Advanced Drug Delivery Reviews 54 (2002) 169190

www.elsevier.com/ locate/ drugdeliv

Poly(ethylene oxide)-block-poly(L-amino acid) micelles for
drug delivery
a a b ,
*
Afsaneh Lavasanifar , John Samuel , Glen S. Kwon
a
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8, Canada
b
School of Pharmacy, University of WisconsinMadison, 777 Highland Ave., Madison, WI 53705-2222, USA
Abstract
Block copolymer micelles encapsulate water insoluble drugs by chemical and physical means, and they may target
therapeutics to their site of action in a passive or active way. In this review, we focus on micelles self-assembled from
poly(ethylene oxide)-block-poly(L-amino acid) (PEO-b-PLAA). A common theme in these studies is the chemical
modication of the core-forming PLAA block used to adjust and optimize the properties of PEO-b-PLAA micelles for drug
delivery. Micelle-forming block copolymerdrug conjugates, micellar nanocontainers and polyion complex micelles have
been obtained that mimic functional aspects of biological carriers, namely, lipoproteins and viruses. PEO-b-PLAA micelles
may be advantageous in terms of safety, stability, and scale-up. 2002 Elsevier Science B.V. All rights reserved.
Keywords: Block copolymer micelles; Drug delivery; Poly(ethylene oxide); Poly(L-amino acid); Conjugates; Encapsulation; Water insoluble
drugs; Passive drug targeting
Contents
1. Introduction ............................................................................................................................................................................ 170
2. Functional properties of polymeric micelles for passive drug targeting ........................................................................................ 170
2.1. Water solubility ............................................................................................................................................................... 170
2.2. Biocompatibility .............................................................................................................................................................. 171
2.3. Micellar stability.............................................................................................................................................................. 171
2.4. Biological half-life ........................................................................................................................................................... 171
2.5. Morphology..................................................................................................................................................................... 172
2.6. Drug loading ................................................................................................................................................................... 173
2.7. Release characteristics ...................................................................................................................................................... 173
3. Polymeric micelles versus surfactant micelles for drug delivery .................................................................................................. 174
4. Block copolymer micelles used for drug delivery....................................................................................................................... 175
5. Micelle-forming PEO-b-PLAAs for drug delivery ..................................................................................................................... 178
5.1. Micelle-forming block copolymerdrug conjugates ............................................................................................................ 178
5.2. Micellar nanocontainers.................................................................................................................................................... 181
5.3. Polyion complex micelles ................................................................................................................................................. 184
6. Conclusions ............................................................................................................................................................................ 185
References .................................................................................................................................................................................. 186
*Corresponding author. Tel.: 11-608-265-5183; fax: 11-608-262-3397.
E-mail address: gsk@pharmacy.wisc.edu (G.S. Kwon).
0169-409X/ 02/ $ see front matter 2002 Elsevier Science B.V. All rights reserved.
PI I : S0169- 409X( 02) 00015- 7
170 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190
1. Introduction enhance properties of PEO-b-PLAA micelles for
drug delivery [33,34].
The concept of selective delivery of drugs to their
site of action was rst introduced by Paul Erhlich
early in the 20th century. He proposed a Magic 2. Functional properties of polymeric micelles
Bullet, i.e. carriers with specic afnity for certain for passive drug targeting
organs, tissues or cells for drug targeting [1]. Since
then delivery systems such as liposomes, micro- Carriers should meet several requirements for
spheres and nanoparticles have been developed for effective drug delivery, including water solubility,
this purpose. In many cases they have been able to non-toxicity, non-immunogenicity, lack of long-term
widen the gap between the efcacy and toxicity, accumulation in host, in vivo stability and selective
i.e. therapeutic index of drugs. There is still a long delivery to the target site. Besides a capacity for the
way towards a real Magic Bullet, however. encapsulation of poorly water-soluble drugs, the
Among different drug carriers used for controlled carrier is required to prevent drug release before
drug delivery, there has been a rising interest in reaching the site of action to achieve targeted drug
self-assembled block copolymers over the past de- delivery. The multiple properties of the core/ shell
cade [214]. This is owed to the similarity of structure in polymeric micelles (Fig. 1) allow the
polymeric micelles to natural carriers, e.g. viruses simultaneous fullment of these somewhat opposing
and serum lipoproteins. Polymeric micelles mimic requirements.
aspects of biological transport systems in terms of
structure and function. A hydrophilic shell helps 2.1. Water solubility
them to stay unrecognized during blood circulation
[15,16]. A viral-like size ( ,100 nm) prevents their Polymeric carriers often tend to precipitate in
uptake by the reticuloendothelial system and facili- water due to a localized hydrophobicity caused by
tates their extravasation at leaky sites of capillaries, the drug and the hydrophobic portion of the poly-
leading to passive accumulation in certain tissues meric chain. The problem is more signicant for
[1720]. The small size may also ease further drugpolymer conjugates where functional water-
penetration of the micellar carrier to cells. The soluble groups of the drug (e.g. amino and carboxyl
incorporation of recognizable moieties on micellar groups) are converted to more hydrophobic groups
surfaces [2124] or the development of thermo or
pH sensitive block copolymers [25,26] has been
pursued to enhance cellular interaction in specic
sites for active targeting. Finally, polymeric micelles
have been used for gene delivery and have shown a
great potency in directing therapeutics to sub-cellular
targets [11,27].
The multifunctional nature of polymeric micelles
appears to full several tasks required for an ideal
carrier capable of selective drug delivery at different
levels. Emphasis has been placed on micelles made
of poly(ethylene oxide)-b-poly(L-amino acid) (PEO-
b-PLAA) as synthetic analogs of natural carriers with
a unique ability for chemical modication. Free
functional groups on a PLAA block provide sites for
the attachment of drugs [2830], drug compatible
moieties [31,32] or charged therapeutics such as
DNA [27]. In either case, it may be possible to ne
tune the structure of the core-forming block and Fig. 1. Sketch of a polymeric micelle loaded with drug in core.
A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190 171
(e.g. amide) by the conjugation process. Typically, sociation rate may exist for polymeric micelles
with a core/ shell structure, the polymeric carrier below the CMC, and polymeric micelles may not
may stay water-soluble if the number of monomers necessarily exist in equilibrium with polymeric un-
in the shell-forming block is more than that of the imers [8,9]. Kinetic stability may be high for poly-
core-forming block. meric micelles with stiff or bulky core-forming
blocks due to hindrance of rotation. The strength of
2.2. Biocompatibility cohesive forces may be characterized by glass transi-
tion temperature (T ) [45], degree of crystallinity and
g
Toxicity studies have been mostly carried out on cross-linkage in the micellar cores.

