Photocontrolled Release of Chemicals from Nano- and Microparticle Containers

Article abstract of DOI:10.1002/anie.201710756

A benzoin-derived diol linker was synthesized and used to generate biocompatible polyesters that can be fully decomposed on demand upon UV irradiation. Extensive structural optimization of the linker unit was performed to enable the defined encapsulation of diverse organic compounds in the polymeric structures and allow for a well-controllable polymer cleavage process. Selective tracking of the release kinetics of encapsulated model compounds from the polymeric nano- and microparticle containers was performed by confocal laser scanning microscopy in a proof-of-principle study. The physicochemical properties of the incorporated and released model compounds ranged from fully hydrophilic to fully hydrophobic. The demonstrated biocompatibility of the utilized polyesters and degradation products enables their use in advanced applications, for example, for the smart packaging of UV-sensitive pharmaceuticals, nutritional components, or even in the area of spatially selective self-healing processes.

Full text of DOI:10.1002/anie.201710756

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Chemicals on demand: Photo-induced release from nano- and
microparticle containers
Authors: Ulrich S. Schubert, Christoph Englert, Ivo Nischang, Cornelia
Bader, Philipp Borchers, Julien Alex, Michael Proehl, Martin
Hentschel, Matthias Hartlieb, Anja Traeger, Georg Pohnert,
Stephanie Schubert, and Michael Gottschaldt
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710756
Angew. Chem. 10.1002/ange.201710756
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http://dx.doi.org/10.1002/ange.201710756

10.1002/anie.201710756
Angewandte Chemie International Edition
COMMUNICATION
Chemicals on demand:
Photo-induced release from nano- and microparticle containers
Christoph Englert,[a,b] Ivo Nischang,[a,b] Cornelia Bader,[a,b] Philipp Borchers,[a,b] Julien Alex,[a,b]
Michael Pröhl,[a,b] Martin Hentschel,[c] Matthias Hartlieb,[a,b,†] Anja Träger,[a,b] Georg Pohnert,[b,d]
Stephanie Schubert,[b,e] Michael Gottschaldt,*[a,b] Ulrich S. Schubert*[a,b]
importance. This is because it can be applied in a very precise
manner by selecting suitable wavelengths, polarization
directions, and intensities in an essentially non-contact approach.
Numerous photo-cleavable polymers, such as polyurethanes,[3]
polyacrylates[4], polyesters[5] or polyethers,[6] have been reported.
Nitroaryl groups, i.e. o-nitrobenzyl groups, are by far the most
commonly used photo-responsive linker units.[7-9] Concerning
particular applications, they suffer from serious drawbacks.
Apart from slow degradation kinetics and unwanted by-products
of the photolysis reaction by the use of o-nitrobenzyl linkers,
these are recognized as reactive chromogenic nitroso carbonyl
compounds, revealing severe cytotoxicity.[10-11] Even in
derivatives, where cleavage kinetics have been improved to as
much as 95% in 3 h,[12] issues such as lengthy synthesis,
sensitivity to sunlight, and reactive side products remain
challenging. This limits their applicability for advanced life
science settings. Alternative methods comprise photo-
responsive phenacyl, coumarin-4-ylmethyl, or arylmethyl groups.
Most common photo-degradable compounds are monofunctional,
rendering them unsuitable to be part of a polymer backbone.
The use of a dithiane protected benzoin derivative (from the
group of arylcarbonylmethyl), firstly described by Sheehan et al.
as a light-sensitive protecting group for carboxylic acids,[13] may
circumvent such limitations. Established for peptide[14] and solid-
phase synthesis,[15-16] the use of diol benzoin derivatives as an
active monomer in the polymerization process of polyesters has,
surprisingly, to the best of our knowledge, not been reported so
far. In this study, we focus on the synthesis of nano- and
microparticle containers, which can be “opened” by UV light in a
simple and well-controlled manner while releasing chemicals on
demand within defined periods of time (within timescales of
minutes to hours). In order to enable potential biomedical,
environmental, and ecological applications, the particles are
based on a biocompatible polyester.
