Photochemically Controlled Drug Dosing from a Polymeric Scaffold

Article abstract of DOI:10.1007/s11095-017-2164-9

Purpose: To develop the first photoactive biomaterial coating capable of controlled drug dosing via inclusion of synthesised drug-3,5-dimethoxybenzoin (DMB) conjugates in a poly(2-methyoxyethyl acrylate) (pMEA) scaffold. Methods: Flurbiprofen- and naproxen-DMB conjugates were prepared via esterification and characterised via NMR spectroscopy and mass spectrometry following chromatographic purification. Conjugate photolysis was investigated in acetonitrile solution and within the pMEA matrix following exposure to low-power 365?nm irradiation. Photo-liberation of drug from pMEA into phosphate buffered saline was monitored using UV-vis spectroscopy. Results: The synthetic procedures yielded the desired drug conjugates with full supporting characterisation. Drug regeneration through photolysis of the synthesised conjugates was successful in both acetonitrile solution and within the pMEA scaffold upon UV irradiation. Conjugates were retained within the pMEA scaffold with exclusive drug liberation following irradiation and increased drug dose with increasing exposure. Multi-dosing capacity was demonstrated though the ability of successive irradiation periods to generate further bursts of drug. Conclusion: This study demonstrates the first application of photochemically controlled drug release from a biomaterial coating and the feasibility of using pMEA as a scaffold for housing the photoactive drug-DMB conjugates.

Full text of DOI:10.1007/s11095-017-2164-9

Pharm Res
DOI 10.1007/s11095-017-2164-9
RESEARCH PAPER
P h o t o c h e m i c a l l y C o n t r o l l e d D r u g D o s i n g
from a Polymeric Scaffold
Louise Donnelly1 & John G. Hardy1 & Sean P. Gorman1 & David S. Jones1 & Nicola J. Irwin1 & Colin P. McCoy1
Received: 29 December 2016 /Accepted: 25 April 2017
#
The Author(s) 2017. This article is an open access publication
ABSTRACT
ABBREVIATIONS
Purpose To develop the first photoactive biomaterial coating
capable of controlled drug dosing via inclusion of synthesised
drug-3,5-dimethoxybenzoin (DMB) conjugates in a poly(2-
methyoxyethyl acrylate) (pMEA) scaffold.
Methods Flurbiprofen- and naproxen-DMB conjugates were
prepared via esterification and characterised via NMR spec-
troscopy and mass spectrometry following chromatographic
purification. Conjugate photolysis was investigated in acetoni-
trile solution and within the pMEA matrix following exposure
to low-power 365 nm irradiation. Photo-liberation of drug
from pMEA into phosphate buffered saline was monitored
using UV-vis spectroscopy.
DCC
Dicyclohexylcarbodiimide
DCM Dichloromethane
DMAP Dimethylaminopyridine
DMB
DMF
3,5-dimethoxybenzoin
Dimethylformamide
HEMA 2-hydroxyethyl methacrylate
PBS Phosphate buffered saline
PMEA Poly(2-methoxyethyl acrylate)
UV Ultraviolet
INTRODUCTION
Results The synthetic procedures yielded the desired drug
conjugates with full supporting characterisation. Drug regen-
eration through photolysis of the synthesised conjugates was suc-
cessful in both acetonitrile solution and within the pMEA scaffold
upon UV irradiation. Conjugates were retained within the
pMEA scaffold with exclusive drug liberation following irradia-
tion and increased drug dose with increasing exposure. Multi-
dosing capacity was demonstrated though the ability of successive
irradiation periods to generate further bursts of drug.
Conclusion This study demonstrates the first application of
photochemically controlled drug release from a biomaterial
coating and the feasibility of using pMEA as a scaffold for
housing the photoactive drug-DMB conjugates.
