Through mixing a pair of

oppositely charged block copolymers in an aqueous

medium, polymersomes may also be formed. These

polymer vesicles are given a new terminology, namely

‘‘PICsomes’’. Typical examples are PICsomes based on

positively charged PEG-block-poly(a,b-aspartic acid) (PEG-



PAsp) and negatively charged PEG-block-poly[(2-ami-

noethyl)-a,b-aspartamide] [PEG-P(Asp-AE)] or PEG-block-

poly[(5-aminopentyl)-a,b-aspartamide] [PEG-P(Asp-AP)].[64]

PICsomes formed by PEG-PAsp and PEG-P(Asp-AP) at an

equal residual ratio of –COO– to –NHþ3 units could

encapsulate Myoglobin, which formed stable oxygen

adducts in muscle, in the PICsome cavity for sustained

release.[65]

Self-assemblies can also be formed by a block copolymer

andapolyelectrolytewithopposite charges. Itwas reported

that a series of primary, tertiary and quaternary amine-

baseddiblockcopolymerswithPEGsegmentscould interact

with heparin at acidic pH to yield assemblies of less than

30nm [Figure 4(c)]. The dissociation of the complexes

occurred with an increase in ionic strength and basifica-

tion.[66] Other self-assembly pairs reported include natural

polyampholyte N-carboxyethylchitosan (CECh) and weak

polycationic (protonated) polyoxyethylene-block-poly[2-

(dimethyl-amino)ethyl methacrylate] (POE-b-PDMAEMA)

diblock copolymers, which could form nanoparticles in a

narrow pH range around 7.0,[67] mPEG-block-poly(a,L-

glutamic acid) diblock copolymer and chitosan,[68] poly-

amidoamine (PAMAM) dendrimer and a monoclonal

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antibody fragment incorporated PEG-block-poly[(propyl

methacrylate)-co-(methacrylic acid)] [PEG-b-P(PrMA-co-

MAA)] for siRNA delivery.[69]

PICs are sensitive to the environment, such as ionic

strength or pH. Although this property is useful for stimuli-

responsive delivery, the instability is unfavorable for some

particular applications. By introducing hydrophobic inter-

actions, PICs could be stabilized. A representative work

involved using anionic amphiphilic copolymer g-PGA-g-L-

Phe(g-PGA-Phe), which was obtained by the modification

of poly(g-glutamic acid) by hydrophobic L-phenylalanine

(L-Phe), as a component to form PICs with cationic

poly(e-lysine). The resultant PICs exhibited significantly

improved stability under physiological conditions.[70]

Two polyelectrolytes with opposite charges can form

self-assembled nanoparticles [Figure 4(d)]. For instance,

the complexation of dextran sulfate or alginate with

chitosan resulted in nanoparticles with a diameter

ranging from 423–850nm, which could be used for

insulin delivery.[71]

Introducing oppositely charged polymers to polycation

gene vectors through electrostatic interactions is an

important strategy to reduce the toxicity and to improve

the in vivo stability of gene delivery systems. For example,

negatively chargedpeptides containingRGD ligands coated

onto positively charged poly(b-amino ester)/DNA com-

plexes could reduce potential toxicity and facilitate cell and

tissue-specific gene delivery [Figure 4(e)].[72,73] In siRNA

delivery, using the complexes formed by electrostatic

complexation of negatively charged hyaluronic acid (HA)

and cationic poly(L-arginine) (PLR) to condense siRNA could

significantly reduce the cytotoxicity.[74] In addition to

improved biocompatibility, electrostatic complexation can

also be utilized to introduce target ligands to gene delivery

systems. For instance, heparin-biotin couldbe coatedon the

surface of polyamidoamine dendrimer/DNA complexes via

electrostatic interactions to form PAMAM/DNA/heparin-

biotin terplexes, which exhibited much higher cellular

uptake into HeLa cells due to the specific interactions

between biotin and biotin receptors on the HeLa cells.[75]