Pluronics , block copolymers composed of PEO and Micelles are subject to extreme dilution upon
poly(propylene oxide) (PPO) (PEO-b-PPO-b-PEO). intravenous injection into humans. If kinetically
They are fairly safe, particularly those with a high stable, slow dissociation allows polymeric micelles
content of PEO [35,36]. PEO is widely used in the to retain their integrity and perhaps drug content in
design of non-immunogenic carriers. Block copoly- blood circulation above or even below CMC for
mers with biodegradable core-forming blocks such as some time. This may give them a chance to reach the
polyesters and poly(L-amino acids) (PLAAs) are of target site before decaying to single chain unimers.
increasing interest because they may undergo hy- In this situation, interactions of polymeric micelles
drolysis and/ or enzymatic degradation, producing with components of blood (serum proteins) and cells
biocompatible monomers. Polyesters such as poly- must be weighed in terms of micellar stability and
(D,L-lactic acid) (PDLLA) have been used safely in drug release.
humans for a long time. Studies on the biocom-
patibility of PLAAs are few. Nevertheless, results 2.4. Biological half-life
indicate a dependence of enzymatic degradability
and immunogenicity on the chemical structure and/ Long circulation times are prerequisite to achieve
or physicochemical properties of PLAA chains [37 depot properties. Carriers with insufcient stabilities
41]. tend to break up and be removed rapidly from blood
Lastly, block copolymers have molecular weights by kidneys. The molecular weight of polymeric
21 6 21
less than 50,000 g mol and can undergo renal micelles ( .10 g mol ) prevents renal elimination
clearance [5]. unless the micelle structure dissociates to unimers
[42,46]. Supramolecular structures with sufcient
2.3. Micellar stability stability often end up accumulating in the liver and
spleen due to a large size or protein adsorption, both
The stability of micellar structures should be triggering a rapid uptake by the reticuloendothelial
assessed in two different aspects: thermodynamic system (RES). For this reason, drug delivery to
stability and kinetic stability. organs other than liver and spleen is limited for such
Large molecular dimensions of the core-forming carriers.
segment in block copolymers induce a strong ten- Delivery systems that are smaller than 200 nm
dency for aggregation, in other words high thermo- have low uptake by RES and may circulate in blood
dynamic stability. This pushes the CMC to very for prolonged periods [9,16,17,19,4749]. Polymeric
small levels [4,42]. A reverse relationship between micelles usually range in size between 10 and 50 nm
the hydrophobicity of the core-forming block and [5,9]. This range is much smaller than the size of
CMC has been shown in many studies [4244]. The other self-assembled delivery systems and similar to
entropy driven self-assembly of block copolymers the size of serum lipoproteins and viral particles.
may be followed by a hydrophobic or electrostatic Based on the results obtained for other colloidal
interaction in the core, depending on the structure of delivery systems, the nanoscopic size is expected to
the core-forming blocks. Strong cohesive forces facilitate the extravasation of polymeric micelles at
resulting from these interactions make the micellar leaky sites of capillaries, e.g. tumours and sites of
system kinetically stable. As a result, a slow dis- inammation [19,47,48] (Fig. 2). They may even
172 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190
Fig. 2. Proposed model for the in vivo fate of polymeric micelles.
enter cells by different mechanisms [5053]. Other on the surface of those carriers was found to affect
advantages associated with nanoscopic dimensions of the pharmacokinetics and biological fate of the
polymeric micelles include the ease of sterilization delivery system, leading to a long circulation and
via ltration and safety of administration [5,7]. accumulation in sites with leaky capillaries [16,54].
The presence of a hydrophilic polymeric brush on
the surface of polymeric micelles (e.g. PEO shell) 2.5. Morphology
induces steric repulsive forces and stabilizes the
micellar interface. This prevents the adsorption of Most of the polymeric micelles designed and used
proteins to the delivery system. As a result, poly- for drug delivery are reported to be spherical,
meric micelles may escape the uptake of RES evidenced by atomic force microscopy (AFM), dy-
efciently. The extent of steric stabilization is depen- namic light scattering (DLS), regular and cryo-TEM
dent on the length of the hydrophilic block and its [30,34,43,44,5559]. A transfer to ellipsoid, rod and
density on colloidal particles [15]. In fact, block lamellar micelles may occur as the proportion of core
copolymers were originally used as stabilizers for to shell-forming block, copolymer concentration,
colloidal dispersions such as emulsions, liposomes or type and concentration of electrolytes in the medium,
nanoparticles. The adsorption of block copolymers temperature, organic solvent and the method of
A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190 173
micellar preparation are altered. The effect of such ture is a prerequisite for control over the rate of drug
factors on the shape of polymeric micelles has been release. For drugs physically encapsulated in stable
reviewed [9,60]. The effect of micellar morphology structures of polymeric micelles, release is controlled
on loading, release and efcacy of drugs remains to by the rate of drug diffusion in the micellar core or
be explored. break up of the micelles (Fig. 3). The diffusion rate
may be quite low if a favourable interaction exists
between the solubilizate and the core-forming block
2.6. Drug loading
in a rigid core [32,69,70]. An inordinate slow release
rate of indomethacin in an unionized form compat-
Micellar cores serve as a nanoreservoir for loading
ible with a nonpolar core of a micellar carrier has
and release of hydrophobic molecules that are conju-
been shown [64].
gated or complexed with the polymeric backbone or
The physical state of the micelle core and en-
physically encapsulated in the core [8,9,27]. The
capsulated drug plays an important role. The same
extent of drug incorporation in polymeric micelles by
factors may contribute to enhanced kinetic stability
physical means is dependent on several factors,
for the micelle structure as described earlier. The
including the molecular volume of the solubilizate,
design of block copolymer micelles with glassy cores
its interfacial tension against water, length of the
under the physiological condition (37 8C) would
core and shell-forming blocks in the copolymer, and
favour the release in a sustained manner. Glassy
the polymer and solubilizate concentration [6163].
cores of poly(styrene) and poly(tert-butyl acrylate)
The partition coefcient of the hydrophobic molecule
have been proposed to slowly release pyrene from a
between the micellar core and surrounding aqueous
218 216
micellar carrier (diffusion constant of 10 to 10
medium describes the extent of drug entrapment in
2
cm / s). In contrast, pyrene was released too rapidly
polymeric micelles [61]. The greatest degree of
to be assessed from swollen cores of poly(2-vin-
solubilization occurs when high compatibility exists
ylpyridine), which are liquid-like under the ex-
between the micellar core and the solubilizate,
perimental conditions [71]. Drug release may be
assessed by the FloryHuggins interaction parameter
sustained following an increase in the loading con-
(x ):
sp
tent, owing to the crystallization of solubilizate in the
2
polymeric carrier, evidenced by differential scanning
x 5(d 2d ) V /RT (1)
sp s p s
calorimetery (DSC) in a few cases [43,44,55]. The
where d and d are the ScatchardHildebrand
localization of the solute in the core/ shell structure, s p
solubility parameter of the solubilizate and the core-
micellar size and molecular volume of the drug are
forming polymer, respectively, V is the molar vol-
among other factors inuencing the rate of drug s
ume of the solubilizate, R is the gas constant and T
diffusion in the polymeric carrier.
the Kelvin temperature. The highest compatibility is
In case of drug conjugates, the covalent bond
achieved when d 5d .
between the therapeutic molecule and the polymer s p
The chemical conjugation of drugs or complex
has to be cleaved for drug release. Water penetration
formation between block copolymers and charged
and hydrolysis of the liable bonds in the micellar
therapeutics has been used as an alternative approach
core (bulk erosion), followed by drug diffusion may
in drug delivery by polymeric micelles [27]. In either
occur in relatively hydrophilic liquid-like core struc-
case, existence and accessibility of functional groups
tures (Fig. 3). Water diffusion into hydrophobic and
on the polymeric backbone is a requirement.
rigid cores may be restricted. Therefore, in this case
release may be dependent on the rate of micellar
2.7. Release characteristics dissociation. The slow dissociation of the micellar
structure to single polymeric chains and further
Evidence points to sustained release characteristics hydrolysis of the liable bonds may result in a
for many solubilizates encapsulated in polymeric sustained drug release [34]. If the micellar structure
micelles by chemical or physical means is sufciently stable, drug release might even be
[30,34,55,6468]. The stability of the micellar struc- delayed until carrier reaches target cells. It might be
174 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190
Fig. 3. Mechanisms of drug release for polymeric micelles.
possible to tailor the chemical structure of polymeric dynamic stability is characterized by low CMC
micelles and adopt either of these mechanisms to values, which are usually in the mmolar range for
full specic requirements of drug release. polymeric micelles. This contrasts with typical mil-
limolar CMC levels of low molecular weight surfac-
tants [42,57]. Following self-association, the con-
3. Polymeric micelles versus surfactant micelles centration of free amphiphile remains at the CMC
for drug delivery level. As a result, one can assume a higher number
of micelles to be formed in a given concentration for
Similar to block copolymers, low molecular block copolymers in comparison to surfactants.
weight amphiphiles are well known to form micelles Schechter et al. suggest the involvement of two

