Acid-Degradable Core-Crosslinked Micelles Prepared from Thermosensitive Glycopolymers Synthesized via RAFT Polymerization

Communication

Acid-Degradable Core-Crosslinked MicellesPrepared from Thermosensitive GlycopolymersSynthesized via RAFT Polymerizationa

Ling Zhang, Julien Bernard, Thomas P. Davis,Christopher Barner-Kowollik, Martina H. Stenzel*

A thermoresponsive block copolymer, namely poly(acryloyl glucosamine)-block-poly(N-isopropylacryamide) (PAGA180-b-PNIPAAM350) was simultaneously self-assembled and cross-linked in aqueousmedium via RAFT polymerization at 60 8C to afford core-crosslinkedmicellesexhibiting a glycopolymer corona and a PNIPAAM stimuli-responsive core. An acid-labilecrosslinking agent, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-undecane, was employed to generate thermosensitive andacid-degradable core-shell nanoparticles. Stable againstdegradation at pH¼ 6 and 8.2, the resulting core cross-linked micelles readily hydrolyzed into well-defined freeblock copolymers at lower pH (30min and 12 h respectivelyat pH¼ 2 and 4).

Introduction

Synthetic polymers containing carbohydrate pendant

groups, referred to as glycopolymers, are emerging as

L. Zhang, T. P. Davis, C. Barner-Kowollik, M. H. StenzelCentre for Advanced Macromolecular Design (CAMD), School ofChemical Sciences and Engineering, The University of New SouthWales, Sydney NSW 2052, AustraliaFax: þ61 2 9385 6250;E-mail: [email protected]; [email protected]. ZhangCooperative Research Centre for Polymers (CRC-P), 8 RedwoodDrive, Notting Hill Vic 3168, AustraliaJ. BernardUniversite de Lyon, Lyon, F-69003, France; INSA de Lyon, IMP/LMM Laboratoire des Materiaux Macromoleculaires, Villeur-banne, F-69621, France; CNRS, UMR 5223, Ingenierie des Materi-aux Polymeres, Villeurbanne, F-69621, France

a: Supporting information for this article is available at the bottomof the article’s abstract page, which can be accessed from thejournal’s homepage at http://www.mrc-journal.de, or from theauthor.

Macromol. Rapid Commun. 2008, 29, 123–129

� 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

potentially important materials for a number of applica-

tions in medicine and biotechnology due to the enormous

density of information conveyed by carbohydrates and its

essential mediating role in a wide range of biological

recognition events.[1–10] In nature, the recognition proce-

dures are based on specific carbohydrate-protein interac-

tions via multivalency[11–13] that is inherent and largely

expressed in synthetic carbohydrate-based polymers,

especially in branched polymers, e.g. comb polymers,[14]

dendrimers[15] as well as micelles and crosslinked hydro-

gels. Glycopolymers are therefore attractive materials for

the delivery of drugs when a certain site within the body is

targeted.[16]

Owing to their small size, their narrow size distribution,

their unique core-shell structure and their high surface

functionality,[17] polymeric micelles from supramolecular

self-assembly of amphiphilic block copolymers in aqueous

solution have received much attention lately as potential

drug vehicles. Given that different values of pH (physio-

logical pH¼ 7.4, 5.5–6 in endosomes, pH¼ 4–5 in lyso-

somes) and temperature (healthy cell versus cancer cell)

can be found throughout the body, the generation of

DOI: 10.1002/marc.200700663 123

L. Zhang, J. Bernard, T. P. Davis, C. Barner-Kowollik, M. H. Stenzel

124

environment-sensitive (pH, T) nano-containers from

supramolecular assemblies of glycopolymers containing

stimuli-responsive polymer sequences is particularly

desirable for controlled drug delivery purposes. Indeed,

such polymeric micelles are promising candidates aiming

at generating drug carriers capable to exhibit selective

drug release at a target site upon stimulus.