Controlled drug delivery devices offer the potential to maxi-
mize the therapeutic activity of drugs while minimizing their
side effects (1). To meet this objective, the ability to target a
drug to its intended site of action and maintain its release rate
within the therapeutic range over an extended time period is
fundamental (2). Since Wichterle and Lim developed the first
hydrogel comprised of 2-hydroxyethyl methacrylate (HEMA)
and ethylene dimethacrylate in the 1950’s (3), which later
found widespread use as a contact lens material (4), the use
of hydrogels in the pharmaceutical (5) and biomedical fields
(6) has increased. Tanaka’s work on the temperature induced
phase transition of polyacrylamides (7) subsequently promot-
ed the development of stimuli-responsive hydrogels with ap-
plications as sensors, switches, artificial muscles and drug de-
livery devices amongst many others are currently being inves-
tigated (8). Although the mechanical fragility of hydrogels,
particularly when in the water-swollen state, can limit their
use as standalone medical devices, they are still useful for
biomedical coatings. In this context, they have been investi-
gated to protect implanted glucose sensors from biofouling (9)
and to provide an encrustation resistant surface on urinary
catheters (10). In addition to improving lubricity and biocom-
patibility of the implantable device, the addition of a hydrogel
.
.
KEY WORDS Controlled drug release Dosing
.
.
Hydrogel Light pMEA
* Colin P. McCoy
c.mccoy@qub.ac.uk
1
School of Pharmacy, Queen’s University Belfast, Belfast
Northern Ireland BT9 7BL, UK

Donnelly et al.
O
O
O
O
layer allows incorporation of active agents and subsequent
drug releasing capabilities from the material.
O
O
The ability to couple the application of a stimulus to the
liberation or release of a from delivery devices upon applica-
tion of stimuli is an attractive concept, allowing high levels of
pharmaceutical control which may not be easily achieved
through conventional delivery modes. In the case of drug de-
livery systems utilising light as an external trigger, therapeutic
control can be both of a temporal and spatial nature and with
the ability to influence intensity, wavelength and duration of
light exposure, the amount of drug released can be
manipulated.
O
O
O
O
F
O
2
3
Fig. 2 Structures of flurbiprofen-DMB ester (2) and naproxen- DMB ester
(3).
McCoy and coworkers have previously reported the use of
a common protecting group in organic synthesis, 3,5-
dimethoxybenzoin (DMB), to synthesize photosensitive drug-
conjugates through esterification of model drug compounds
(11,12). Photoactivity was demonstrated in acetonitrile solu-
tion following exposure to low power, minimally damaging
365 nm UV-A radiation. The UV-vis absorption spectra of
irradiated solutions illustrated the depletion of the conjugate
and simultaneous liberation of drug and formation of a pho-
tochemical by-product 5,7-dimethoxy-2-phenylbenzofuran
(1) as depicted in Fig. 1.
In this study, we investigate the synthesis of two further
drug-conjugates of DMB prepared from two non-steroidal
anti-inflammatory drugs (NSAIDs), namely flurbiprofen and
naproxen. Chronic use of these medications, which are used
during eye surgery and for the treatment of rheumatoid ar-
thritis, ankylosing spondylitis, and degenerative joint disease
for the reduction of pain, fever and inflammation (13), has
shown efficacy for treatment of gastric or duodenal ulcers in
patients. Moreover, masking the free carboxylic group has
been shown to improve gastrointestinal tolerability (14). It is
this carboxylic acid group which lends itself to facile esterifi-
cation with DMB for formation of the light-sensitive conju-
gates which are depicted in Fig. 2.
MATERIALS AND METHODS
Materials
Flurbiprofen, naproxen, anhydrous dichloromethane (DCM),
dimethylaminopyridine (DMAP), dicyclohexylcarbodiimide
(DCC), dimethylformamide (DMF) ethylene glycol
dimethacrylate, 2-methoxyethyl acrylate, phosphate buffer
tablets (pH 7.3
0.2 @ 25°C), silica, silica plates and
triethylamine were all purchased from Sigma-Aldrich
(Gillingham, Dorset, UK). All other chemicals were of
AnalaR or equivalent grade and purchased from BDH labo-
ratories (Poole, Dorset, UK).