Abstract: A benzoin-derived diol linker was synthesized and used to
create biocompatible polyesters, which can be fully decomposed on
demand triggered by UV light. Extensive structural optimization of
the linker unit was performed to enable a defined encapsulation of
structurally diverse organic compounds in polymeric structures and a
well-controllable polymer cleavage process. Selective tracking of
release kinetics of encapsulated model compounds from the
polymeric nano- and microparticle containers was enabled by
confocal laser scanning microscopy as
a proof-of-principle for
desired applications. The model compounds comprised physico-
chemical properties from fully hydrophilic to fully hydrophobic.
Demonstrated biocompatibility of the utilized polyesters and
degradation products enables advanced applications, e.g. for smart
packaging of UV-sensitive pharmaceuticals or nutrition components,
or even in the area of spatially-selective self-healing processes.
The incorporation of stimuli-responsive units into polymer
networks imparts smart properties to these materials, thus
enabling
a controlled release of compounds by external
triggers.[1] Such concepts can be realized by different
approaches. One of them is the use of cleavable, bifunctional
linker units, which represents a method for triggering the
complete decomposition of the polymeric material using external
stimuli.[2] Among the different stimuli, light is of outstanding
[a]
C. Englert, Dr. I. Nischang, C. Bader, P. Borchers, J. Alex, M. Pröhl,
Dr. M. Hartlieb, Dr. A. Träger, Dr. M. Gottschaldt, Prof. Dr. U. S.
Schubert
Laboratory of Organic and Macromolecular Chemistry (IOMC)
Friedrich Schiller University Jena
Humboldtstrasse 10, 07743 Jena
E-mail: Ulrich.schubert@uni-jena.de
[b]
C. Englert, Dr. I. Nischang, C. Bader, P. Borchers, J. Alex, M. Pröhl,
Dr. M. Hartlieb, Dr. A. Träger, Prof. Dr. G. Pohnert, Dr. S. Schubert,
Dr. Gottschaldt, Prof. Dr. U. S. Schubert
Jena Center for Soft Matter (JCSM)
Friedrich Schiller University Jena
Humboldtstrasse 10, 07743 Jena
[c]
[d]
M. Hentschel
Analytik Jena AG
Konrad-Zuse-Str. 1, 07745 Jena
Prof. Dr. G. Pohnert
Institute for Inorganic and Analytical Chemistry (IAAC)
Friedrich Schiller University Jena
Humboldtstrasse 8, 07743 Jena
Scheme 1. Schematic representation of A) the synthesis of the photo-
sensitive linker 4 (green) and 5 (blue) as well as polyester 6 (orange), and B)
their cleavage after UV irradiation for defined time scales. a) tert-
butyl(chloro)dimethylsilane (TBDMSCl), THF, triethylamine, 0 to 20 °C; b) 2-
[e]
[†]
Dr. S. Schubert
Institute of Pharmacy, Department of Pharmaceutical Technology
Friedrich Schiller University Jena
Otto-Schott-Str. 41, 07745 Jena
Current address: Institute of Biomaterial Science, Helmholtz-
Zentrum Geesthacht, Kantstr. 55, 14513 Teltow, Germany.
phenyl-1,3-dithiane,
n
butyllithium, THF,
0
°C; c) Cs2CO3, DMF/H2O; d)
mercury(II) perchlorate hydrate, CH3CN/H2O; e)
4
dimethylaminopyridin,
butyryl chloride, CH2Cl2; f) adipoyl dichloride, THF, pyridine.