Considerable efforts have been recently devoted to the

subsequent stabilization of these multimolecular assem-

blies through covalent (or non-covalent) crosslinking of the

shell[18] or the core.[19]

Various polymerization techniques have been devel-

oped to synthesize glycopolymers,[20] such as living ionic

polymerization,[21] ring opening polymerization,[22,23]

ring opening metathesis polymerization,[24,25] click

chemistry,[26,27] cyanoxyl-mediated free radical poly-

merization,[28–30] atom transfer radical polymerization

(ATRP),[31,32] and nitroxide-mediated polymerization

(NMP).[33] Nevertheless, these techniques exhibit limita-

tions such as severe reaction conditions for ionic poly-

merization, and the requirement of metal catalyst removal

(ring opening polymerization and ATRP). In addition, the

recourse of protecting and deprotecting chemistry is

required in most cases. However, recently Narain et al.

Scheme 1. Synthesis of crosslinked PAGA180-b-PNIPAAm350 via RAFT p



have reported the first synthesis of unprotected sugar-

based monomers, 2-glucoamidoetyhl methacrylate and

2-lactobionamidoethyl methacrylate, via ATRP.[34,35]

During the last decade, the RAFT (Reversible Addition

Fragmentation chain Transfer) process has been demon-

strated to be a very suitable tool to design a range of

complex macromolecular architectures with a large range

of monomers.[36] The preparation of well-defined linear or

branched glycopolymers in aqueous medium has been

reported using the RAFT process[37,38] without protecting

chemistry including thermoresponsive[39,40] and pH-

responsive block copolymers with carbohydrate moi-

eties.[41] Moreover, micelles or vesicles from self-assembled

RAFT made amphiphilic block copolymers can easily be

crosslinked. Indeed, the presence of dithioester groups on

the block copolymers affords, by simple addition of divinyl

compounds to the multimolecular assemblies in solution,

the growth of a third macromolecular block via the RAFT

process. This block connects the polymer chains and, thus

captures the self-assembled structure. Depending on the

design of the block copolymer and the location of the RAFT

agent (at the end of the hydrophilic or the hydrophobic

block), crosslinking of the core,[42–44] the shell[45] or the

nexus between both blocks[46] can be achieved.

rocess and its degradation procedure.

DOI: 10.1002/marc.200700663

Acid-Degradable Core-Crosslinked Micelles Prepared from Thermosensitive Glycopolymers . . .

However, permanent crosslinking of micelles may not

be a desirable property for drug delivery purposes. The

decomposition of the nanocontainers under specific

conditions would lead to a faster drug release and an

easier clearance of the polymer. The degradation of the

nanoparticles can thus be achieved by using acid-cleavable

groups such as acetals, orthoesters or anhydrides. Espe-

cially acetals have attracted attention for biomedical

application,[47–49] since they are stable at higher pH

conditions, but degrade in an acidic environment.

In the present study, we report the preparation of

acid-degradable core-crosslinked micelles from RAFT-

synthesized thermosensitive poly(acryloyl glucosamine)-

block-poly(N-isopropylacrylamide) block copolymer

(PAGA180-b-PNIPAAm350).[40] The self-assembly in aqueous

solution of the block copolymer into micellar systems

above the Lower Critical Solution Temperature (LCST) and

the stabilization of the resulting particles via RAFT

polymerization of an acetal-type crosslinking agent, 3,9-

divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane, is described

(Scheme 1). The propensity of the core-crosslinked micelles

to decompose in an acidic environment is finally

investigated.

Experimental Part

Materials

3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane (acid-degradable

crosslinking agent, ACL) (Aldrich, 98%), 4,40-azobis(cyanopenta-

noic acid) (ACPA) (Fluka, 98%), deuterium water (Aldrich, 99.9

atom-%), sodium dihydrogen orthophosphate (Univar, >99%),

di-sodium hydrogen orthophosphate anhydrous (Univar, >99%),

citric acid (Univar, >99%) were used without any further

purification. All solvents were HPLC grade (Asia Pacific Specialty

Chemicals).