that solubilize hydrophobic drugs. For the purpose of different mechanisms for solubilization in Pluronic
drug delivery clear advantages may exist for poly- micelles versus surfactant micelles [72]. Their results
meric micelles, mainly due to the polymeric nature also indicate the advantage of some polymeric
of these systems (Fig. 4). micelles to surfactant micelles in solubilization
The tendency for micellization is overall much capacity, which might be attributed to the higher
higher in block copolymers in comparison to surfac- number of micelles formed from self-assembly of
tants since the exposure of a long hydrophobic block block copolymers and/ or larger cores.
to water is unfavourable to a greater extent. Thermo- Upon dilution in blood, the polymeric micelles
A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190 175
Fig. 4. Break up of polymeric micelles versus low molecular weight surfactant micelles.
may remain kinetically stable, while the surfactant drug depot and inuence the pharmacokinetics of
micelles are diluted to values below CMC and drugs in a favourable manner. In this sense, poly-
rapidly dissociate [4]. The concentration of the low meric micelles mimic serum lipoproteins for drug
molecular weight surfactant cannot be raised to delivery.
compensate for the situation, since high concen-
trations of low molecular weight surfactants are
usually toxic and not suitable for administration [73]. 4. Block copolymer micelles used for drug
The slow dissociation rates (in hours and days) have delivery
been reported for polymeric micelles under sink
conditions even below their CMC [2]. The kinetic Micelle-forming block copolymers have been the
stability of polymeric micelles with rigid cores is in focus of several studies over the past few years
sharp contrast to surfactant micelles, which tend to [3,4,9,50,63,7479]. Efforts have led to the prepara-
break up in milliseconds upon dilution and are in tion of micellar carriers that can be safely adminis-
continuous exchange with their unimers in solution tered to humans and adequately solubilize drugs. The
1
[2]. H NMR and uorescent probe studies [30,42] hydrophilic block in these systems is usually PEO
provide evidence for the existence of rigid cores in with a molecular weight ranging from 1000 to
21
polymeric micelles. 20,000 g mol . PEO has been used safely in
Unlike low molecular weight surfactant micelles humans and is approved by regulatory agencies for
that typically have mobile cores, sustained and administration. The use of other hydrophilic poly-
controlled drug release may be achieved with poly- mers as shell-forming blocks has been reported for
meric micelles. As a result, the rapid loss of drug bioadhesive [80] or thermoresponsive [56,77,81]
with attendant risk of intravascular precipitation of properties. Unlike the shell-forming block, the choice
water-insoluble drug poses less risk. Further, poly- for a core-forming block is relatively diverse. The
meric micelles may potentially act as a nanoscopic length of the core-forming block is usually equal or
176 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190
shorter than the PEO block to maintain water testosterone in 63.9 and 0.74% w/ w drug to poly-
solubility and form spherical core/ shell micelle mer, respectively [57]. The greater extent of solubili-
structures. zation for sudan black B was attributed to its higher
Most of the studies on block copolymers have hydrophobicity. A family of PEO-b-poly(lactic acid)

