Tailoring pH-responsive acrylic acid microgels with hydrophobic crosslinks for drug release

Article abstract of DOI:10.1039/c5tb00222b

Amphiphilic microgels based on the hydrophilic acrylic acid (AA) and hydrophobic crosslinks of different compositions were synthesised using a lab-on-a-chip device. The microgels were formed by polymerising hydrophobic droplets. The droplets were generated via a microfluidic platform and contained a protected form of AA, a hydrophobic crosslinker (ethylene glycol dimethacrylate, EGDMA) and a free radical initiator in an organic solvent. Following photopolymerisation and subsequent hydrolysis, AA based microgels of amphiphilic nature were produced and it was demonstrated that they can successfully deliver both hydrophilic as well as hydrophobic moieties. The model drug delivery and the swelling ability of the microgels were influenced by the pH of the aqueous solution as well as the crosslinking density and hydrophobic content of the microgels.

Full text of DOI:10.1039/c5tb00222b

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Materials Chemistry B
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Tailoring pH-responsive acrylic acid microgels
with hydrophobic crosslinks for drug release
Cite this:DOI: 10.1039/c5tb00222b
a
a
a
b
B. Lu, M. D. Tarn, N. Pamme* and T. K. Georgiou*
Amphiphilic microgels based on the hydrophilic acrylic acid (AA) and hydrophobic crosslinks of different
compositions were synthesised using a lab-on-a-chip device. The microgels were formed by polymerising
hydrophobic droplets. The droplets were generated via a microfluidic platform and contained a protected form
of AA, a hydrophobic crosslinker (ethylene glycol dimethacrylate, EGDMA) and a free radical initiator in an
organic solvent. Following photopolymerisation and subsequent hydrolysis, AA based microgels of amphiphilic
nature were produced and it was demonstrated that they can successfully deliver both hydrophilic as well as
hydrophobic moieties. The model drug delivery and the swelling ability of the microgels were influenced by the
pH of the aqueous solution as well as the crosslinking density and hydrophobic content of the microgels.
Received 30th January 2015,
Accepted 5th May 2015
DOI: 10.1039/c5tb00222b
www.rsc.org/MaterialsB
to fabricate amphiphilic microgels, one hydrophilic reagent
and one hydrophobic would have to be stabilised and mixed
Introduction
Microgels are gel particles with sizes ranging from 0.1 to together in a droplet without diffusing into the CP. However, if
00 mm, and consisting of three-dimensionally crosslinked the CP is aqueous then the hydrophilic reagent will diffuse
polymer networks. Such microgels have many exciting applica- from the droplets to the CP and vice versa. If the CP is based on
1
1
–10
tions, including bioapplications in drug delivery,
tissue oil or an organic solvent, the hydrophobic reagents will diffuse
2
11
engineering, and biosensing, as well as applications in areas from the droplets to the CP. Thus, amphiphilic microgels are
coatings and usually prepared using post-modifications
food industry. Depending on the chemistry of the polymer multi-step procedures.
1
2
13,14
15
1,4,7,17–21
of the oil industry, organic dye removal,
and/or
1
6
6,22
Commonly, hydrophilic microgels
chains, microgels can be dispersed in organic and/or aqueous are fabricated and then modified to produce amphiphilic
solvents. For bioapplications like drug delivery it is important microgels by covalently or electrostatically binding amphiphilic
1
,4,7,18–21
that the microgels are dispersed in water, i.e. they should or hydrophobic moieties.
contain hydrophilic components that will stabilise and disperse In this study we have used a microfluidic device to form
the microgels in water. However, it would be more advantageous droplets that were subsequently polymerised and hydrolysed
if the microgels were amphiphilic, i.e. if they contained both to fabricate amphiphilic microgels that were based on acrylic
hydrophobic and hydrophilic groups, as they would be able to acid (AA, ionisable and hydrophilic) and hydrophobic cross-
encapsulate and release both hydrophilic and hydrophobic drugs. links based on the hydrophobic crosslinker ethylene glycol
Amphiphilic microgels, however, are challenging to fabricate dimethacrylate (EGDMA). The application of a microfluidic platform
because most of the production methods, such as conventional offers the advantages of generating droplets, and consequently
emulsion templating, involve the formation of droplets in an microgels, of narrower size distribution, while the size of the
16,23–26
immiscible continuous phase. The droplets contain pre-gels droplets can be tailored by varying the flow rates.
