Controllable exploding microcapsules as drug carriers

Article abstract of DOI:10.1039/c1cc10337g

Controllable exploding polyelectrolyte microcapsules were developed by layer-by-layer assembly of poly(allylamine hydrochloride) (PAH) and poly(sodium 4-styrenesulfonate) (PSS) on a dextran microgel core containing a cleavable disulfide bond fabricated via click chemistry. The microcapsules can explode upon the injection of DTT with an explosive release of the drug.

Full text of DOI:10.1039/c1cc10337g

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COMMUNICATION
Controllable exploding microcapsules as drug carriersw
Jing Zhang, Cao Li, Ya Wang, Ren-Xi Zhuo and Xian-Zheng Zhang*
Received 18th January 2011, Accepted 22nd February 2011
DOI: 10.1039/c1cc10337g
Controllable exploding polyelectrolyte microcapsules were
developed by layer-by-layer assembly of poly(allylamine hydro-
chloride) (PAH) and poly(sodium 4-styrenesulfonate) (PSS) on
a dextran microgel core containing a cleavable disulfide bond
fabricated via click chemistry. The microcapsules can explode
upon the injection of DTT with an explosive release of the drug.
membrane to explode. However, for biomedical applications,
the core destruction has to take place under physiological
conditions. Whether a similar explosion can occur at physio-
logical pH (7.4) remains a big challenge.9
Here, we aimed to design controllable exploding micro-
capsules, which are able to achieve sudden drug release under
physiological conditions. First, through ‘‘click chemistry’’,
biodegradable dextran microgels containing disulfide bonds
were prepared. The obtained microgel is called a dextran click
microgel. Secondly, a layer-by-layer (LbL) membrane was
applied to coat the prepared microgels. As shown in
Scheme 1, the so-called ‘‘controllable exploding’’ microcapsule
consists of a biodegradable microgel and a surrounding LbL
membrane. The synthesis route of dextran click microgels
based on alkyne-modified dextran (dex-CRC) and azide
modified dextran (dex-N3) is represented in Scheme 2. Dextran
click microgels are biodegradable due to the reduction
of disulfide bonds by dithiothreitol (DTT).10,11 Upon the
addition of DTT, the crosslinkages containing disulfide bonds
are cleaved, leading to increased swelling pressure of the
dextran core. When the swelling pressure is higher than the
membrane can resist, the surrounding LbL membrane will
rupture followed by an exploding release of the entrapped
drug. Using this controllable exploding microcapsule, the
Drug delivery methods can have a significant effect on the
therapeutic efficacy of the drug.1 Conventional methods for
drug delivery, such as oral and injecting delivery systems
always produce a rapid initial increase of drug concentration
to a peak above the therapeutic range, followed by a fast
decrease in concentration to a level below the range of effective
therapy. The initial high concentration can cause a serious risk
of toxicity and related complications for potent drugs.2
Controlled drug release therefore focused on achieving a
constant release of drug over a long period. However, under
some conditions, sustained or continuous release is not
optimal. Recently, cancer therapy has focused on modifying
the drug carriers with targeting moieties.3–5 Typically, these
devices are capable of targeting a certain tissue and releasing
the drug over a period ranging from minutes to months or
years. But these devices also have disadvantages, in that the
loaded drug suffered sustained release in the circulation of
blood before reaching the target tissue. It is desirable for
therapies that the drug can be suddenly released from the
drug carrier at a certain location after being hosted for a while
during the process of blood circulation. Thus, to develop drug
carriers that can reach an appointed target before explosive
drug release is critically important.
Recently, De Geest et al. proposed a self-exploding micro-
capsule, which consists of a degradable dextran-hydroxyethyl
methacrylate microgel core loaded with a macromolecular
drug and a surrounding semipermeable membrane.6–8 The
explosion-like release of the drug was realized by adjusting
the pH to 13–14 via the addition of 1 M NaOH solution. When
the microgel core degrades by hydrolysis of carbonate esters, a
solution of free polymers is formed in the microcapsule, leading
to a high osmotic pressure, which forces the surrounding
Scheme 1 Schematic representations of the exploding microcapsules:
(I) Fabrication of the dextran microgel via click chemistry. (II) LbL
assembly of the (PAH/PSS)3 membrane on the surface of the microgel.
(III) The microgel degrades by adding DTT to cleave the disulfide
bond in the crosslinkages of the dextran chains. As degradation
proceeds, the three-dimensional network of the microgel changes to
free dextran chains. After degradation, the core of the microcapsule
has become a dextran solution and the corresponding swelling
pressure causes the microcapsule to swell (IV) and finally explode (V).
Key Laboratory of Biomedical Polymers of Ministry of Education,
Department of Chemistry, Wuhan University, Wuhan, 430072,
P. R. China. E-mail: xz-zhang@whu.edu.cn; Fax: +86-27-6875 4509;
Tel: +86-27-6875 4061
w Electronic supplementary information (ESI) available: [DETAILS].
See DOI: Experimental details.10.1039/c1cc10337g
c
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Fig. 1 FTIR spectra of alkyne-modified dextran (A), azide-modified
dextran (B) and a dextran click microgel (C). The extra curve is an
expansion of the alkyne stretch shown in curve A.
Scheme 2 The synthesis route to azide-modified dextran (4) and
alkyne-modified dextran (6). A click reaction between (4) and (6)
crosslinks the dextran chains (7). Cleavage of the disulfide bond by
DTT degrades the dextran network and produces free dextran chains.
controlled sudden release of a drug can be achieved under
physiological conditions by injecting DTT at the exact