Preparation of Block Copolymers

The thermoresponsive block copolymers PAGA180-b-PNIPAAm350,

were prepared according to a procedure described earlier.[40]

NIPAAm (0.268g, 2.37 10�3 mol) and PAGA180 (MnðNMRÞ ¼42 200 g �mol�1; MnðGPCÞ ¼ 52 480 g �mol�1; PDI¼1.10) (0.25 g, 5.92 �10�6 mol)

were dissolved in 1.5 mL of water. After complete dissolution of the

macro-RAFT agent, ACPA (0.6 mg, 2.14 �10�6 mol) was added as

DMSO-d6 solution (1.5 mL). The solution was transferred to a Schlenk

tube which was thoroughly deoxygenated by five consecutive

freeze-pump-thaw cycles. The tube was then placed in a constant

temperature water bath at 60 8C for 4 h (conversion: 88%,

MnðtheoÞ ¼ 82 000 g �mol�1, MnðGPCÞ ¼100 000 g �mol�1, PDI¼1.25).

Figure 1. Particle size vs. temperature for PAGA180-b-PNIPAAm350(&) and crosslinked PAGA180-block-PNIPAAm350-b-PACL2�165 (*)at pH¼ 8.2 (c¼ 1 g � L�1).

Preparation of Crosslinked Micelles

PAGA180-b-PNIPAAm350 (20 mg, 2.43�10�7 mol), crosslinking

agent 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane (9.6 mg,



4.53� 10�5 mol), and ACPA (2.56�10�2 mg, 9.06�10�8 mol)

were combined with 20 mL phosphate buffer D2O solution

(pH¼8.2) in a Schlenk tube, after degassing by five freeze-pump-

thaw cycles, the chain extension polymerization was carried out

at 60 8C in water bath. Aliquots of the reaction mixture were taken

out at intervals for dynamic light scattering (DLS) and NMR

analysis. The polymerization was terminated by placing the

samples in an ice bath for 5 min. The polymer was purified by

dialysis against ammonia water (adjusted to pH¼ 8.5) for 3 d

using a tubular membrane with a molecular weight cut-off of

12 000 g �mol�1. Water and Ammonia were removed via freeze-

drying.

Dynamic Light Scattering (DLS)

Hydrodynamic diameters were obtained using a Brookhaven

Zetaplus particle size analyzer and a solution of polymer in

different buffer solutions at different temperatures. Samples were

purified by microfilter (0.45 mm) before analyzing, and run for at

least 6 times. The mean diameter was obtained from the

arithmetic mean using the relative intensity of each particle size.

Results and Discussion

The RAFT synthesized block copolymer PAGA-b-PNIPAAm,

with a theoretical number of 180 acryloyl glucosamine and

350 N-isopropyl acrylamide repeating units, was fully

water-soluble up to a temperature of 28 8C, which is below

the LCST of PNIPAAm. DLS analysis confirmed the presence

of molecularly dissolved unimers exhibiting a hydro-

dynamic diameter equal to 20 nm at pH¼ 7 (Figure 1).

Above this temperature, the measured hydrodynamic

diameters rapidly raised to 90 nm indicating the

micellization of the block copolymer. Indeed, due to the

www.mrc-journal.de 125


Figure 2. Particle size versus crosslinker conversion for dilutedreaction mixtures of the crosslinking reaction of PAGA180-b-PNIPAAM350 with 3,9-Divinyl-2,4,8,10-tetraoxaspiro[5.5]undecaneat 25 (&) and 60 8C (*) at c¼0.5 g � L�1, pH¼8.2.

126

dehydration of the PNIPAAm blocks above the LCST, the

block copolymer exhibits an amphiphilic character that

induces the micellization. The water-insoluble PNIPAAm

and water-soluble PAGA blocks form the core and the

corona of the micelles respectively with the dithioester

endgroup located within the core of the multimolecular

assemblies.