Thus, the
or polymerisable reagents that are later reacted to form the microgels are tailorable in terms of their size but also in terms
microgel. Thus, when fabricating hydrophilic microgels, the hydro- of their composition since the crosslinking density, and so
philic reagents are dispersed in the droplets while the continuous amphiphilicity, can also be varied by adjusting the molar ratio
phase (CP) is an organic solvent in which the reagents have reduced of the components. Finally, when using a microfluidic device,
or no solubility. The opposite applies when forming hydrophobic immediate reactions following droplet generation can be per-
microgels; hydrophobic reagents are dispersed in the droplets formed, thereby enabling the polymerisation of some relatively
while the CP is usually an immiscible aqueous solution. In order unstable and easily hydrolysed monomers. For example,
(
meth)acrylic monomers when in contact with water tend to
2
7
hydrolyze to (meth)acrylic acid, but (meth)acrylic acid will not
be miscible in an organic solvent that contains another hydro-
phobic (macro)monomer or (macro)crosslinker in order to
produce amphiphilic microgels.
a
b
Department of Chemistry, University of Hull, HU6 7RX, Hull, UK.
E-mail: n.pamme@hull.ac.uk
Department of Materials, Imperial College London, SW7 2AZ, London, UK.
E-mail: t.georgiou@imperial.ac.uk
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Therefore, in order to produce amphiphilic microgels, a hydro-
Journal of Materials Chemistry B
Synthesis of protected acrylic acid monomer, tetrahydro-
phobic monomer that is a protected form of AA, specifically pyranyl acrylate (THPA). The synthesis of THPA was similar
tetrahydropyranyl acrylate (THPA), was synthesised in-house and to the previously described synthesis of tetrahydropyranyl
2
8–30,34,35
then copolymerised with the hydrophobic crosslinker, EGDMA, in methacrylate.
In a 500 mL three neck round bottom
chloroform droplets that were formed using microfluidic devices. flask that containing 1 g of phenothiazine (free radical inhibitor)
The protective group of tetrahydropyranyl was chosen because it is 125 mL of DHP (116.25 g, 1.38 mol), 20 drops of a 50% v/v
a good leaving group and it can be easily be hydrolysed even in sulfuric acid solution in water were added drop-wise. The colour
28–31
macrogels.
The hydrolysis of the THPA groups produced should change to brown. Following this, a mixture of 125 mL
anionic gels which we have chosen because they have shown DHP (116.25 g, 1.38 mol) and 94.6 mL AA (99.4 g, 1.38 mol) and
3
2
33
promise in drug delivery and protein delivery. Specifically, 1 g phenothiazine (using a dropping funnel) was added and the
in this study microgels of differing crosslinking ratios were round bottom flask was placed in an oil bath. The mixture was
produced, collected and polymerised off-the chip and then then left to react overnight at 50 1C.
hydrolysed to produce AA based microgels. The pH responsiveness
of the AA based microgels was evaluated by studying their NaHCO
The next day, once the mixture had cooled down, 10 g of
and 40 g of Na SO were added and allowed to stir for
3
2
4
swelling in different pH environments. Finally, to prove that 2–3 h. The solids were then filtered out and the monomer
the amphiphilic nature of the microgels assists in the delivery mixture was passed through a basic alumina column twice
of drugs of different hydrophilicities, the encapsulation and (to remove the un-reacted AA). The removal of AA was con-
1
delivery of both hydrophobic and hydrophilic moieties was firmed by H NMR. A free radical inhibitor, DPPH, was added
investigated. To the best of our knowledge, this is the first into the THPA monomer and the monomer was stored in the
report of covalently linked microgels of amphiphilic nature that fridge. It was distilled under vacuum prior to use.
have been prepared using a microfluidic platform.