Synthesis and Characterisation of Photoconjugates
The synthesis of DMB was carried out as previously reported
in the literature (11,12) and all procedures were carried out
under protection from light. Nuclear magnetic resonance
spectra were recorded on a Bruker 400 Ultrashield Plus in-
strument with the chemical shifts reported as parts per million
(ppm) as referenced to tetramethylsilane (TMS) as an internal
standard. Mass spectra were recorded on a Thermofisher
LTQ Orbitrap XL in electrospray mode.
Here, we incorporate our synthesized drug conjugates into
poly(2-methoxyethyl acrylate) (pMEA) in order to demon-
strate the first application of light-triggered release from a
biomaterial coating. Two aspects of drug release were consid-
ered, firstly, the ability to regulate drug release by changing
the longevity of light exposure and secondly, the ability to
release multi-doses of drug by multiple exposures to UV
irradiation.
1-(3,5-Dimethoxyphenyl)-2-Oxo-2-Phenyl-Ethyl]
2-(3-Fluoro-4-Phenyl-Phenyl)Propanoate (2)
Compound 2 was synthesized via DCC mediated esterifica-
tion. Flurbiprofen (0.82 g, 3.35 mmol), DMB (1.01 g,
3.7 mmol), and DMAP (45 mg, 0.37 mmol) were dissolved
in anhydrous DCM (50 ml) with stirring prior to the addition
Fig. 1 Photochemical
deprotection of DMB esters.
O
O
O
O
O
365 nm
O
+
O
R
OH
O
R
O
1

Photochemically controlled drug dosing
of DCC. The mixture was stirred at room temperature over-
night during which time dicyclohexylurea precipitated from
solution. The filtrate was washed with 0.2 M HCl, saturated
sodium bicarbonate solution and brine prior to drying over
magnesium sulfate. The filtrate was concentrated using rotary
evaporation and the product purified by flash chromatogra-
phy on a silica gel column using DCM as the eluent. The
product was isolated as a white solid (1.13 g, 67.7%).
δ(CDCl3): 7.94 & 7.88 (d, 2H, J = 8.16 & 8.08, 2 x O = C-
C-CH); 7.597–7.316 (m, 9H, aromatic H); 7.234–7.101 (m,
2H, aromatic H); 6.74 & 6.72 (s, 1H, O = C-CH-O-); 6.56 &
6.53 (s, 2H, 2 x -CH-C-O-CH3); 4.016–3.872 (m, 1H, −CH-
CH3); 1.61 (dd, 3H, −CH3). m/z (%): 499.19 (M + 1, 100),
255.10 (20).
interfaced with UV WinLab software at recorded time inter-
vals during the irradiation period.
Preparation of Drug-DMB Loaded pMEA
Conjugate loaded polymers were prepared by mixing MEA,
the appropriate drug-DMB conjugate (5% w/w), EGDMA
(1% w/w) and AIBN (0.5% w/w) with a magnetic stirrer until
dissolution was complete. Solutions were injected between
molds prepared from two glass plates lined with silicone-
coated release liner, separated by silicone tubing (3 mm inter-
nal diameter, 18 mm wall thickness) and clamped together
with bulldog clips. The molds were heated at 60°C for 18 h.
Polymer sheets were then removed from the mould and
soaked in phosphate buffered saline (PBS) for 7 days to re-
move any unreacted monomer. During this period, no detect-
able conjugate release was observed by UV-visible
spectroscopy.
1-(3,5-Dimethoxyphenyl)-2-Oxo-2-Phenyl-Ethyl]
2-(6-Methoxy-2-Naphthyl)Propanoate (3)
Compound 3 was synthesized via esterification following ac-
ylation of naproxen. Naproxen (0.69 g, 3 mmol) in anhydrous
DCM (ca. 15 ml) was added dropwise to thionyl chloride
(0.26 ml, 3.6 mmol) and DMF (2 drops). The mixture was
refluxed (3 h) and evaporated down to yield a yellow solid.