In addition to a pair of oppositely charged polymers,

nanoparticles can also be formed by a charged polymer and

an oppositely charged compound. For instance, the cationic

block copolymer PEG-poly{N-[N’-(2-aminoethyl)-2-ami-

noethyl]aspartamide} [PEG-pAsp(DET)] could form stable

micelles with anionic modified proteins. After the PIC

micellesenteredcells, themodifiedproteinswereconverted

to the original proteins.[76] Nanosized complex micelles

could be spontaneously produced from ionic interactions

between folate incorporated PEG-conjugated oligonucleo-

tide and a cationic lipid, lipofectamine,which could beused

for target gene delivery.[77] The block copolymer PEO-block-

poly(tert-butyl methacrylate) (PEO-b-PMA) and an oppo-

sitely charged surfactant (hexadecyltrimethylammonium




bromide) formed nanoparticles with sizes in the 60–90nm

range [Figure 4(f)]. Decreasing the ionization degree of the

PMA block upon decreasing the pH caused elevation of the

particle size at pH< 5.5, followed by formation of large

aggregates at pH< 4.[78] Two types of negatively charged

polymers (one with an S–S bond) and a positively charged

surfactant could formmicelle-typeassemblies,whichcould

bedisassembled throughtailoringtheredoxcharacteristics,

ionic strength and pH of the medium.[79] Due to the

electrostatic interaction between the polymers with

negatively charged segments and cationic ions, polymeric

micelles with crosslinked ionic cores could be formed. For

example, PEO-block-poly(methacrylic acid) and Ca2þ could

formmicelles displaying pH- and ionic strength-responsive

properties [Figure 4(g)].[80,81]

The layer-by-layer (LbL) assembly technique based on

electrostatic interactions is commonly used to fabricate

films and microsized particles, yet LbL assembly can also

been utilized to prepared nanosized particles. For LbL

assembly, inorganic substrates, such as CaCO3, MnCO3 and

CdCO3, which can be conveniently removed by dissolution

with an ethylenediamine tetraacetate (EDTA) solution, are

now used more frequently.[82] For the purpose of drug

delivery, drug nanoparticles can be used as the cores for LbL

assembly [Figure 4(h)]. As reported, nanoparticles could be

formed by the LbL assembly of poly(allylamine hydro-

chloride) and poly(styrene sulfonate) (PSS) on the surface of

drug nanoparticles (dexamethasone, a steroid used in

conjugation with chemotherapy) followed by further

modification through covalently attaching PEG to the outer

surface of the nanoparticles.[83] Through ultrasonic treat-

ment of microsized poorly soluble drug particles (the anti-

cancer drugs tamoxifen and PTX), the size of drug particles

could be decreased to the nano level (between 100 and

200nm). Through LbL coating of the polycation poly(di-

methyldiallylamideammonium chloride) (PDDA) and

negatively charged PSS, a stable coated nanocolloidal drug

dispersion was formed with a high drug loading content.

The drug release rate from such nanocolloidal particles

could be easily controlled by adjusting the density and

thickness of the assembling multilayers. After further

introducingmonoclonalnucleosome-specific2C5antibody,

the nanoparticles showed promising application for cancer

targetingdrugdelivery.[84] The LbLassembly techniquewas

also applied for the surface modification of biodegradable

PLGA nanoparticles, using PAA and PEI as building blocks.

After five layers of PAA and PEI were deposited, the

multilayers were crosslinked with amino terminated PEG

or amino terminated folate decorated PEG (PEG-FA). These

nanoparticles couldpotentiallybeusedas specific targeting

carriers for anti-cancer drugs.[85] Other reported cores for

LbL assembly include sulfate modified fluorescent poly-

styrene nanobeads with a diameter of 200nm for LbL

deposition of PLL, chitosan and heparin sulfate,[86] and gold

1, 11, 576–589


Figure 5. Polymer nanoparticles self-assembled through stereo-complexation: (a) diblock stereo copolymer, (b) triblock stereocopolymer, (d) Y-shaped stereo copolymer, and (d) graft stereocopolymer.

584

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nanoparticles with a size of �10nm for LbL coating with

poly(allylamine) (PAH) and PSS.[87]

Polymer Nanoparticles Self-Assembledthrough Stereocomplexation

In comparison to low-molecular-weight surfactant

micelles, polymeric micelles feature unique attributes,

including higher thermodynamic and kinetic stabilities.

However, for in vivo applications, the stability of polymeric

micelles still remains a major concern. It is reported that

micelles prepared from PEG-b-PDLLA dissociated after

intravenous injection and were rapidly excreted in urine.