Fabrication of microgels
Microfluidic chip fabrication and setup. Droplets containing
THPA–EGDMA were were generated in a flow focusing chip
geometry with a CP inlet, a dispersed phase (DP) inlet, and a
Experimental
Materials and methods
Acrylic acid (AA, 99%), 2,3-dihydro-2H-pyran (DHP, 99%), ethylene single straight outlet channel (Fig. 2a). The channel structure
glycol dimethacrylate (EGDMA), sodium dodecyl sulphate (SDS), was etched in glass to a depth of 50 mm and a width of 150 mm
3
6
2
9
,2-diphenyl-1-picrylhydrazyl hydrate (DPPH, free radical inhibitor, via photolithography and wet etching techniques. Fused silica
9%), 1-hydroxy-cyclohexyl phenyl ketone (HCPK, 99%) as the capillaries (150 mm i.d., 363 mm o.d., CM Scientific, UK) were
free-radical initiator, Sudan I, trypan blue, phenothiazine (98%), glued into the inlet and outlet holes and connected to 500 mL
sulfuric acid, sodium bicarbonate (NaHCO ), sodium sulphate glass syringes (SGE, Sigma-Aldrich, UK) with syringe adaptors
3
2 4
(Na SO ) hydrochloric acid, sodium hydroxide and basic alumina (IDEX Health & Science, UK) (Fig. 2b). Two syringe pumps
were purchased from Sigma-Aldrich (Dorset, UK). EGDMA was (PHD2000, Harvard Apparatus, UK) were used to control the flow
À1
À1
passed through a basic alumina column to remove the free radical rates of the CP and DP between 0.5 mL min and 50 mL min . A
initiator prior use. The organic solvent used to prepare the hydro- 5 cm long piece of Tygon tubing (254 mm i.d., 762 mm o.d., Cole-
phobic droplets was chloroform (99%), and was purchased from Parmer, UK) was attached to the outlet capillary at one end, while
Fisher Scientific (Loughborough, UK). The chemical structure the other end was placed onto a microscope slide or a Petri dish
of the main reagents used (AA and EGDMA) and the in-house for droplet collection. Droplets were photographed with a colour
synthesized THPA monomer, synthesis described below, are CCD camera (MTV-63V1N, Mintron, Taiwan) attached to an
shown in Fig. 1.
inverted microscope (Eclipse Ti, Nikon, UK), with images cap-
tured using WinDVD Creator 2 (Corel Ltd, UK) software. ImageJ
freeware was used for the analysis of droplet size and colour
Fig. 2 (a) Layout and photograph of the flow focusing chip employed for
microgel precursor droplet formation. The design featured a central
channel for the oil based DP, containing the reagents, and outer channels
for the CP, which merged into a 5 mm long outlet channel. (b) Experi-
mental setup for on-chip droplet generation and collection of the droplets
onto a slide or dish for UV initiated photopolymerisation.
Fig. 1 Chemical structures of the monomers and crosslinker.
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intensity. Photopolymerisation was achieved using a 15 W UV
light source (XX-15S, Ultra-Violet Products Ltd, UK). The entire
setup was covered with a thick black cloth to in order to protect
users from UV irradiation. Chips and syringes were covered with
aluminum foil to prevent the reagents from gelating prior to
their collection as droplets.
Formation of droplets and polymerisation of microgels. The
DP was based on chloroform containing THPA and EGDMA
with varying molar ratios (though the total concentration of
the two reagents was always 30 wt%), and 4 wt% of HCPK
Fig. 3 Chemical structures of (a) hydrophobic Sudan I, and (b) hydrophilic
(free radical photo-initiator). The CP was an aqueous solution
trypan blue.
of 0.1 wt% SDS. The concentration of SDS was below the critical
3
7
micelle concentration. The flow rates of the CP and DP were
À1
À1
at regular time intervals (every 1 min or 5 min depending on
how fast the release was). ImageJ freeware was used for the
analysis of the colour intensity.