Anhydrous DCM was used to resuspend the solid before
adding dropwise to a solution of DMB (0.826 g, 3 mmol),
and triethylamine (0.7 ml, 5 mmol) in anhydrous DCM (ca.
20 ml). The mixture was stirred at ambient temperature over-
night. The brown solution was diluted with further DCM and
washed with 0.2 M HCl, saturated sodium bicarbonate solu-
tion and brine prior to drying over magnesium sulfate. The
filtrate was concentrated by rotary evaporation and the prod-
uct purified using flash chromatography on a silica gel column
using DCM as the eluent. The product was isolated as a white
solid (0.56 g, 38.5%). δ(CDCl3): 7.92 & 7.84 (d, 2H, J = 8.4. &
8.8 Hz, 2 x O = C-C-CH-); 7.73–7.65 (m, 3H, aromatic H);
7.54–7.4 (m, 3H, aromatic H); 7.39 & 7.28 (t, 2H, J = 7.4 &
8.0 Hz, 2 x O = C-C-CH-CH-); 7.16–7.08 (m, 2H, aromatic
H); 6.71 & 6.69 (s, 1H, O = C-CH-O-); 6.51 & 6.47 (d, 2H,
J = 2.24 & 2.24 Hz, 2 x -CH-C-O-CH3); 6.37 & 6.34 (t, 1H,
J = 2.28 & 2.28 Hz, −O-C-CH-C-O-); 4.1–3.99 (m, 1H,
−CH-CH3); 3.92 & 3.91 (s, 3H, −O-CH3); 3.69 & 3.67 (s,
6H, 2 x -O-CH3); 1.65 & 1.63 (d, 3H, J = 7.16 & 7.2 Hz,
CH3). m/z (%): 502.2218 (100), 485.1956 (M + 1, 61),
255.1019 (9), 232.2022 (15).
Characterization of Drug-DMB Loaded pMEA
Polymer samples were prepared in the PBS swollen state with
the use of a cork borer (10 mm diameter). All subsequent
irradiation experiments were carried out on samples housed
in PBS using a 15 W Hg discharge UV lamp kept at a fixed
distance of 30 mm from the polymer samples under study.
For dose regulation studies, conjugate loaded pMEA sam-
ples were irradiated for a total of 10 or 30 min with samples
being flipped to expose the lower surface at the halfway point
while immersed in PBS (10 ml). Solutions were retained and
samples suspended on needles which were transferred individ-
ually to universal containers housing fresh PBS and placed
into an oscillating water bath at 37°C. At recorded time inter-
vals, samples were removed and transferred to fresh buffer
solutions in order to maintain sink conditions while retaining
the previous solution for analysis. Retained solutions were
analysed by UV-vis spectroscopy (using wavelengths of maxi-
mum absorption of flurbiprofen and naproxen of 246 nm and
261 nm respectively) and concentrations of liberated drug
calculated against a standard calibration curve.
Flurbiprofen standard curve : y ¼ 0:101x þ 0:0116 R2
¼ 0:9999 ðup to 25μg=mlÞ
Naproxen standard curve : y ¼ 0:0224x−0:0019 R2
Photolysis of Photoconjugates in Solution
¼ 0:9997 ðup to 50 μg=mlÞ
Solutions of 2 and 3 (2 x 10−5 M) were prepared in acetonitrile
and irradiated using a 15 W Hg discharge UV lamp source at
365 nm in a 1 cm path length quartz cuvette maintained at a
distance of 10 mm from the light source. UV-visible absorp-
tion spectra were collected between 200–400 nm using a
Perkin Elmer Lambda 650 UV-visible spectrophotometer
For multi-dose capacity studies, samples were treated as
before with a total of 10 min of irradiation exposure followed
by storage at 37°C in an oscillating water bath and assessment
of drug release. When drug was no longer detectable in the
release media, samples were removed from needles and re-
exposed to a further period of irradiation (10 min) and

Donnelly et al.
