COMMUNICATION
Biodegradable microcapsules designed via ‘click’ chemistry{
Bruno G. De Geest,*ab Wim Van Camp,{c Filip E. Du Prez,c Stefaan C. De Smedt,b Jo Demeesterb and
Wim E. Henninka
Received (in Cambridge, UK) 13th September 2007, Accepted 7th November 2007
First published as an Advance Article on the web 14th November 2007
DOI: 10.1039/b714199h
respectively 20 (dex-CMC and dex-N3) and 5 (dex-N3), as
determined by 1H-NMR spectroscopy, were synthesized. The
covalent cross-linking of the dextran chains, through the formation
of a triazole ring by ‘clicking’ dex-CMC and dex-N3, was performed
in aqueous medium. An aqueous solution containing both dex-
CMC and dex-N3 was emulsified in an external aqueous
polyethylene glycol phase (note that dextran and polyethylene
glycol do not mix at elevated concentrations).5 The ‘click’ reaction
was performed under standard conditions by addition of CuSO4
and sodium ascorbate. After 30 min water was added and solid
dextran hydrogel microcapsules were obtained after centrifugation
and washing with pure water. The conversion of the azide and
alkyne moieties to a triazole ring was demonstrated by attenuated
reflection infrared spectrometry (ATR-IR). Spectra of the
lyophilized dex-CMC, dex-N3 and ‘clicked’microcapsules are shown
in Fig. 1 and observed absorption bands are listed in Table 1. The
characteristic azide peak is clearly visible at 2113 cm21 in the case
of dex-N3 whereas this peak is significantly reduced in the
spectrum of the ‘clicked’ microcapsules, indicating the consump-
tion of the azide function.
Dextrans modified with alkyne and azide groups through
hydrolysable carbonate esters form degradable microcapsules
after CuI catalysed ‘click’ reaction between azides and alkynes
yielding triazole cross-links.
‘Click’ chemistry offers the possibility of carrying out covalent
reactions with high selectivity and yield under extremely mild
conditions.1 The most widespread variant is the CuI-catalysed
Huisgen reaction comprising the 1,3-dipolar cycloaddition of
azides and alkynes forming a highly stable triazole compound.1
In this paper we apply ‘click’ chemistry for the preparation of
microcapsules for drug delivery. Drug encapsulation in polymeric
microparticles often requires the use of organic solvents or radical
polymerization which may denaturize the therapeutic biomolecules
(like peptides, proteins and nucleic acids) to be encapsulated.2 The
non-stringent reaction conditions, such as aqueous medium and
ambient temperature, make ‘click’ chemistry highly attractive for
the design of polymeric microcapsules. On the other hand,
biodegradability is ubiquitous for the purpose of drug delivery.2
We present a novel approach for the synthesis of biodegradable
polymeric microcapsules based on the use of biodegradable ‘click
linkages’.
Dextrans (40 kDa) modified with respectively alkyne and azide
groups which are connected to the dextran backbone through
(biodegradable) hydrolysable carbonate esters (see Scheme 1) were
cross-linked via ‘click’ chemistry. While others have reported on
hydrogel formation via ‘click’ chemistry3 or functionalisation of
intrinsically degradable aliphatic polymers4 by ‘click’ chemistry, we
are to the best of our knowledge the first to introduce
biodegradable ‘click’ linkages in macromolecular structures.
As shown in Scheme 1, dextran propargyl carbonate (dex-CMC)
and dextran azidopropyl carbonate (dex-N3) are synthesized by
activating propargyl alcohol and 3-azidopropanol, respectively
with carbonyl diimidazole (CDI). Subsequently the activated
compounds are grafted onto dextran chains resulting in the
formation of a carbonate ester between the dextran backbone and
the pending propargyl and azidopropyl moieties, respectively. Dex-
CMC and dex-N3 with a degree of substitution (DS; i.e. the number
of alkyne/azide moieties per 100 glucopyranose units) of
aDepartment of Pharmaceutics, Utrecht University, 3584 CA Utrecht,
The Netherlands. E-mail: br.degeest@ugent.be; Fax: +32 9 2648189;
Tel: +32 9 264 80 74
Scheme 1 Reaction scheme of the synthesis of dextran propargyl
carbonate (3) and dextran azidopropyl carbonate (4). Propargyl alcohol
and 3-azidopropanol are activated with CDI yielding (1) and (2). Dextran
is grafted with the activated compounds (1) and (2) yielding alkyne (3) and
azide (4) modified dextran. Click reaction between (3) and (4) cross-links
the dextran chains (5). Hydrolysis of the carbonate esters degrades the
dextran network with the formation of dextran chains, CO2 and a low
molecular weight triazole compound as degradation products.
bLaboratory of General Biochemistry and Physical Pharmacy, Ghent
University, 9000 Ghent, Belgium
cPolymer Chemistry Research Group, Department of Organic
Chemistry, Ghent University, 9000 Ghent, Belgium
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b714199h
{ This author and the first author contributed equally to this paper.
190 | Chem. Commun., 2008, 190–192
This journal is ß The Royal Society of Chemistry 2008
De Geest, Bruno G.