5
mL min and 0.5 mL min , respectively, and were chosen
following preliminary results which showed that stable droplets
were formed at these flow rates. After droplet formation in the
microfluidic device, the droplets were collected on a micro-
scope slide or Petri dish and immediately polymerised by UV
irradiation for 30 min. Three THPA–EGDMA microgels of
Results and discussion
differing compositions were formed, with molar ratios of Microgel fabrication and pH responsiveness studies
3
0 : 4, 50 : 4, and 70 : 4 THPA : EGDMA. The polymerised micro-
Three types of amphiphilic AA–EGDMA microgels of different
crosslinking densities and hydrophobic contents were success-
fully fabricated via a microfluidic approach. Specifically, droplets
of THPA:EGDMA in chloroform were formed in an aqueous
CP and collected on a slide or dish, then polymerised via
UV-initiated free radical polymerisation. Following polymerisation,
these THPA–EGDMA microgels were hydrolysed by suspending
them in a pH 1 solution to produce AA–EGDMA microgels. The
hydrolysis step caused the microgels to shrink due to protonation
of the ionisable AA units. For example, when the 50 : 4 THPA–
EGDMA microgel (Fig. 4a) was hydrolysed to AA–EGDMA
gels were then hydrolysed in 1 M HCl overnight to produce
pH responsive AA–EGDMA microgels. The hydrolysis was con-
firmed with FTIR spectroscopy.
Swelling studies in different pH environments
Aqueous solutions of NaOH (1 M) and HCl (1 M) were used to
vary the pH of the AA–EGDMA microgel suspensions, from pH 1
to pH 14, in order to study the responsiveness of the microgel
particles. The microgels were photographed with the colour CCD
camera and inverted microscope setup described previously, with
ImageJ used for image analysis. The extent of swelling and
shrinking (relative size) was calculated by dividing the microgel
size at a given pH by their original size measured at pH 7.
(Fig. 4b) the microgel shrank from 131 mm to 98 mm. However,
when the AA–EGDMA microgel was then suspended in a pH 14
solution it swelled to 203 mm.
The pH responsiveness of each type of AA–EGDMA microgel
formed with each molar ratio of THPA : EGDMA (30 : 4, 50 : 4,
and 70 : 4) was studied by measuring the size of the microgels at
different pH values. As can be observed in Fig. 5, the size of the
microgels increased with the increase in the pH of the solution.
This was expected and was due to the ionisable and hydrophilic
AA units of the microgels, as it was confirmed by the microgels
a
pK determination
The pK of the three synthesised microgels was determined by
a
potentiometric titration. Specifically, 0.02 g of each microgel was
dispersed in water, 1 M NaOH was added to increase the pH above
1
0
1 and then the titration was performed by repeatedly adding
.05 mL of 0.1 M HCl and measuring the pH after each addition.
pK
a
s that were determined with potentiometric titration. Specifi-
s were found to be 6.1, 6.2 and 6.2 for the three
Dye encapsulation and release studies
cally the pK
a
Two types of dye were encapsulated in the microgels via two
different methodologies, in order to determine the capability of
the microgels to encapsulate and release both hydrophilic and
hydrophobic moieties. 0.5 wt% hydrophobic Sudan I was mixed
into the DP when the droplets were being prepared in the
microfluidic channel, hence the dye was already present
inside the microgel following the polymerisation step. 0.5 wt%
hydrophilic trypan blue was loaded into already polymerised
AA–EGDMA microgels in a pH 14 solution by diffusion with
sonication. The chemical structures of both dyes are shown in
Fig. 3. The model drug release was monitored using the colour
camera of the microscope, in particular how the colour inten-
microgels with different AA : EGDMA ratios, 30 : 4, 50 : 4, and 70 : 4,
respectively, similar to that of pAA based stars. Hence the AA
units are negatively charged at high pH due to deprotonation,
38
Fig. 4 THPA–EGDMA (50 : 4 molar ratio) microgels (a) before hydrolysis
at pH 7, (b) after hydrolysis (forming AA–EGDMA microgels) at pH 1, and (c)
sity of the microgels changed during release. Images were taken at pH 14.