The transition from unimers to micelles was shown to

be fully reversible over cooling/heating cycles with

unimers and micelle sizes remaining roughly constant

(Figure S2, Supporting Information).

Aiming at capturing the micelle structure, a divinyl

acetal-type cross-linking agent – namely 3,9-divinyl-

2,4,8,10-tetraoxaspiro[5.5]undecane – was added to the

buffered aqueous solution (pH¼ 8.2) and RAFT polymer-

ization was reinitiated using 4,40-azobis(cyanopentanoic

acid) (ACPA), a water-soluble initiator. Since the dithioester

group was positioned within the centre of the core-shell

structure, core-crosslinking was expected to occur via the

formation of triblock copolymers PAGA180-b-PNIPAAm350-

b-PACLx. Prior to the polymerization, the stability of the

acid-degradable crosslinking agent, 3,9-divinyl-2,4,8,10-

tetraoxaspiro[5.5]undecane, was investigated in a buffer

solution at pH¼ 8.2 to estimate its sensitivity against

degradation under these conditions. NMR analysis – before

and after heating of the solution for 24 h at 60 8C –

confirmed the stability of the crosslinking agent under

polymerization conditions. Also the RAFT agent 3-(benzyl-

sulfanylthiocarbonylsulfanyl)propionic acid employed

was found to be stable under the current conditions.

However, it should be noted, that depending on the RAFT

agent and the pH value of the aqueous solution significant

hydrolysis of the RAFT agent can be observed.[50]

The molar ratio of crosslinking agent to dithioester

chain ends was adjusted to 185 (the ratio between vinyl

groups and RAFT agents was therefore 370), while the

molar ratio of dithioester chain ends to initiator was kept

constant at 2.5. During the course of the polymerization,

the samples remained opalescent as expected for micellar

solutions. No gel formation occurred during the cross-

linking step confirming, as previously reported,[42–46] that

the polymerization of the crosslinking agent was indeed

mediated by the dithioester chain ends.

The consumption of the crosslinking agent was mon-

itored by 1H NMR (see Supporting Information). The

bifunctional monomer was totally consumed after 32 h

of polymerization. The first-order kinetic plot was linear

indicative for a constant radical concentration – no

inhibition period in the early stages of the polymerization

was observed (Figure S1, Supporting Information).

The evolution of hydrodynamic diameter for the

reaction mixture (aqueous solution; pH¼ 8.2) with cross-

linking agent conversion and temperature was subse-

quently studied (Figure 2). For this purpose, aliquots of



reaction mixture were drawn at varying time intervals and

hydrodynamic diameters were determined by DLS at 25

and 60 8C.

At 25 8C, the hydrodynamic diameter raised slightly

with increasing crosslinking agent conversion. Since

PAGA180-b-PNIPAAm350 solely exists as molecularly dis-

solved unimers in aqueous solution at 25 8C, this trend

undoubtedly corroborates the occurrence of the core-

crosslinking reactions.

In contrast, increasing the temperature well above

the LCST of PNIPAAm (60 8C) resulted in the formation

of self-assembled aggregates as depicted in Figure 1. In

the beginning of the polymerization, a hydrodynamic

diameter of approximately 85 nm was observed. With

proceeding crosslinking reaction the size of the core-shell

particle decreased similarly to earlier reports (Figure 2).[51]

The lowering of hydrodynamic diameters with cross-

linking agent conversion at 60 8C may be assigned to the

contraction of the core caused by the crosslinking process

or to altered aggregation numbers.

Up to high crosslinking agent conversion the hydro-

dynamic diameter was found to be higher at 25 than at

60 8C. Above the LCST the increased hydrophobicity caused

an enhanced aggregation with more partly crosslinked

micelles assembling to higher structures. It should be

noted here that, in contrast to shell-crosslinked micelles,

core-crosslinked micelles are still very dynamic structures

behaving rather like star polymers than hard spheres.