Chemical crosslinking of either core or shell segments is the

common strategy to retain the integrity of polymer

micelles.However, the crosslinkingmayunfavorably affect

the bioactivity of encapsulated drugs and the biodegrad-

ability of the system. Stabilizing the core through stereo-

complex formation is an alternative strategy, which could

overcome the disadvantages caused by the chemical

crosslinking.[88]

The most commonly studied polymers for stereocom-

plexation are PDLA and PLLA.[89] Other polymers that could

form stereocomplexes, investigated for biomedical pur-

poses, include enantiopure homopolymers of N-acryloyl-

D,L-leucine methyl ester.[90]

In previous studies, the PDLA/PLLA segment contained

copolymerswith various architectureswere synthesized to

form stereocomplex self-assemblies. The investigated

stereocomplex pairs include block copolymers PEG-b-

PDLA/PEG-b-PLLA [Figure 5(a)],[88,91,92] PDLA-b-PEG-b-

PDLA/PLLA-b-PEG-b-PLLA [Figure 5(b)],[93] Y-shaped copo-

lymers [Figure 5(c)] PEG-PDLA-PDLA/PEG-PLLA-PLLA, PEG-

PLLA-PDLA/PEG-PDLA-PLLA[94] and the graft copolymers

dextran-g-PLLA/dextran-g-PDLA [Figure 5(d)].[95]

Due to the stereocomplexation, stereocomplex self-

assemblies exhibit strong thermodynamic stability as well

as kinetic stability, and stereocomplex micelles are less

prone to aggregation during the lyophilization pro-

cess.[88,95] In addition, both drug loading level and

encapsulation efficiency could be improved through

stereocomplexation,[92] and the drug release is slower from

stereocomplex micelles than it is from corresponding

conventional micelles without stereocomplexation.[92,94]

Besides, the polydispersity of stereocomplex micelles is

lower compared with conventional micelles.[94]

Polymer Nanoparticulate Self-Assemblieswith Host/Guest Interactions

Host/guest interactions have always been considered to

be an important class of noncovalent interactions for

inducing self-assembly. For biomedical applications, the



most commonly investigated host/guest interactions are

based on the cyclodextrins (CDs). CDs are a series of cyclic

oligosaccharides with a hydrophobic cone-shaped central

cavity, which can act as hosts for many macromolecular

guests to form polyrotaxanes (PRs) by threading CD

molecules onto polymer chains with the inclusion driven

by the geometric compatibility and hydrophobic interac-

tions between the CDs and the polymer segments.[96] The

interactions in PRs can be cleaved by temperature changes

and pH changes to induce ionization of the polymer

segments and shearing. As a result, CDmolecules canmove

along the polymer chain and even de-thread, resulting in

thedisassociationof thePRaggregates. Thisunique stimuli-

response character is favorable in controlled drug release.

Generally, to form PR-based self-assemblies with host/

guest interactions, other noncovalent interactions, such

as hydrogen bonding among CDs and hydrophobic inter-

1, 11, 576–589


Figure 6. Polymer nanoparticles self-assembled through host/guest interactions:(a) micelle formed by PEO-b-PAA with PEO segment threaded in CDs, (b) micellesformed by a polymer with CDs in side groups through hosting hydrophobic smallmolecules and a polymer with hydrophobic groups, (c) nanoparticles formed by a graftcopolymer with hydrophobic side chains and a cyclodextrin polymer, and (d) nanopar-ticle formed through CD/Ad recognition.


www.mbs-journal.de

actions, are still involved in the self-assembly. For example,

PEG-b-PLL with PEG segments threaded in a-CDs could

form pH switchable nanoparticles. At pH> 10, PLL seg-

ments became less soluble and aggregated in aqueous

solution, leading to gel formation.[97] PEO-b-PAA with PEO

threaded in a-CDs could self-organize to formmicelleswith

a spherical shape and a size of 100nm in alkaline media

[Figure 6(a)]. Decreasing the pH led to the deionization of

free PAA segments and thus made assemblies fuse to form

microspheres.[98]

In addition to forming assemblies through threading CD

molecules onto polymer chains, CD-based self-assemblies

can be formed in other patterns. For instance, diblock

copolymer PEG-b-PCDwith a PEG block and a block bearing

b-CD side groups could be dissolved in water, and could

assemble into core/shell nanocarriers if the b-CDs in the

side groups served as the hosts and formed inclusion

complexeswithvariouscompounds includinghydrophobic

small molecules such as pyrene and particular polymers




such as poly(b-benzyl-L-aspartate) (PBLA)

[Figure 6(b)]. The assemblies prepared by

this procedure exhibited chemical sensi-

tivity, which was of importance for

responsive delivery and bio- or chemical

sensing.[99] The association of two hydro-

soluble polymers, dextranbearinghydro-

phobic lauryl side chains and a cyclodex-

trin polymer (b-CD crosslinked with

epichlorohydrin), in aqueous media led

to the formation of spherical-shaped

nanogels of 100–200nm due to the

inclusion of lauryl chains in b-CD moi-

eties [Figure 6(c)]. The remaining

unthreaded b-CD cavities were available

for the inclusion of hydrophobic mole-

cules. [100] Using three building blocks,

adamantine-grafted polyamidoamine

dendrimer (n-Ad-PAMAM), b-CD-grafted

branched polyethylenimine (CD-PEI) and

Ad-functionalized PEG (Ad-PEG), supra-

molecular nanoparticles through CD/Ad

recognition could be prepared

[Figure 6(d)]. By tuning the mixing ratios

of the three building blocks, the sizes of

the nanoparticles could be controlled

from 30–150nm.[101]