For this purpose, a dithiane protected diol was synthesized and
activated as well as used for the step growth polymerization in
order to incorporate it into the polyester structure. The inactive
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201710756
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COMMUNICATION
diol
precursor
3-(hydroxy(2-phenyl-1,3-dithian-2-yl)methyl)-
three-step
In order to form photo-degradable materials, the activated diol
functional linker 4 was polymerized with adipoyl dichloride to
obtain polyester 6 by polycondensation (see Scheme 1). Size
exclusion chromatography could be used to determine the
apparent weight-average molar mass (Mw) of 2,800 g mol-1
(SEC: CHCl3/iPrOH/NEt3, polystyrene standard). The step-
growth polymerization results in several molar mass fractions.
Under UV illumination, the population of the low molar mass
fractions increases with irradiation time, while high molar mass
species successively disappear (Figure 2A). While NMR
characterization is possible for the polymeric species 6 (see ESI,
Figure S15), the determination of the degree of cleavage is
hindered by indistinct signals of the degradation products.
UV absorption investigations showed similar cleavage kinetics
for polymer 6 (see ESI, Figure S16) as obtained for the small
molecule linkers 4 and 5. A comparison of the UV absorbance
after different times of irradiation at λ = 304 nm revealed a
significantly faster degradation of the small molecule linker 5
compared to the polymeric species (Figure 2B). This fact can be
explained with the preferred leaving group character of
butyric acid. Further UV absorption measurements of the
polyester confirmed stability at increased temperatures (up to
80 °C) and, as expected, decomposition under daylight, which
phenol (Scheme 1A, 3) was synthesized in
a
approach via a Corey-Seebach addition reaction starting from 3-
hydroxybenzaldehyde.[14] Subsequently, the product was
activated to obtain 2-hydroxy-2-(3-hydroxyphenyl)-1-phenyl-
ethan-1-one (4), or esterified using butyryl chloride prior to
activation (5). The experimental data as well as the
spectroscopic and spectrometric characterization can be found
in the Supporting Information (ESI). The NMR evaluation,
including 1H NMR-, 13C NMR-, HSCQ-, NOESY- and ROESY-
spectroscopy, is exemplified for the esterified linker
5
(see ESI, Figures S10-S13). The use of crystallization instead of
column chromatography for purification renders the synthesis of
the photo-degradable linker very efficient compared to other
approaches. The cleavage mechanism of benzoin derived linker
structures is depicted in Scheme 1B. Upon UV irradiation
(λ = 300 to 350 nm), the substituted benzoin undergoes
a
photosolvolytic
cleavage
process
and
subsequent
rearrangement to an isomeric benzofuran derivative.[10] The
dithiane protecting group prevents premature photolysis, which
increases the shelf-life of the linker-precursor (3).[14] The small
linkers (4, 5) were used for kinetic investigations and the
development of a well-controlled release strategy under UV
irradiation (UV cube with broadband radiation spectrum, see ESI, occurs at significantly slower rate compared to direct
Figure S1). Figure 1A represents the proton NMR spectra of the
esterified linker 5 before and after UV irradiation. A clear upfield
shift of the phenyl Ph-2 protons at δH 7.96 ppm (signal K to K’)
UV irradiation (see ESI, Figure S17).
indicates
a successful degradation and was explored to
determine the degree of cleavage. The disappearance of δH 6.87
ppm (signal D, -CHOR-) and the appearance of δH 7.05 ppm
(signal X, newly formed aromatic proton) are further indices for
the proposed cleavage mechanism. UV-VIS spectroscopy
represents a simple and highly-sensitive method for further
investigations concerning cleavage and stability of the photo-
degradable linkers. The degradation kinetics for irradiation of
linkers 4 and 5 are presented in Figure 1B. The absorption
spectra of the cleaved linkers reveal an increasing absorption in
the range of 275 to 325 nm (exemplified for linker 5 in
Figure 1C).
Figure 2. A) Size exclusion chromatography of the photo-degradable
polyester
6
treated with UV light for different time scales
(N,N-dimethylacetamide, 0.21% LiCl); B) UV absorption to monitor the kinetics
of the cleavage of the photo-sensitive linker 5 and the polyester 6 at the
defined absorption wavelength of λ = 304 nm.