They consequently can further assemble into higher

aggregates.[52,53]

At very high cross-linking agent conversion (>90%), the

micellar system appeared to be fully crosslinked. Tempe-

ratures above the LCST – here 60 8C – led to the contraction

DOI: 10.1002/marc.200700663


Table 1. Degradation study on PAGA180-b-PNIPAAm350-b-PACL2�165 at varying pH values, (25 8C).

Buffer concentration Type of buffer pH Particle size at t¼ 0 min Time for complete

degradationnm

0.05 M Phosphate buffer 8.2 85 No degradation for 2 d

0.05 M Phosphate buffer 6.0 150 No degradation for 2 d

0.05 M Citrate-phosphate buffer 4.0 250 �12 h

0.05 M Citrate-phosphate buffer 2.0 310 30 min

Figure 3. Hydrodynamic diameter obtained via DLS and scatteringintensity vs. degradation time of PAGA180-b-PNIPAAm350-b-PACL2�165, c¼ 1 g � L�1, pH¼4.

of the core-forming PNIPAAm block. To investigate this

observation in detail, the hydrodynamic diameter of

this crosslinked micelle – PAGA180-b-PNIPAAm350-b-

PACL2�165 – was measured at varying temperatures

(Figure 1). Above the LCST, stable core-shell particles with

a hydrodynamic diameter of 40 nm were observed.

Lowering the temperature of the aqueous solution below

the LCST of PNIPAAm (25 8C) resulted in a dramatic

increase of the particle size (65 nm) indicative for the

swelling of the hydrophilic PNIPAAm core while no trace of

molecularly dissolved unimers could be detected.

The thermoresponsive transition in both polymers –

crosslinked and noncrosslinked – was with 28 8C observed

to be slightly lower than the LCST of PNIPAAm in water. A

higher ionic strength and a pH value deviating from the pH

value of pure water can be responsible for a decreased

phase transition.[46,54]

The degradation of the core crosslinked micelles

was subsequently investigated in buffer solutions with

pH ranging from 2 to 8.2 (Table 1). Before acid-induced

degradation (t¼ 0), the hydrodynamic diameter increased

from 85 nm at pH¼ 8.2 to 310 nm at pH¼ 2 indicating

that acidic conditions were promoting the aggregation of

crosslinked micelles. This result is consistent, in contrast

to shell-crosslinked micelles, with the star polymer-like

behaviour of core-crosslinked micelles.[52,53] Moreover,

rearrangement of aggregation number under the influence

of altered pH values or additives has frequently been

observed with amphiphilic glycopolymers.[55,56] The main

focus here is, however, not the initial hydrodynamic

diameter but the influence of the buffer solution acidity

on the rate of particle degradation. The acetal-type

crosslinking agent, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-

undecane, is stable at high pH values but tends to

decompose in acidic conditions resulting in the formation

of an aldehyde and an alcohol (Scheme 1). The formation of

triblock copolymers with a polyacrolein block PAGA180-b-

PNIPAAm350-b-PAx was therefore expected (Scheme 1). As

a consequence of the degradation process, the block

copolymers were cleaved of the crosslinked micelle

resulting in the reduction of the numbers of connected

chains, thus the measured hydrodynamic diameter.



When the crosslinked micelles were dissolved in buffer

solutions at pH¼ 8.2 and 6, no alteration of particle size at

25 8C could be observed over a period of 2 d confirming the

stability of the acetal linkages over these pH conditions

(Table 1).

Increasing the acidity of the buffer solution to pH¼ 4

was expected to promote the cleavage of the acetal

linkages and thus release triblock copolymers (Scheme 1).

A more acidic buffer solution resulted instantaneously in a

dramatic lowering of the scattering intensity indicative for

the formation of smaller particles (Figure 3). During the

first eleven hours, the hydrolysis proceeded smoothly

leading to a slow decrease of the hydrodynamic diameter.