subsequent drug release assessment. The irradiation and re-
lease cycle was completed a total of 5 times.
the pMEA matrix by diffusion. Photolysis rates of 2 and 3
while embedded in the polymer matrix were calculated from
plots of ln[A]t/[A]0 as a function of irradiation time. The
conjugate photolysis rates were determined as 5.6 x 10−2
and 5.5 x 10−2 min−1 respectively in pMEA.
To characterise the stability of the conjugate in the pMEA
matrix, samples were similarly immersed in PBS and UV-
visible spectra obtained of the PBS solution every 24 h over
a period of 7 days. The absorbance values at wavelengths
where the relevant chromophores for flurbiprofen and
naproxen absorb (246 nm and 261 nm respectively) showed
no detectable absorbance, indicating no release of the conju-
gate from the matrix in the absence of irradiation.
DISCUSSION
This work describes the application of UV light to trigger drug
release from a biomaterial coating which was prepared by the
incorporation of synthesised photoactive drug conjugates into
pMEA-based hydrogels. Each of the photochemical conju-
gates were synthesised in good yield via DCC mediated or
direct acid chloride esterification reactions. Conjugates were
characterised using mass spectrometry and NMR spectrosco-
py in which a split in some proton signals was observed due to
the use of a drug racemate in each synthesis, and the
corresponsing diastereoisomeric character of the photoactive
compounds.
To investigate the photochemical behaviour of the synthe-
sised conjugates upon exposure to UV light and to assess the
ability and rate at which a drug dose can be generated on
demand, solutions of 2 and 3 were prepared in acetonitrile
and exposed to increasing periods of UV irradiation. Fig. 3
illustrates the changes in acetonitrile solutions of the conju-
gates as the photochemical reaction progresses. Light expo-
sure was shown to lead to depletion of the drug conjugate
(decreasing band at 246 nm) while benzofuran formation
and simultaneous drug regeneration was apparent through
the increasing absorption band at 300 nm. In each case, the
presence of isosbestic points at 233 nm and between 262–
264 nm demonstrates the clean nature of the photolysis reac-
tion. The rate of photolysis is analogous to the rate of
benzofuran formation and hence can be calculated from the
rate of the appearance of the 300 nm absorption band. Both
reactions were shown to follow first order reaction kinetics and
rate constants were calculated as 4.6 x 10−3 and 7.7 x 10−3 s−1
for 2 and 3 respectively. The more rapid photodissociation of
the naproxen ester in comparison to its flurbiprofen counter-
part may be explained by the extended π-conjugation that
exists in this molecule, allowing higher excitation through
more efficient absorption of 365 nm. This work has confirmed
the ability to rapidly liberate drugs from the conjugates using
UV irradiation, the amount of which is controlled by the
duration of light exposure.
RESULTS
Synthesis and Characterisation of Photoconjugates
Flurbiprofen and naproxen esters of DMB were synthesised
via DCC and acyl chloride mediated esterifications of the
parent drug respectively according to the aforementioned syn-
thetic procedures. 2 and 3 were isolated as white solids in
67.7% and 38.5% yield, respectively. The structures of the
molecules was assigned using NMR spectroscopy and mass
spectrometry.
Photolysis of Photoconjugates in Solution
Conjugate photolysis was assessed in acetonitrile and Fig. 3
illustrates representative overlaid spectra corresponding to a)
2 and b) 3 photolysis respectively. The rates of photolysis of 2
and 3 in acetonitrile were calculated from plots of ln[A]t/[A]0,
where [A]0 and [A]t are the concentrations of drug-conjugate
initially and at time t, as a function of time. Determination of
the gradient, corresponding to –k, allowed calculation of the
reaction rates as 4.6 x 10−3 and 8 x 10−3 s−1 respectively.