To allow a well-controlled release of chemicals on demand, the
formation of microparticle containers from the presented
polymers was approached. Using the (double-) emulsion
technique,[17] a hydrophobic (Nile Red) as well as a hydrophilic
dye (Rhodamine B) were incorporated in microparticle
containers composed of the photo-cleavable polyester
(Nile Red: 7n, Rhodamine: 7r). Scanning electron microscopy
confirmed particle sizes in a range of 2 to 7 µm (Figure 3A).
This microparticle approach allows a fast and simple production
of containers cleavable under UV irradiation, with the dyes being
stable under such conditions (see ESI, Figure S18). The cargo
revealed different behavior upon UV triggered degradation of the
microcontainers, in fact due to their varying solubility in the
particle surrounding liquid phase. While Nile Red shows a clear
decrease of the fluorescence intensity (due to precipitation of the
dye in the hydrophilic environment outside the dispersed
particles[18]), Rhodamine
B
release results in increased
fluorescence intensities outside the microcontainers (Figure 3B).
To illustrate that even short UV irradiation times are sufficient to
generate a significant release of cargo from such particles, the
microcontainers were exposed to UV light for 10 s and then kept
in the dark to monitor such imposed release characteristics.
The experiment revealed a direct release of ca. 20% of the
cargo (i.e. Nile Red) followed by a kinetically slow release over a
timescale of 16 min (20%, Figure 3B). This behavior could be
used in future applications for smart packaging of UV-sensitive
Figure 1. A) Schematic representation of the 1H NMR spectra of the esterified
linker
(300 MHz, CDCl3); B) 1H NMR kinetics of the cleavage of linker 4 (green) and
esterified linker (blue); C) UV-VIS absorption spectra monitoring the
cleavage of the esterified linker 5.
5
before (blue) and after UV irradiation (60 min, black)
5
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10.1002/anie.201710756
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pharmaceuticals or nutrition components. The biocompatible
containers can be loaded with dyes of different physicochemical
properties, demonstrated here for the two example cases of a
fully hydrophobic and a fully hydrophilic dye. In addition, dye-
loaded containers could be added in pharmaceutical
formulations, e.g., for spatially ensuring the absence of harmful
irradiation.
can be performed by a single dose of UV light, followed by
retained and relatively slow release or further accelerated
release by prolonged UV light exposure. The concept can be
widened by using different tailored polymer classes for drug
delivery applications, e.g. for the controlled release of particular
drugs of interest via endoscopy, smart packaging of
UV-sensitive pharmaceutical or nutrition components, or even in
the area of spatially-selective self-healing processes.
Figure 3. A) Scanning electron microscopy image of Nile Red encapsulated
microparticle 7n; B) cleavage of dye encapsulated microparticles under UV
irradiation (Nile Red: 7n, red & orange; Rhodamine B: 7r, green; blank: black).
The wavelength-dependent photo-induced release from the
microparticle containers could be visualized by confocal laser
scanning microscopy. As
a proof-of concept, Nile Red
encapsulated microparticles were irradiated via a laser, emitting
light at λ = 405 nm. Since this wavelength is outside the
absorption band of the polyester, no change in fluorescence
intensity could be observed after 10 cycles (1 cycle = 1 s laser
irradiation, 10% laser intensity) (Figure 4A). In contrast, laser
irradiation at λ = 355 nm in the same timescale resulted in a
clear decrease of the fluorescence intensity within the exposed
area caused by
a release of the cargo (Figure 4B).
An immediate zoom-out of the irradiated region after 10 cycles
further illustrates the local precision of the photo-induced
cleavage process (Figure 4C). Thus, we demonstrated that
defined irradiation in the submillimeter range ensures selective
release at the desired location.