However, no traces of unimer could be detected at the early

stages of the hydrolysis, probably due to the intrinsically

weak scattering intensity exhibited by low molecular

weight objects. Afterwards, the particle size rapidly

dropped below 20 nm, and the scattering intensity

remained stable in agreement with the unique presence

of molecularly dissolved triblock unimers (Figure 3).

A further decrease of buffer solution pH value (pH¼ 2)

significantly accelerated the rate of degradation of the

crosslinked micelles leading to the complete disappear-

ance of multimolecular assemblies after 30 min.



128

After removal of the buffer and pentaerythriol via dia-

lysis against water, the final triblock copolymer, PAGA180-

b-PNIPAAm350-b-PA330, resulting from the hydrolysis of

the crosslinked micelles, was characterized by FT-IR

spectroscopy and GPC analysis. The purified triblock

copolymer PAGA180-b-PNIPAAm350-b-PA330 with its poly-

acrolein sequence is expected to be reactive in solution

towards the presence of alcohols and amines.

It is worth noting that NMR studies could not be

employed since solvents suitable for the resulting triblock

copolymer – water and DMSO-d6 – do not allow the

observation of aldehyde groups due to the rapid exchange

of water with aldehyde via hydrate formation. In addition,

aldehyde groups may undergo further acetal formation

with sugar moieties under these conditions.

To support the formation of the polyacrolein third block

after the acidic treatment, FT-IR spectroscopy analysis of

freeze-dried samples were carried out before and after

hydrolysis. While no trace of aldehyde group could be

detected prior to the hydrolysis, the post-hydrolysis

samples exhibited a typical band at 1720 cm�1 that

clearly confirmed the presence of aldehyde groups and

thus corroborated the formation of a polyacrolein block

(Figure S3, Supporting Information).

The molecular weight of the block copolymer obtained

after hydrolysis – PAGA180-b-PNIPAAm350-b-PACLx – was

analyzed using GPC and compared to the original block-

copolymer PAGA180-b-PNIPAAm350. A clear molecular

weight shift and a low PDI of 1.2 is observed confirming

that the acid-degradable crosslinker was indeed incorpo-

rated via a living process leading to well-defined

block copolymers after hydrolysis (Figure S4, Supporting

Information). A small high molecular weight peak

appeared in the hydrolyzed sample obtained from a high

crosslinker conversion. Its origin is currently unknown and

can be attributed to incomplete hydrolysis or to gel-

forming side reactions between aldehydes and sugar

groups.

Conclusion

In this study, we explored the synthesis of acid-degradable

micelles using thermosensitive glycopolymers block copo-

lymers. While the block copolymer was fully water soluble

at room temperature, it underwent self-assembly into

micelles above the LCST of PNIPAAm. Subsequent chain

extension via the RAFT process using an acetal-type

crosslinking agent, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-

undecane, resulted in stable core-shell structures at high

pH values while the micelles readily decomposed in an

acidic environment. Further investigations will be devoted

to the detailed mechanism of the crosslinking process and

the micelle degradation.



Acknowledgements: We thank the University of New SouthWales(UNSW) and CRC-P (Cooperative Research Centre for Polymers) for ascholarship for LZ. MS acknowledges the ARC (Australian ResearchCouncil) for financial support for this project. We like to thank JimHook of the NMR facilities unit at UNSW for helpful discussions.TPD acknowledges an Australian Federation Fellowship and CBKan Australian Professorial Fellowship. We also would like toacknowledge the excellent management of the research centre(CAMD) by Leonie Barner and Istvan Jacenyik.

Received: September 18, 2007; Revised: October 26, 2007;Accepted: October 26, 2007; DOI: 10.1002/marc.200700663

Keywords: acid-degradable; crosslinked micelle; glycopolymer;reversible addition fragmentation chain transfer (RAFT); stimuli-sensitive polymers

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