been conducted on Pluronics . Like low molecular (PEOPLA) block copolymers with different lengths

weight surfactants, Pluronics demonstrate solubiliz- of the PLA block were prepared recently and used to
ing effects for parenteral drug administration encapsulate a water-soluble drug [90]. In this case an

[35,36,82]. Pluronics have been used to solubilize increase in the length of the PLA block caused an
haloperidol [21,83], indomethacin [84], doxorubicin increase in the size of nanoparticles but did not affect
(DOX) [78], epirubicin [78] and amphotericin B their encapsulation properties.

(AmB) [85]. Overall, many Pluronics used for drug Micelles of PEO and PDLLA, poly(D,L-lactic acid-
solubilization have high ratios of PEO to PPO and co-caprolactone) (PDLLACL) or poly(glycolic acid-
are non-toxic relative to many low molecular weight co-caprolactone) (PGACL) have been used to en-
surfactants, e.g. Tween 80, especially in terms of cell capsulate taxol [91]. The greatest physical stability
membrane lysis, e.g. haemolysis. was observed for the taxol formulation in PEO-b-

Relatively hydrophobic Pluronics , on the other PDLLA micelles with no sign of precipitation in 24
hand, have been used to induce immune responses, h. This was attributed to higher hydrophobicity and

i.e. act as an adjuvant [86,87]. Pluronics have T of the PDLLA block. The loading weight propor-
g
shown other important biological effects, inhibiting tion of taxol in PEO-b-PDLLA micelles with higher
P-glycoprotein, which is believed to be at least partly PDLLA contents reached 25% and its solubility
responsible for multi-drug resistance in cancer cells increased 5000-fold [92], which contrasts with the