Concerning potential life science applications, such as
biomedical and ecological, biocompatibility represents a very
critical parameter. In vitro studies with L929 cells confirmed no
cytotoxicity of the polyester-based microparticles and their
respective cleavage products after 2 and 16 min UV irradiation
with IC50 values > 500 µg mL-1 (see ESI, Figure S19).
Furthermore, it was demonstrated that the containers can also
be scaled-down successfully to nanoparticulate containers using
the emulsion technique, yielding photo-degradable nanometer-
scale light-responsive objects (see ESI, Table S1, Figure S20).
In vitro studies confirmed no cytotoxicity of the nanoparticulate
containers and their degraded fragments even when
approaching the highest degrees of cleavage, consequently
degradation, according to Figures 1 and 2. After 60 and 120 min
UV irradiation, IC50 values > 300 µg mL-1 were detected (see ESI,
Figure S21).
In summary, we present a new approach for the efficient
photo-induced degradation of nano- and microparticle containers
to release chemicals on demand with different physicochemical
properties, opening the gate for numerous applications. With a
bottom-up design, starting from the synthesis of a bifunctional
photo-sensitive benzoin linker, we were able to create polyester
structures that can be fully decomposed on demand, triggered
by UV light. The formulation and design of biocompatible nano-
and microparticle containers by emulsion techniques allowed the
encapsulation and targeted release of organic compounds at the
desired location of interest, evidenced by confocal laser
scanning microscopy. The controlled “opening” of the containers
Figure 4. Confocal laser scanning microscopy (CLSM) of photo-cleavable
polyester-based microparticles with encapsulated Nile Red 7n (1 cycle = 1 s
laser irradiation, 10% laser intensity): A) laser irradiation at 405 nm;
B) laser irradiation at 355 nm; C) immediate zoom-out of the irradiated region
after 10 cycles.
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10.1002/anie.201710756
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Experimental Section
Full experimental details are provided in the Supporting
Information.
Acknowledgements
The authors would like to thank Carolin Kellner and Elisabeth
Moek for the support with the bio assays, Steffi Stumpf for SEM
and Dr. Stephanie Höppener for cryo-TEM measurements. The
funding of the collaborative research center ChemBioSys
(SFB 1127) by the Deutsche Forschungsgemeinschaft (DFG) is
highly acknowledged. AT is grateful for the financial support in
the frameworks of ‘‘Carl-Zeiss-Strukturmaßnahme’’ and the Carl-
Zeiss Stiftung. MH gratefully acknowledges the DFG (GZ: HA
7725/1-1) for funding. Furthermore, the authors acknowledge
support of this study from the Thüringer Ministerium für
Wirtschaft, Wissenschaft und Digitale Gesellschaft (TMWWDG,
ProExzellenz II, NanoPolar). The LSM880 ELYRA PS.1 was
further funded with a grant from the DFG. The SEM/TEM
facilities of the Jena Center for Soft Matter (JCSM) were
established with a grant from the DFG and the European Fonds
for Regional Development (EFRE).
Keywords: micro- & nanostructures • photochemistry •
polyesters • benzoin-derivative linker • UV light
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COMMUNICATION
COMMUNICATION
C. Englert, I. Nischang, C.Bader,
P. Borchers, J. Alex, M. Pröhl,
M. Hentschel, M. Hartlieb, A. Träger,
G. Pohnert, S. Schubert, M. Gottschaldt,
U. S. Schubert*
Page No. – Page No.
Chemicals on demand: Biocompatible polyesters were synthesized, which can be
fully decomposed on demand triggered by UV light. The creation of nano- and
microparticles enables the defined encapsulation of structurally diverse organic
compounds, and a well-controllable cleavage process. Respective particles can be
utilized for advanced applications, such as smart packaging of UV-sensitive
pharmaceutical or nutrition components, or even in the area of spatially-selective
self-healing processes.
Chemicals on demand: Photo-induced
release from nano- and microparticle
containers
This article is protected by copyright. All rights reserved.