To prepare self-assemblies based on

CDs, a great challenge that exists is the

insolubility of CD-based self-assemblies

in most solvents because of the strong

intermolecular hydrogen bonds between

CDs, leading to the unfavorable precipi-

tation of CD-contained amphiphiles.

Using modified CD derivates, such as

maleic anhydride modified a-CD, could effectively over-

come this problem through weakening the intermolecular

hydrogen bonding.[102]

Polymer Nanoparticulate Self-Assemblieswith Hydrogen Bonding

Hydrogen bonding interactions exist in many self-

assembled systems, with association of other noncovalent

interactions such as hydrophobic interactions and electro-

static forces. Yet, in some self-assembly systems, the

hydrogen bonding interactions are of critical importance

in the self-assembly process. In this section, only systems

with hydrogen bonding that plays a critical role in self-

assembly and the properties of the self-assemblies are

discussed.

It has been reported that, in addition to hydrophobic

interactions, hydrogen bonding between PVPhol segments

im585

Figure 7. Polymer nanoparticle self-assemblies with hydrogenbonding: (a) micelle formed by two block copolymers with hydro-gen bonded PVP and PVPhol segments as a core (yellow area), (b)micelle formed by two block copolymers with hydrogen bondedP4VP and PAA segments as amiddle layer (yellow area), (c) micelleformed by a star terpolymer with hydrogen bonded PEG andPMMA segments as a core (yellow area), and (d) vesicle withhydrogen bonding between stilbazole group and gallic acidgroup.

586

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and PVP segments played an important role in the

formation of mixed micelles composed of two copolymers,

tris(dibenzoylmethanato)europium(III)-coordinated

poly{N-isopropylacrylamide-co-4-(1-ethyl-1H-imidazo[4,5-

f][1,10]phenanthrolin-2-yl)phenyl methacrylate}-block-

polyvinylphenol [P(NIPAAm-co-EIPPMMA)-b-PVPhol] and

FITC-conjugated poly[N-isopropylacrylamide-co-(hydroxy-

lethyl methacrylate]-block-polyvinylpyridine [P(NIPAAm-

co-HEMA)-b-PVP] [Figure 7(a)]. The fluorescence properties

of the micelles could be controlled by temperature and pH

changes due to the phase transition of temperature

sensitive PNIPAAm contained segments and the deproto-

nation/protonation of PVP segments. An in vitro study

showed that the micelles incorporated by A549 cells also

exhibited temperature and pH-sensitive fluorescence.[103]

Among hydrogen-bonded self-assemblies, an important

class is the stimuli-responsive micelles, where their pH

sensitive segments deionize at particular pH ranges and

thus the hydrogen bonding becomes the dominant driving

force to induce the self-assembly. A good example is multi-



layered micelles prepared using three copolymers, PS-b-

PAA, PNIPAM-b-P4VP and PEG-b-P4VP. The micelles were

composed of a core of PS segments, a middle layer

constructed through the electrostatic interactions and

hydrogen bonding between the PAA block and the P4VP

block, and a corona consisting of PNIPAM and PEG chains

[Figure 7(b)]. At temperatures higher than the LCST, the

PNIPAMchains collapsedonto thePAA/P4VP complex layer

while the PEG chains still stretched into the solution

through the collapsed PNIPAM layer,which could act as the

hydrophilic channels for drug release. The drug release rate

could be controlled by changing the ratio of PEG chains to

PNIPAM chains in the corona.[104] Another typical example

is self-assemblies based on the ABC miktoarm star

terpolymer PEG(-b-PMAA)-b-PDEA consisting of PEG, poly-

(methacrylic acid (PMAA)) and poly[2-(diethylamino)ethyl

methacrylate (PDEA)] arms. PEG(-b-PMAA)-b-PDEA could

self-assemble into three types of aggregates at different

pHs, namely, at pH< 4, hydrogen bonding interactions

between fully protonated PMAA and PEG led to the

formation of micellar aggregates stabilized by protonated

PDEA coronas [Figure 7(c)]; at pH¼ 5–7, micelles possessed

polyion complex cores formed by charge compensation

between partially ionized PMAA and partially protonated

PDEA sequences; above pH¼ 8,micelleswith deprotonated

PDEA cores and PEG/ionized PMAA coronas were

formed.[105]