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Fig. 6 (a) 50 : 4 THPA–EGDMA microgels with hydrophobic Sudan I dye
encapsulated during droplet generation. (b) 50 : 4 THPA–EGDMA droplets
after polymerisation (pH = 7). (c) Sudan I dye release from 50 : 4 AA–EGDMA
microgels in pH 14 solution.
that the dye was already present in the microgels when they
were then polymerised. THPA–EGDMA (50 : 4 molar ratio) dro-
plets containing the Sudan I are shown in Fig. 6a, while Fig. 6b
shows the microgels following polymerisation. The THPA–EGDMA
Fig. 5 Swelling ratios of the AA–EGDMA microgels in different pH environ-
ments. Microgels formed from THPA :EGDMA molar ratios of 30: 4, 50: 4 microgels were hydrolysed in pH 1 solution to form AA–EGDMA
and 70: 4 are represented as squares, circles and triangles.
microgels. When the 50 : 4 AA–EGDMA microgels were dispersed
in pH 14 solution, as shown in Fig. 6c, the dye, which appears
orange in the pictures although the colour is actually red, can
clearly be seen diffusing out of the microgel. As described in the
previous section, when suspended in basic solution the microgel
swells due to extension of the polymer chains via repulsive ionic
interactions, thereby enlarging the pores in the microgels and
allowing the dye to be released. Furthermore, the AA units become
more hydrophilic when they are transferred from acidic to basic
pH, and so they are no longer able to retain the hydrophobic dye.
The release of the hydrophobic model drug was further
evaluated by studying the release of Sudan I over time for all
three types of microgels. The results are shown in Fig. 7. As can
be clearly observed, the crosslinking density and hydrophobic
content of the microgel strongly affects the release of Sudan I.
Specifically, by increasing the crosslinking density (EGDMA
content) the rate, as well as the amount, of hydrophobic dye
released is reduced. This was expected, since by increasing the
while they are not ionised at low pH because they are protonated.
Thus, at high pH values the polymer chains expand and extend
due to the repulsive forces caused by the negatively charged AA
units. When the polymer chains expand the entire microgel
structure expands/swells. Returning the microgels to a lower
pH environment causes them to shrink again as a result of
deprotonation. This reversible pH responsive behaviour was
expected, and has been observed previously for (meth)acrylic
4
,5,39
29,30,34
acid containing microgels
and macrogels,
and this
property makes the AA–EGDMA microgels promising for encap-
sulation and release of various moieties. Note that the size of
the microgels at very high pH reduces because of increased
ionic strength due to the higher NaOH concentration, as it has
2
9,30
been observed in macrogels.
When comparing the three types of microgels in Fig. 5, it
was apparent that by increasing the crosslinking density and
the hydrophobic content, the size of the microgels decreased,
as anticipated since the crosslinks avert the microgel from
expanding. This expected trend, that has been observed before
crosslinking density the mesh/pore size of the microgels
43,44
decreases
so it is more difficult for the dye to diffuse out.
In addition, by increasing the EGDMA (crosslinker) content,
4
,39
40
in microgels
as well as macrogels, was only apparent in
high pH solutions in which the AA units were ionised. At lower
pH values, the polymer chains of the microgels were not
extended, i.e. the microgels were in a collapsed (shrunken)
state, so the crosslinks no longer interfered with the polymer
chain movement and expansion.
Dye encapsulation and release studies
A hydrophobic and a hydrophilic dye were encapsulated and
released in order to prove that the amphiphilic nature of the
AA–EGDMA microgels could be utilised for the capture and
delivery of moieties of varying hydrophobicity/hydrophilicity,
4
1,42
similarly to amphiphilic macrogels.
The release of the
model drugs was triggered by making the pH of the environ-
ment basic such that the AA units became ionised and the
microgels swelled, allowing the dyes to diffuse out.
Hydrophobic dye – Sudan I. Sudan I (see the chemical
structure in Fig. 3a) was encapsulated into the microgel by
Fig. 7 Hydrophobic drug release at basic pH (pH 4 11). The plots show
the relative Sudan I colour intensity versus time for all three types of
AA–EGDMA microgels with different crosslinking densities. Squares, circles
and triangles represent the 30: 4, 50 : 4 and 70: 4 AA: EGDMA molar ratios,
adding it to the oil based DP for droplet formation, meaning respectively.