[50,78]. Lastly, Pluronics have been used to in- loading of 0.5% for the same drug in Pluronic
crease the transport of drugs across membrane micelles.
barriers [21,51]. Taxol in PEO-b-PDLLA micelles shows a similar
To avoid long-term toxicities, biodegradable block in vitro cytotoxicity, a vefold increase in maximum
copolymers with polyester core-forming structures tolerable dose and an increased efcacy after intra-
such as poly(lactic acid), poly(glycolic acid), poly- peritoneal injection in murine P388 leukemia model
(caprolactone) and their copolymers have been de- in comparison to its standard formulation in Cre-
veloped and used for drug delivery. Polyesters have mophor [93]. Slow drug release from the micellar
a history of safe use in humans as biodegradable carrier was anticipated based on a high core viscosity
surgical sutures, bone fracture xture devices and and an interaction between taxol and PDLLA seg-
1
controlled drug delivery systems. PEO-b-polyesters ment evidenced by H NMR and solubility data,
were introduced back in the 1950s [88]. In 1994, respectively [92]. A similar distribution in protein
Gref et al. prepared block copolymers of PEO-b- components of the human plasma for free and PEO-
poly(lactic-co-glycolic acid) (PEO-b-PLGA) and b-PDLLA incorporated taxol [94], rapid dissociation
PEO-b-poly(caprolactone) (PEO-b-PCL). Following of tritium-labelled taxol after i.v. injection to rat
self-assembly by an O/ W emulsion process, nanos- models and the elimination of micellar carrier within
pheres with an average diameter of 140 nm were 15 h, however, did not support a sustained drug
formed from PEO-b-PLGA, showing an enhanced release behaviour for taxol in PEO-b-PDLLA mi-
blood circulation particularly at a high PEO content. celles [91,95]. This formulation of taxol is in clinical
The carrier was used successfully to encapsulate trials in Canada.
lidocaine and prednisolone (45% w/ w drug to PEO-b-PCL self assembles into micelles that can
polymer) [55]. encapsulate indomethacin [70,96], dihydrotestos-
In a separate study long circulating nanospheres of terone [69], taxol [90] and a number of neurotrophic
PEO-b-PDLLA were developed [89]. The same agents with hydrophobic properties [76,97]. There
block copolymer has been shown to form a micellar are reports on the use of PGA [98], PLGA [99] and
fraction (,50 nm in size), which is able to solubilize PLA [100] as core-forming blocks for the encapsula-
model hydrophobic drugs, such as sudan black B and tion of indomethacin and DOX. The size of resulting
A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190 177
particles was found to be above 100 nm in those micellar peak in SEC chromatograms. Recently, the
cases, however. authors have reported on the conjugation of peptidyl
Kataoka et al. have reported on the preparation of ligands to the aldehyde group of the micellar surface
functional PEO-b-PDLLA micelles with aldehyde through Schiff base formation and further reduction
groups on their surface by a method illustrated in [23]. Chemical engineering of the core-forming
Fig. 5 [22,59]. More than 80% of the acetal group on blocks in such carriers is underway [101].
the micelle surface was converted to aldehyde within In a separate approach, PEO blocks having site-
4 h of reaction under acidic conditions [59]. No specic sugar groups at their chain ends have been
change in micellar size and shape was evidenced achieved through ring opening polymerization using
after this conversion. The reaction of aldehyde group D,L-lactide. The block copolymer forms micelles with
with benzoic hydrazide as a model compound was glucose or galactose moieties on their surfaces. The
evidenced by an increase in the UVabsorption of the galactose residues bind sugar binding sites of an
Fig. 5. Preparation of PEO-b-PDLLA micelles with functional groups on their surface. (Reprinted with permission from Ref. [22].
Copyright 1995 American Chemical Society.)
178 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190
RCA1-lecetine molecule [102]. Such strategies may systems based on PEO-b-PLAA block copolymers
be used to achieve intelligent polymeric micelles for have been investigated (Table 1).
active targeting by receptor-mediated endocytosis.
1. Micelle-forming block copolymerdrug conju-
gates.
2. Micellar nano-containers.
5. Micelle-forming PEO-b-PLAAs for drug 3. Polyion complex micelles.
delivery
5.1. Micelle-forming block copolymerdrug
Micelles based on PEO-b-PLAA block copoly- conjugates
mers are unique among drug carriers owing to a
tailor-made non-polar core of PLAA, which can take In the 1980s, Ringsdorf et al. were the rst to
up and protect water-insoluble drugs. A primary prepare a micelle-forming drugcopolymer conju-
advantage of PEO-b-PLAA over other micelle-form- gate. They attached a cytotoxic agent, a cyclophos-
ing block copolymers is a potential for attachment of phamide-suldo derivative, to the poly(L-lysine) of a
drugs, drug compatible moieties, genes or intelligent PEO-b-poly(L-lysine) block copolymer and used
vectors in the micellar core through free functional hydrophobic moieties (palmitic acid) to induce the
groups (e.g. amine or carboxylic acid) of the amino required amphiphilicity for micelle-formation (Fig.
acid chain. A systemic alteration in the structure of 6) [104]. Micelle formation was evidenced by
the core-forming block may lead to better control solubilization of a hydrophobic dye [53]. The libera-
over the extent of drug loading, release or activation. tion of the active metabolite, 4-hydro-cyclophospha-
Preparation of PEO-b-PLAA micelles with func- mide, could be varied within a time scale of minutes
tional groups on the surface for the attachment of to hours, depending on the structure of the conjugate.
recognizable moieties has recently been reported Pendant palmitic acid residues had a marked effect
[103]. Lastly, there is evidence that PEO-b-PLAA on drug release. In vitro studies indicated that the
micelles may easily be sterilized by ltration, freeze- cyclophosphamide-containing block copolymer acts
dried, reconstituted and administered safely [5]. as an intracellular depot for the active metabolite. In
To date, three different types of drug delivery vivo studies indicated enhanced antitumor effects of
Table 1
Micelle-forming block copolymers based on PEO-b-PLAA used for drug delivery
Polymeric micelle Core-forming block Encapsulated Reference
delivery system molecule
Drug conjugates Poly(L-lysine) Cyclophosphamide [104]
P(Asp) Doxorubicin [28,105]
Cisplatin [29,115]
Poly(hydroxyalkyl-L-aspartamide) Methotrexate [30,34]
Nano-containers P(Asp)-(DOX) Doxorubicin [114]
PBLA Pyrene [119]
Doxorubicin [66,67,125]
Indomethacin [64]
Amphotericin B [127,128]
PHSA Amphotericin B [129]
P(BLA, C-16) KLN-205 [31,126]
PBLG Noroxacin [44]
Clonazepam [43]
Polyion complex micelles Poly(L-lysine) Poly(L-aspartic acid) [133,134]
Plasmid DNA [135]
P(Asp) Lysozyme [136,137]
Poly(L-lysine/ L-glycine) DNA [138]
A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190 179
cores lled with self-aggregated drug. A 4050% of
DOX substitution on P(Asp) and a decrease in