Characterisation of Drug-DMB Loaded pMEA
The cumulative fraction of total drug liberated from the cor-
responding conjugate housed in pMEA following 10 and
30 min irradiation periods is shown in Fig. 4. Following irra-
diation, drug is liberated from the conjugate and free to diffuse
out of the pMEA matrix with the amount of drug clearly
controlled by the longevity of UV exposure.
Multi-Dosing Capacity
The cumulative fractional release of total flurbiprofen and
naproxen liberated from the corresponding conjugate housed
in pMEA during successive periods of irradiation is shown in
Fig. 5. Following different periods of irradiation, the drug dose
liberated is clearly controlled by the application of 365 nm
irradiation as demonstrated through the stepped profile of
the graph. Subsequently, the liberated dose is released from
Successful UV triggered drug regeneration in solution war-
ranted conjugate inclusion in a polymeric scaffold in order to
investigate the potential for triggered release of drug from a
biomaterial matrix. Careful consideration of the choice of
matrix is essential to ensure the retention of the drug-DMB
conjugate and photo-generated benzofuran side product
while facilitating the release of the drug. In previous studies

Photochemically controlled drug dosing
Fig. 3 Overlaid representative
UV-vis spectra of (a) 2 and (b) 3 in
acetonitrile (2 x 10−5 M) after
various periods of 365 nm
irradiation. Arrows indicate
absorbance trends with time and
irradiation times used were 0, 30,
60, 90,120,150, 240, 300,
360,450, 570, and 690 s,
respectively.
(11,12), a copolymer of HEMA and methyl methacrylate cross
linked with EGDMA met these requirements by allowing
drug to diffuse into surrounding medium upon irradiation
yet retain the conjugate and the photochemical
byproduct while in the hydrated state. With increasing
markets for biomedical devices, materials that display
high biocompatibility are increasing sought for their
manufacture or, alternatively, surface modification. As
such, the ability of pMEA to act as a successful housing for
the photoactive conjugates was examined. pMEA is an
amphiphilic polymer (16) comprised of a hydrophobic poly-
ethylene chain and a mildly hydrophilic tail which is used
commercially as a coating for artificial organs (17). The hy-
drophilicity of this polymer is reportedly lower than that of the
pHEMA material used in our previous study as determined by
sessile drop contact angle measurements, 47° vs 33° in the
hydrated state (18). As a result, pMEA may be more condu-
cive for retention of the drug conjugates without warranting
the inclusion of MMA. Materials were prepared from MEA
using EGDMA (1% w/w) as a crosslinker and were loaded
with conjugates (5% w/w) prior to polymerisation. The trans-
parency of the resulting polymeric film in theory should per-
mit light to effectively penetrate the material allowing the
photoreaction to take place.
The conjugate-loaded films were soaked in aqueous media
in darkness to allow any residual unpolymerised material to
elute from the matrix and subsequent analysis of the wash
solutions showed the absence of both drug and conjugate.
This demonstrates the viability of pMEA for housing of the
conjugates, preventing elution and hydrolytic cleavage of the
conjugates while embedded in the polymer, and that no con-
jugate or drug is released in the absence of light. This

Donnelly et al.
Fig. 4 Graphs illustrating the
amount of drug released following
irradiation periods of 10 (−) and 30
(♦) min (mean st. dev, 4
replicates).
entrapment of drug-conjugate is not only essential to prevent
diffusion of the conjugate from the device coating when in use,
but is also crucial so as to ensure that should a device require
submergence in water to activate the hydrophilic coating prior
to insertion, the full loading will remain intact and available
for release on demand.