As well as hydrogen bonded micelles, hydrogen bonded

vesicles have also been reported. For example, vesicleswith

a bilayer structure could be formed by Py-EO12 (a PEO chain

with a stilbazole head group) and TCB-COOH (a dendron of

gallic acid with three alkyl chains) through hydrogen

bonding between the stilbazole group and the gallic acid

moiety [Figure 7(d)].[106]

Other Self-assembled Polymer Nanoparticles

In addition to the dominant noncovalent interactions

inducing theself-assemblydiscussedabove, somepolymer-

based self-assembled systems may involve multi/inter-

molecular interactions. For example, in some natural

polymer-based self-assembled systems, the self-assembly

is realized by precisely adjusting the hydrophilic/hydro-

phobic balance of the polymer chains by the addition of

inorganic ions. The natural polymers, such as alginate and

pectin with carboxyl groups, have particular pKa values. In

basic and neutral solutions, the polymer chains exist in the

form of a stretching conformation, due to the repulsion

betweenthedeprotonatedcarboxylgroups, andhaveahigh

hydrophilicity. While in an acidic solution, the polymer

chains tend to aggregate because of the protonation of

carboxyl groups, which leads to the decreased hydrophi-

licity. Precisely controlling the hydrophilic/hydrophobic

1, 11, 576–589



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balance of the polymer chains is critical to inducing self-

assembly of natural polymers. As ionic polysaccharides,

alginateandpectinhavetheability tobinddivalent cations,

and the divalent cations can induce interchain association,

leading to the formation of junction zones. As reported,

through adjusting the concentrations of Ca2þ ions, which

coordinate with alginate[107] and pectin[108] chains, and

carbonic ions (CO2�3 ), which stabilize the systems due to the

electrostatic interaction with Ca2þ ions, the hydrophilic/

hydrophobicbalanceof thenaturalpolymerchainscouldbe

fine tuned, i.e., the polymer chains in theCa2þ-rich domains

became more condensed, whereas the polymer chains in

the Ca2þ deficient domains had the stronger electrostatic

repulsion between the –COO– groups and thus had a higher

affinity with water molecules. The hydrophilicity differ-

ence between the Ca2þ rich domains and the Ca2þ deficient

domains led to the formation of aggregates with different

morphologies includingnanospheresandvesicles.With the

presence of Ca2þ and CO2�3 in the natural polymer-based

nanospheres/vesicles, thepermeabilityof theencapsulated

drug could be reduced, resulting in effectively sustained

drug release. The release rates from nanospheres and

vesicles were strongly affected by the pH value of the

release medium. Another example of inducing the self-

assembly of natural polymers is to use K2S2O8 as amediate

proton donor agent to prepare assemblies of alginate by

partial protonation of carboxyl groups in alginate chains in

water. The decreased number of dissociated carboxylic

groups in alginate chains made alginate lose its hydro-

philicity to some extent, leading to the formation of

alginate assemblies. The size of the alginate assemblies

decreased with decreasing pH because of the increased

hydrophobic segments in the alginate chains.[109]

Summary and Perspectives

Despite the numerous efforts rendered on versatile nano-

sized delivery systems based on polymers with different

chemical structures and properties for the delivery of

different therapeutics (chemotherapeutic agents, proteins,

DNAs and RNAs), in vivo experimental data to comprehen-

sively understand the influence of polymer structures and

long time polymer degradation on the fate of drugs is still

very limited. Since toxicological and immunological issues

for new polymers and carriers are of high concern, features

that are often ignored during the research phase, more

extensive work combining expertise in chemistry, phar-

maceutics and biology is urgently required.

In the years to come, it is expected that the emergence of

nanotechnology platforms and progress in pharmaceutics,

biology and polymer science will catalyze the further

development of multifunctional nanoparticulate delivery

systems to meet the ultimate goal for controlled drug




release, which is to maximize therapeutic activity while

minimizing the negative side effects of the drug.

Acknowledgements: Financial support from National NaturalScience Foundation of China (21074099) is gratefully acknowl-edged.

Received: October 21, 2010; Published online: December 27, 2010;DOI: 10.1002/mabi.201000427

Keywords: drug delivery systems; micelles; nanoparticles; self-assembly; vesicles

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Self-Assembly Strategy for the Preparation of Polymer-Based Nanoparticles for Drug and Gene Delivery

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