proportion of P(Asp)-DOX to PEO segment was
necessary to achieve stable micelles [33,108]. Long
PEO chains were favorable avoiding the formation of
secondary aggregates, and micelle interaction by
biological components [2,28,109]. The physicochem-
ical properties of this system have been reviewed
elsewhere [110].
Optimized structures of PEO-b-P(Asp)DOX
formed stable micelles that could dissociate into
unimers at a slow rate over a period of days in
phosphate buffer saline [108]. In the presence of
10% rabbit serum, the dissociation rate of PEO-b-
P(Asp)DOX micelles doubled [33,108]. Sub-
sequently, radioiodinated PEO-b-P(Asp)DOX mi-
celles were found to circulate for prolonged periods
in blood in healthy ddy mice in comparison to free
DOX. The volume of distribution was 2000 ml for
DOX and 3.6 ml for PEO-b-P(Asp)DOX. The
accumulation of DOX in major organs was reduced,
especially at the heart, where DOX expresses dose-
limiting cardiotoxicity [109,111].
Fig. 6. First models of micelle-forming block copolymerdrug
The biodistribution of long-circulating PEO-b-
conjugates and rst example with cyclophosphamide. (Reprinted
P(Asp)DOX conjugates was assessed in tumor-
with permission from Ref. [104]. Copyright 1985 Plenum Press.)
bearing mice (female CDF1 mice, transplanted with
C26 tumor cells). For PEO-b-P(Asp)DOX micelles
21
cyclophosphamide-containing block copolymer com- with a 12,000 and a 2100 g mol of PEO and
pared to free drug (L1210 model) [104]. P(Asp) blocks, respectively, the delivery of DOX to
The hydrophobicity of a therapeutic molecule solid tumors was enhanced in comparison to drug
itself has been utilized to achieve the amphiphilicity alone, and the tumor to heart selectivity of DOX was
required for micellization of a conjugate prepared improved from 0.9 to 12 at 24 h [112].
from PEO-b-poly(L-aspartic acid) and doxorubicin In a murine carcinoma model (P338), DOX was
(PEO-b-P(Asp)DOX) (Fig. 7). Yokoyama et al. active at 15 mg/ kg after intraperitoneal injection
attached DOX onto the P(Asp) backbone through an [106]. DOX caused a remarkable weight loss in
amide bond between the carboxylic group of aspartic animals at that dose. A similar level of activity for
acid and the amino group of the glycosidyl residue PEO-b-P(Asp)DOX was obtained at a much higher
on DOX [28,105]. The level of conjugated DOX was dose (200 mg/ kg of DOX), accompanied by a
varied by changes in reaction conditions, e.g. level of temporary weight loss. A similar trend was observed
drug. Depending on the length of the PEO chain, for several tumor models after intravenous injection
substitution level of DOX on the polymeric back- of PEO-b-P(Asp)DOX [111]. Judging from these
bone had to be under a certain level to avoid results, the superiority of the PEO-b-P(Asp)DOX
precipitation. DLS and SEC studies were able to conjugates over free drug was mainly due to lowered
reveal the presence of micelles with an average toxicity (20 times decrease in DOX maximum
diameter of 15 to 60 nm [2,28,106,107]. The quench- tolerable dose) as opposed to improved efcacy
1
ing of DOX uorescence and lack of H NMR peaks [106,107,111]. This allowed for the administration of
for the P(Asp) block for the conjugate in water higher doses of DOX. Adjusting the composition of
(D O) signaled the presence of micelles with rigid the block copolymer and the dose of DOX led to
2
180 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190
Fig. 7. Synthesis of micelle-forming poly(ethylene oxide)-b-poly(aspartic acid)doxorubicin conjugates. (Reprinted with permission from
Ref. [28]. Copyright 1992 American Chemical Society.)
improved efcacy, evidenced by a complete dis- existence of micelles with an average diameter of 20
appearance of C26 tumors in animal subjects [113]. nm at a critical substitution molar ratio of cisplatin to
It was later found that PEO-b-P(Asp)DOX conju- Asp units of 0.5. The cisplatin complexed micelle
gates are not the active species causing tumor was stable in distilled water at room temperature. In
disappearance in C26 transplanted mice [32,114]. 0.15 M NaCl, however, an exchange between the
The antitumor activity was in fact caused by non- chloride ion and cisplatin led to a sustained release
conjugated DOX encapsulated in the micellar struc- of drug from its polymeric complex over 50 h [115].
ture. As it turns out, the amide linkage was too stable Accordingly, a time-dependent cytotoxicity was ob-
for drug release. This nding led to the use of served for cisplatin complexes of PEO-b-P(Asp),
PEO-b-P(Asp)DOX conjugates as nanocontainers with an overall vefold increase in the cytotoxic
for physically encapsulated DOX [114]. concentration against B16 melanoma cells [29].
Cisplatin has been complexed with carboxyl Cisplatin complexes of PEO-b-P(Asp) demonstrated
groups on PEO-b-P(Asp) to form a metal complex plasma AUC and tumor accumulation 5.2 and 14
micelle (Fig. 8). DLS and SEC [29] showed the times greater than cisplatin alone, respectively, and
A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190 181
Fig. 8. Complex formation of cisplatin and PEO-b-P(Asp). (Reprinted with permission from Ref. [29]. Copyright 1996 Elsevier Science.)
caused less nephrotoxicity [116]. A cisplatin com-
plex of PEO-b-poly(a-glutamic acid) (PEO-b-
P(Glu)) has shown greater stability, a prolonged
circulation in blood stream and an improved accumu-
lation in tumor site in comparison to the PEO-b-
P(Asp) complex of cisplatin [117].
To overcome the excessive stability of an amide
linkage between a drug and core-forming block, an
ester bond has been utilized to attach another cyto-
toxic agent, methotrexate (MTX), to create a hydro-
lysable micelle-forming conjugate (Fig. 9). The slow
release of steroids attached to poly(hydroxyalkyl-L-
glutamate) through an ester bond for long periods of
time after a subcutaneous injection of conjugate
microparticles had been reported by Feijen et al.
[118]. MTX esters of PEO-b-poly(2-hydroxyethyl-L-
aspartamide) were prepared and shown to self assem-
ble to micellar structures with an average diameter of
14 nm as determined by TEM. MTX conjugate
micelles gradually released the drug, owing to ester Fig. 9. Synthesis of MTX conjugates of PEO-b-poly(2-hydroxy-
ethyl-L-aspartamide). (Reprinted with permission from Ref. [34].
hydrolysis in PBS, pH57.4 at room temperature.
Copyright 2000 Plenum Press.)
Notably, MTX conjugate micelles were quite stable
and could elute entirely as micelles during SEC
HPLC. Adjusting the level of attached MTX was the block copolymer, thereby inuencing micelle
used to control the stability of the polymeric micelles stability and controlling drug release.
as well as inuence the rate of drug release. It was
concluded that MTX esters of PEO-b-poly(2-hy- 5.2. Micellar nanocontainers
droxyethyl-L-aspartamide) could be structurally
modied by varying the degree of drug substitution, The physical encapsulation of drugs within poly-
which in turn changed the overall hydrophobicity of meric micelles is generally a more attractive ap-
182 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190