Under light conditions, i.e. exposure to 365 nm irradiation,
the ability of pMEA to act as polymeric scaffold for light-
triggered drug delivery was shown. Sole diffusion of
flurbiprofen and naproxen into the surrounding release media
was established by UV spectroscopy illustrating the success of
the photochemical reaction within the matrix, subsequent
drug release capabilities and also the retention of the
benzofuran by-product of the reaction. Fig. 4 illustrates the
cumulative fraction of flurbiprofen and naproxen released
from pMEA following irradiation periods of 10 and 30 min.
In each case, prolonging the longevity of exposure is shown to
significantly increase the amount of drug released from the
matrix.
The ability to deliver multi-doses of drug from the pMEA
matrix was established by exposure of the system to sequential
cycles of irradiation and storage in darkness. Fig. 5 illustrates
the ability to induce the release of drug via the application of
365 nm irradiation, with each step in the profile of the cumu-
lative fractional release graph illustrating the point at which a
further cycle of 10 min 365 nm irradiation was applied. From
the cumulative drug release data, the amount of conjugate
consumed during each irradiation period was calculated and
subsequently, the photolysis rate of the drug conjugates in
pMEA determined from plots of ln[A]t/[A]0 as a function of
irradiation time. In this case, at the end of the fifth irradiation
cycle, it was assumed that all drug has been released and as
such, [A]0, the concentration of ester at time 0, is derived from
the total cumulative amount of drug released from all cycles.

Photochemically controlled drug dosing
Fig. 5 Cumulative fraction of total
photo-liberated drug released from
pMEA conjugate matrix following
successive periods of 365 nm
irradiation as indicated by arrows
(mean st. dev, 4 replicates).
In pMEA, similar rates of photolysis were experienced by both
flurbiprofen and naproxen DMB esters, which were calculat-
ed as 5.48 x 10−2 and 5.61 x 10−2 min−1 respectively.
Although slower than experienced in solution as may have
been anticipated, photolysis in the pMEA matrix has proved
successful, proceeding in a clean manner with precise control
over onset and dose of drug delivery provided through appli-
cation and longevity of light exposure.
responsive system has been developed whereby the release of
a therapeutic can be triggered on demand by exposure to UV
irradiation. In addition, dosing can be tailored through dura-
tion and quantity of light exposures. While we recognise that
there are some safety concerns around using light, it is impor-
tant to note that UVA (315–400 nm) is employed in both
tanning beds and in phototherapy in the clinical to treat types
of lymphoma that affect the skin, such as cutaneous T cell
lymphoma or indeed other skin conditions such as eczema,
psoriasis, vitiligo and graft versus host disease (15,19). Here,
the use of minimally damaging 365 nm irradiation has proven
to be successful and as such, the use of such a system can be
foreseen in an extensive range of applications including direct
application to tissue surfaces and to more indirect sites with
the use of fibre optics. Such possibilities include the applica-
tion of light to urinary catheters or endotracheal tubes via
CONCLUSION
The synthesis and photochemical behaviour of light-sensitive
conjugates of flurbiprofen and naproxen has been examined.
Through incorporation and successful retention of these drug
conjugates in a pMEA scaffold, a biocompatible photo-

Donnelly et al.
5. Peppas NA, Bures P, Leobandung W, Ichikawa H. Hydrogels in
pharmaceutical formulations. Eur J Pharm Biopharm. 2000;50(1):
27–46.
6. Pal K, Banthia AK, Majumdar DK. Polymeric hydrogels: charac-
terization and biomedical applications. Des Monomers Polym.
2009;12(3):197–220.
7. Tanaka T. Collapse of gels and the critical endpoint. Phys Rev Lett.
1978;40(12):820–3.
8. Miyata T, Uragami T, Nakamae K. Biomolecule-sensitive
hydrogels. Adv Drug Deliv Rev. 2002;54(1):79–98.
9. Yu B, Wang C, Ju Y, West L, Harmon J, Moussy Y, Moussy F. Use
of hydrogel coating to improve the performance of implanted glu-
cose sensors. Biosens Bioelectron. 2008;23(8):1278–84.