location.
Fig. 2 CLSM images of dextran click microgels (A) and (PAH/PSS)3-
coated dextran click microgels. (The scale bar is 10 mm).
Dextran click microgels were fabricated by the rapid
vortexing of an aqueous dex-CRC/dex-N3 phase and an
aqueous poly(ethylene glycol) (PEG) phase.12 Due to the
immiscibility of the two phases, a water-in-water emulsion
was obtained. Subsequently, a click reaction between the
dex-CRC’s pendent alkyne moieties and dex-N3’s pendent
azide moieties was initiated. Dextran click microgels with an
average diameter of 7 mm were obtained after several washes
with de-ionized (DI) water. The conversion of the alkyne and
azide moieties to a triazole ring was confirmed by Fourier
Transform-Infrared Spectroscopy (FTIR). The FTIR spectra
of lyophilized dex-CRC, dex-N3 and dextran click microgels
are displayed in Fig. 1. The typical peaks of the azide in
azide-modified dextran and the alkyne in alkyne-modified
microgels to hold a z-potential of À19 mV. Because propargyl
cystamine (3) connected to the dextran backbone contains a
cleavable disulfide bond, the degradation of the dextran click
microgels will occur by the addition of DTT, yielding dextran
chains.
We then tried to coat the dextran click microgels with
polyelectrolytes using LbL deposition.13–15 Here, poly(allylamine
hydrochloride) (PAH) served as polycations and poly(sodium
4-styrenesulfonate) (PSS) served as polyanions. In order to
visualize the coating membrane, PAH was modified with
rhodamine B. Fig. 2B shows the CLSM image of (PAH/PSS)3-
coated dextran click microgels. The (PAH/PSS)3-coated dextran
click microgel is designated as a microcapsule. It can be seen
that the microcapsule has a regular red ring, which indicates a
polyelectrolyte membrane is successfully formed to surround
the microgel.
dextran are clearly visible at 2108 cmÀ1 and 2124 cmÀ1
,
respectively. In the spectrum of dextran click microgels,
the two typical peaks are significantly reduced or have even
disappeared, indicating the consumption of the azide and
alkyne functional groups.
To investigate how the degradation of the dextran click
microgel core influences the LbL coating, the microcapsules
were incubated in both DI water (pH 7.4) and 1 M DTT
solution at 37 1C, respectively. After one day, the microcapsules
were observed under CLSM. Fig. 3A represents microcapsules
incubated in DI water (pH 7.4). One can see that all the
microcapsules remained intact and filled with dex-FITC. This
demonstrates that a drug can be hosted by the microcapsules
at pH 7.4. In contrast, Fig. 3B shows the ones incubated in
1 M DTT solution. It was found that most of the microcapsules
were ruptured and the model drug dex-FITC got released,
Fig. 2A shows the confocal laser scanning microscopy
(CLSM) image of dextran click microgels loaded with
fluorescein isothiocyanate modified dextran (dex-FITC),
which was used as a model drug. It was found that dex-FITC
stays inside the microgels. To obtain microgels with anionic
surface charge, to enable sequential LbL assembly, only some
of the carboxyl groups of carboxymethyl dextran (CMD, 5 in
Scheme 2) were reacted with propargyl cystamine (3 in
Scheme 2) during the synthesis of dex-CRC. The remaining
carboxyl groups of the dextran chains enable the resulting
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polymer chains, and osmotic pressure started to accumulate.
At the 18th min, it was found that the microcapsules had
swelled up due to the increasing osmotic pressure inside. At
the 24th min, explosion of the coating membrane occurred and
the encapsulated dex-FITC was suddenly released from the
carriers. As a control we also followed the behavior of
uncoated dextran microgels. As shown in Fig. 4B1–B4, the
microgels degraded gradually in the DTT solution and the
encapsulated dex-FITC was released gradually.
In conclusion, we demonstrate the explosive release of a
loaded drug from a novel controllable exploding microcapsule
under physiological conditions (pH 7.4). This device shows the
appealing ability to achieve sudden drug release upon addition
of DTT. In this way, normal tissue can avoid being damaged
by the potent drug, and these controllable exploding micro-
capsules will have great potential in cancer therapy.
Fig. 3 CLSM images of (PAH/PSS)3-coated dextran click microgels
after one day of incubation in DI water (pH 7.4) (A) and 1 M DTT
solution (B) at 37 1C. (The scale bar is 10 mm).
We acknowledge the financial support from the Ministry of
Science and Technology of China (2009CB930300), Trans(New)-
Century Training Programme Foundation for the Talents
from the Ministry of Education of China and Natural Science
Foundation of Hubei Province, China (2009CDA024).
Notes and references
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Fig. 4 Snapshots of the exploding process of the microcapsule
(A1–A4) and the degradation of the uncoated dextran click microgel
(B1–B4). The time interval between the snapshots is 6 min. (The arrow
in Fig. 4A4 indicates the gap through which the drug is released).
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As shown in Fig. 3B, only the debris of broken poly-
electrolyte shells was observed after the degradation of the
dextran click microgel core. To prove the explosion of the
microcapsules after the addition of DTT, we tried to witness
the explosive behavior of the microcapsules. Both dextran
click microgels and the microcapsules were incubated in 1 M
DTT aqueous solution (pH 7.4) at room tempertature. The
particles were subsequently examined by CLSM and followed
over time. Fig. 4A1–A4 shows four snapshots of the micro-
capsules taken at 6, 12, 18 and 24 min respectively. In the first
6 min, the small molecule DTT penetrated into the microgel
core and the disulfide bonds began to cleave. In the next 6 min,
more and more disulfide bonds got cleaved to produce free
¨
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4457–4459 4459