proach than micelle-forming polymerdrug conju- solubilized haloperidol was enhanced by Pluronic
gates since many polymers as well as drug molecules micelles, presumably owing to increased uptake into
do not bear reactive functional groups, e.g. carboxyl, the brain. The penetration of the micellar carrier to
hydroxyl or amino groups, for chemical conjugation, brain was enhanced when a monoclonal antibody
or the free functional site may be required for the against specic antigen of brain glial cells, i.e. anti-

pharmacological effectiveness of the drug. In addi- a -GP Ab, was partially inserted on the Pluronic
2
tion, conjugates of drugs may exhibit markedly micelles (P85). As a result, mortality was drastically
dissimilar biological properties relative to parent decreased in animals receiving haloperidol in anti-

drugs, leading to inherent difculties in characteriza- a -GP Pluronic micelles in comparison to subjects
2

tion and regulatory approval even for already ap- treated with haloperidol in standard Pluronic mi-
proved drugs. celles. The delivery of digoxin to brain has been

Physical encapsulation of drugs in the polymeric revealed to be enhanced by Pluronic P85 by the
micelles is usually carried out through dialysis or same group [120].

O/ W emulsion methods [31,32,64,66,67]. In the Physically encapsulated DOX in Pluronic mi-

dialysis method polymer and drug are both dissolved celles (L61 and F127) signicantly increased the
in an organic solvent. The solution is then dialyzed antitumor effects of the drug in vivo, owing to
against distilled water to remove the free drug and enhanced delivery to solid tumors, increase in the
organic solvent. In the O/ W emulsion method, drug inux of DOX, a decrease in the efux of DOX
is dissolved in a volatile solvent, which is also (inhibition effects on P-glycoprotein), and changes in
immiscible with water, such as chloroform, and intracellular trafcking of DOX (reviewed elsewhere
added to an aqueous solution of polymeric micelles. [121]). A parenteral formulation of DOX in

The mixture is homogenized by sonication and Pluronic micelles has entered phase I clinical trials
chloroform is evaporated in an air open system. Free in Canada.
drug is removed by ultra-ltration. The choice of The primary advantage of PEO-b-PLAA micelles
organic solvent and loading process seem to be as tailor-made nanocontainers for encapsulation and
important factors affecting micellar stability, size and release of compatible drugs is best illustrated for
extent of encapsulation [31,64,66]. DOX and PEO-b-P(Asp)DOX conjugate micelles
Similar to micelle-forming polymerdrug conju- [32]. A strong interaction between the conjugated
gates, micellar nanocontainers are expected to resist and physically encapsulated DOX is believed to be
uptake by the RES and dissociation in blood com- the basis for the improved micellar stability and
partment, which may lead to preferential accumula- sustained release properties. A careful control of the
tion of the carrier at target sites. The carrier may pH during the encapsulation was necessary to keep
then act as a depot, releasing its drug content without DOX in its unionized form, which favours a non-
going through an extra step of drug cleavage. The polar environment. The same factor affected drug
drawbacks for micellar nanocontainers are the possi- release from polymeric micelles. DOX encapsulated
bility of low encapsulation capacity or the rapid in PEO-b-P(Asp)DOX conjugate micelles were
release of encapsulated drugs, i.e. dose dumping. The active against P388DI mouse leukemia cells in vitro
encapsulation and release characteristic of polymeric and against C26 tumours in vivo. The presence of
micelles might be modied for each particular drug physically encapsulated DOX was important for
or class of drugs through the attachment of drug antitumour activity in both cases [32,122]. Physical
compatible moieties to the core-forming block, encapsulation resulted in an increase in the maxi-
which is easily attainable for PEO-b-PLAA micelles mum tolerable dose of DOX from 20 to 40 mg/ kg/
[5,32,57,119]. day. In a C26 murine model, tumours completely
In the late 1980s, Kabanov et al. reported on the disappeared at a dose of 10 mg/ kg/ day for all
physical encapsulation of drugs in polymeric mi- animals treated with the micelle formulation. At the
celles as nanocontainers for drug delivery. They same dose, DOX alone caused tumour disappearance
encapsulated haloperidol [21,83] and DOX [78] in in just two out of ve animals.