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which is itself hydrophobic, the hydrophobic dye will be crosslinking ratio in a similar manner to the release of
retained in the microgel structure to a greater extent due to the hydrophobic dye (Sudan I). In particular, by increasing
van der Waal’s interactions.
the crosslinking density and thus reducing the mesh size, the
Hydrophilic dye – trypan blue. A hydrophilic dye, trypan blue release of the hydrophilic dye was slower. This was expected
(see the chemical structure in Fig. 3b), was also investigated. In since the higher mesh/pore size allows the dye to diffuse more
this case, 0.5 wt% trypan blue was loaded into the AA–EGDMA easily and faster through the microgel structure.
microgels after they had already been polymerised and hydro- Compared to the hydrophobic Sudan I release, the release
lysed. This was achieved by suspending the AA–EGDMA micro- of trypan blue from the AA–EGDMA microgels was much faster
gels into pH 14 solution of trypan blue in order to make them for all three types of microgel. For example, it took more than
swell, allowing gradual diffusion of the trypan blue into the 25 min for the release of the hydrophobic Sudan I from the
microgels which was assisted by sonication. Fig. 8a shows this 70 : 4 AA–EGDMA microgel at basic pH to reach a plateau,
process for 50 : 4 molar ratio AA–EGDMA microgels. As the pH while the plateau was reached in only 5 min when the hydro-
was then reduced to pH 1, the microgels shrank and the trypan philic trypan blue dye was being released. This can be attrib-
blue was encapsulated and concentrated within the gel particle. uted to the difficulty of the hydrophobic dye to diffuse into
After purification, the pH was increased again to pH 7 (Fig. 8b), an aqueous environment compared to the hydrophilic dye
where it was found that the hydrophilic trypan blue was gradually as well as the fact that the hydrophobic domains of the
released into the surrounding water. It can be seen that the blue microgels retain the hydrophobic dye for longer through van
colour intensity inside the microgel faded within an hour (Fig. 8c), der Waals interactions.
indicating release of the dye from the microgel.
In summary, the AA–EGDMA microgels were able to encap-
The release of the hydrophilic dye was further investigated sulate and deliver both hydrophobic and hydrophilic dyes, and
over time for all three types of AA–EGDMA microgels in a basic it has been demonstrated that the rate of release can be varied
pH solution (BpH 8.5). The results are shown in Fig. 9, and it is by adjusting the crosslinking density and hydrophobic content
apparent that the release of trypan blue was influenced by the of the microgel.
Conclusions
Amphiphilic microgels based on hydrophilic, ionisable AA
and the hydrophobic crosslinker EGDMA were successfully
synthesised from droplets formed in a microfluidic platform.
The use of microfluidics enabled the systematic variation of
Fig. 8 Hydrophilic trypan blue encapsulation in, and release from, 50 : 4
the crosslinking density and the synthesis of microgels with
AA–EGDMA microgels. (a) Encapsulation of the dye in pH 14 solution via
narrower size distributions than those prepared by conven-
diffusion. (b) Microgels containing the trypan blue immediately after their
tional methods. The microgels were pH responsive. By increas-
introduction into a pH 7 environment, and (c) after an hour of dye release
at pH 7.
ing the pH of the solution, the size of the microgels increased
due to ionisation of the AA units and the resultant electrostatic
repulsion between them inside the gel particles. The swelling of
the microgels increased by decreasing the crosslinking density.
Finally, the encapsulation and release of a hydrophobic and
a hydrophilic dye, which were used as model drugs, was
investigated. The hydrophobic dye was incorporated during
the droplet generation stage, while the hydrophilic dye was
absorbed by microgels that had already been polymerised. The
subsequent delivery was investigated and it was proven that the
pH can be used to trigger the release. Thus, the amphiphilic
nature of the AA–EGDMA microgels allowed the encapsulation
and delivery of both types of model drugs, and as expected the
hydrophilic dye was released faster than the hydrophobic dye
since it was able to diffuse faster through the microgel and into
the aqueous surroundings.
Fig. 9 Hydrophilic dye release in basic pH solution (BpH 8.5). The plots
show the relative trypan blue colour intensity versus time for all three types
of AA–EGDMA microgels with different crosslinking densities. Squares,
circles and triangles represent the 30 : 4, 50 : 4 and 70 : 4 AA : EGDMA
molar ratios, respectively.
Acknowledgements
University of Hull is thanked for funding Mr Lu’s PhD
studentship.
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