10. Cox AJ, Millington RS, Hukins DW, Sutton TM. Resistance of
catheters coating with a modified hydrogel to encrustation during
an in vitro test. Urol Res. 1989;17(6):353–6.
11. McCoy CP, Rooney C, Edwards CR, Jones DS, Gorman SP.
Light-triggered molecular-scale drug dosing devices. J Am Chem
Soc. 2007;129(31):9572–3.
12. McCoy CP, Rooney CR, Jones DS, Gorman SP, Nieuwenhuyzen
M. Rational design of a dual-mode optical and chemical prodrug.
Pharm Res. 2007;24(1):194–200.
13. Damiani P, Bearzotti M, Cabezó MA. Spectrofluorometric deter-
mination of naproxen in tablets. J Pharmaceut Biomed. 2002;29(1–
2):229–38.
fibre optic probe allowing release of therapeutic agents at the
intended site of action helping to minimise associated side
effects. The approach presented here potentially addresses
two significant hurdles which still exist in the controlled drug
delivery field; the ability to control the precise location, and to
control the precise dose, of drug delivered. Our approach of
coupling light, which can be controlled precisely in terms of
wavelength, intensity and position of application, directly to
drug release in a practical drug delivery scaffold, is a signifi-
cant step towards systems able to meet the Bwhat, where and
when^ requirements of an ideal drug delivery system.
ACKNOWLEDGMENTS AND DISCLOSURES
We would like to thank the EPSRC National Mass
Spectrometry Service (Swansea, UK) for mass spectroscopic
analysis of the synthesised conjugates and the EPSRC (Grant
reference EP/H012249/1) for funding of this research.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which per-
mits unrestricted use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made.
14. Mohan R, Ramaa CS. Ester prodrugs of flurbiprofen: synthesis,
plasma hydrolysis and gastrointestinal toxicity. Indian J Chem.
2007;46B(07):1164–8.
15. Breuckmann F, Gambichler T, Altmeyer P, Kreuter A. UVA/
UVA1 phototherapy and PUVA photochemotherapy in connec-
tive tissue diseases and related disorders: a research based review.
BMC Dermatol. 2004;4:11.
16. Tanaka M, Motomura T, Kawada M, Anzai T, Kasori Y, Shiroya
T, Shimura K, Onishi M, Mochizuki A. Blood compatible aspects
of poly(2-methoxyethylacrylate) (PMEA)–relationship between pro-
tein adsorption and platelet adhesion on PMEA surface.
Biomaterials. 2000;21(14):1471–81.
REFERENCES
17. Ye S, Morita S, Li G, Noda H, Tanaka M, Uosaki K, Osawa M.
Structural changes in poly(2-methoxyethyl acrylate) thin films in-
duced by absorption of bisphenol a: an infrared and sum frequency
generation (SFG) study. Macromolecules. 2003;36(15):5694–703.
18. Hirota E, Tanaka M, Mochizuki A. Relationship between blood
compatibility and water structure - comparative study between 2-
methoxyethylacrylate- and 2-methoxyethylmethacrylate based ran-
dom copolymers. J Biomed Mater Res A. 2007;81A(3):710–9.
19. Baron ED, Stevens SR. Phototherapy for cutaneous T-cell lympho-
ma. Dermatol Ther. 2003;16(4):303–10.
1. Langer R. Drug delivery. Drugs on target Science. 2001;293(5527):
58–9.
2. You J-O, Almeda D, Ye GJ, Auguste DT. Bioresponsive matrices in
drug delivery. J Biol Eng. 2010;4:15.
3. Wichterle O, Lim D. Hydrophilic gels for biological use. Nature.
1960;185:117–8.
4. Wheeler JC, Woods JA, Cox MJ, Cantrell RW, Watkins FH,
Edlich RF. Evolution of hydrogel polymers as contact lenses, sur-
face coatings, dressings, and drug delivery systems. J Long-Term
Eff Med Implants. 1996;6(3–4):201–17.