Pluronic micelles. The neuroleptic activity of In pharmacokinetic studies, free DOX disappeared
A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190 183
in 15 min from the blood of tumour-bearing mice probably due to ionization of the 39 NH group at
2
14
[122]. For C labelled DOX encapsulated in PEO-b- that pH, resulting in a reduced hydrophobic inter-
P(Asp)DOX conjugate micelles, on the other hand, action between drug and micellar core.
24.6% of the injected dose remained in blood Overall, the results of biological studies with this
circulation after 24 h and 9.6% of the dose was system were not as impressive as DOX encapsulated
detected per g of the tumour at this time. The latter in PEO-P(Asp)DOX micelles. Twenty-four hours
level was 1.3% for free drug. The highest con- after intravenous injection into healthy BDF1 mice,
14
centration of free drug in tumour site was observed 1 only 5% of the C labelled DOX encapsulated in
h after its administration. In case of PEO-b-P(Asp) PEO-b-PBLA micelles was in blood. The tolerable
DOX conjugate micelles, DOX levels at tumour site dose of DOX increased from 10 mg/ kg to 23 mg/ kg
increased between 15 min and 24 h. Based on the for DOX loaded in PEO-b-PBLA micelles after
ndings, the superior antitumour activity of DOX in administration to C26 tumour transplanted CDF
1
polymeric micelles was attributed to the accumula- mice. In comparison to free DOX-treated animals,
tion of PEO-b-P(Asp)DOX conjugate micelles at the tumour volume after 24 days decreased sig-
tumour sites. This system has been characterized in nicantly for DOX encapsulated in PEO-b-PBLA
detail [122,123] and is going to move into clinical micelles administered in its maximum tolerable dose.
trials in Japan [27]. After 60 days tumours disappeared in three out of
The intermediate polymer in the synthesis of PEO- ve animal subjects. For free DOX complete re-
b-P(Asp)DOX conjugates (Fig. 7), poly(ethylene covery took place in one animal subject [125].
oxide)-b-poly(b-benzyl-L-aspartate) (PEO-b-PBLA), PEO-b-PBLA micelles were also used to solubil-
was also used by Kataoka et al. to encapsulate ize indomethacin in a separate study [64]. SEC
hydrophobic model molecules [42,119], anticancer conrmed encapsulation and DLS provided data,
[66,67] and anti-inammatory drugs [64]. The exist- illustrating an increase in the diameter of PEO-b-
ence of aromatic groups was the common feature in PBLA micelles as a result of drug loading. Similar to
the chemical structures of all encapsulated mole- DOX, the rate of indomethacin release was sustained
cules. A pp interaction between the benzyl core of from PEO-b-PBLA micelles in a pH-dependent
the micelles and aromatic ring of the drug provided manner. The maximum control was achieved in
means for formation of a stable system even in the acidic pH, where indomethacin was unionized and
presence of serum proteins [32]. PEO-b-PBLA was favoured the nonpolar environment of PBLA core in
shown to form spherical micelles around 20 nm in polymeric micelles. A sharp rise in the rate of drug
size with rigid cores at very low concentrations [42]. release was observed between pH 4 to 5, which is
A spherical shape and narrow size distribution of a close to the pK of indomethacin (4.5).
a
pyrene conjugate of this block copolymer micelle has The synthesis of another class of PEO-b-PLAA-
recently been illustrated by AFM [124]. SEC showed based block copolymer with aromatic structure in the
prohibition of protein adsorption to PEO-b-PLAA core has been reported by Kim et al. Di and tri block
micelles where micelles were incubated with serum copolymers of PEO-b-poly(g-benzyl-L-glutamate)
albumin in PBS, pH 7.0 [67]. (PEO-b-PBLG) were prepared and self-assembled
The rst attempt for drug loading for PEO-b- [43,44]. The dimensions of the colloidal system were
PBLA micelles was carried out with DOX [66,67]. in the range of nanoparticles rather than micelles
Evidence for the encapsulation of DOX by PEO-b- (200300 nm) possibly due to the formation of
PBLA micelles was provided by SECHPLC and secondary aggregates. This system has been utilized
uorescence techniques. PEO-b-PBLA micelles to solubilize clonazepam and noroxacin.
protected DOX from chemical degradation in an Yokoyama et al. engineered the chemical structure
aqueous environment. The release of DOX from of the core-forming block in PEO-b-PBLA through
PEO-b-PBLA micelles was slow over several days partial replacement of its benzyl group by an ali-
and pH-dependent [66]. Fifty percent of encapsulated phatic chain, cetyl ester residue, PEO-b-P(BLA,C16)
DOX was released in 72 h in pH 7.4 at 37 8C. The to encapsulate a cytotoxic agent, KRN 5500, which
release was accelerated by decreasing the pH to 5.0 has an aliphatic moiety (Fig. 10) [31]. The average
184 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190
Fig. 10. Synthesis of PEO-b-P(BLA,C16) and chemical structure of KRN5500. (Reprinted with permission from Ref. [31]. Copyright 1998
Elsevier Science.)
diameter of the colloidal system was found to be acid ester core was enhanced 13 times in comparison
above 100 nm, which was reduced to 70 nm by to the benzyl core of PEO-b-PBLA micelles. The
sonication without any loss in the drug content. haemolytic activity of AmB was reduced drastically
Similar to free drug, cytotoxic effects of KRN 5500 as a result of its encapsulation in poly(ethylene
encapsulated in PEO-b-P(BLA,C16) micelles was oxide)-b-poly(N-hexyl stearate-L-aspartamide) (PEO-
not strongly time dependent in in vitro and in vivo b-PHSA) micelles. This is attributed to a reduced
assessments. This contrasts with previous ndings rate of AmB release from the micellar carrier
for formulation of DOX in PEO-b-P(Asp)DOX (unpublished data).
micelles, implying the possibility of a rapid drug
release or a direct interaction of the micellar system 5.3. Polyion complex micelles
with tumor cells [126].
The physical encapsulation of amphotericin B Depending on the type of amino acid, PEO-b-
(AmB) in PEO-b-PBLA at an alkaline pH has been PLAA block copolymers may bear positive or nega-
reported [127,128]. We have developed a PEO-b- tive charge at their side chains. Therefore, oppositely
PLAA-based micellar system with AmB compatible charged macromolecules such as DNA or peptides
moieties, i.e. saturated fatty acid esters, in the core can form poly ion complexes with the PLAA seg-
that can encapsulate AmB effectively at a neutral pH ment of the block copolymer, neutralize the charge
(Fig. 11) [129,130]. AmB encapsulation in a stearic and induce required amphiphilicity for micellization
A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190 185
Fig. 11. Chemical structure of PEO-b-PHSA and AmB.
of the complex. The incorporation of DNA and of polymeric micelles over other colloidal systems
peptides in polymeric micelles may lead to stabiliza- for site-specic drug delivery. While small size may
tion against digestive enzymes such as nuclease and lead to an improved penetration of the micellar
facilitate their penetration in cells. The polyion carrier to extravascular environment and cell mem-
complex micelles are salt-sensitive. They will fall branes, it may also restrict the space for drug
apart and release their content as the salt concen- encapsulation and limit the ability of polymeric
tration increases above a certain value [131]. There micelles for a sustained drug release, due to a large
has been a rising interest in this novel application of total surface area. The problem might be overcome if
PEO-b-PLAA micelles over the past few years the drug is stably encapsulated in the core of
(Table 1) with promising results for the use of polymeric micelles via chemical or physical means.
polyion complex micelles in the areas of diagnosis, In this context polymeric micelles of PEO-b-PLAA
biotechnology and gene therapy. These delivery are of interest since the attachment of drugs, drug
systems have been reviewed elsewhere compatible moieties or charged molecules through
[11,12,27,132]. the functional side chain of the PLAA block is easily
attainable in those structures. This concept has been
used to design self-assembling block copolymers for
6. Conclusions drug and gene delivery as summarized above. The
effect of variations in the chemical structure of
Polymeric micelles have a great potential for micelle-forming PEO-b-PLAA block copolymers on
selective drug delivery in a passive or active manner functional properties of polymeric micelles for site-
[11,2127]. The stability of micellar structure as specic drug delivery requires further attention. Such
well as nanoscopic size are the two main advantages assessments may lead to the development of nely
186 A. Lavasanifar et al. / Advanced Drug Delivery Reviews 54 (2002) 169190
distribution of amphipathic poly(ethylene glycol)-containing
tuned polymeric micelles for a targeted drug or gene
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[19] F. Yuan, M. Leuning, S.K. Huang, D.A. Berk, D. Papahad-
jopoulos, R.K. Jain, Microvascular permeability and intersti-
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