Photoinduzierte Wirkstoff- und Farbstofffreisetzung aus hydrophilen Polymeren
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Philipps-Universität Marburg
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Abstract
Cataract is an eye disease caused by a dysfunction of the metabolism in the eye, leading
to an opacification of the natural lens [1, 2]. About 20 million people worldwide have lost
their vision due to cataract [3, 4]. The standard treatment is the extracapsular cataract
extraction (ECCE), i.e. the implantation of a posterior-chamber intraocular lens (IOL)
[5, 6].
The most frequent complication arising from this treatment is the posterior capsule opacification
(PCO) that occurs in 15 % to 50 % of all cases within three to five years of
lens replacement [7–10].
The common treatment of PCO is laser capsulotomy [11], which leads to thermal destruction
of the posterior capsular bag [25]. Typical complications are retinal detachment and
macular oedema [26].
Several experimental studies using drugs such as colchicine, methotrexate, retinoic acid
and 5-fluorouracil (5-FU) were used in animal models to treat PCO. The studies showed
that 5-FU is one of the most effective cytotoxic drugs [14–18, 27–29].
The pathogenesis of PCO is attributed to the persistence and response of lens epithelial
cells (LECs) [30]. A fibrotic type of PCO can be observed, accompanied by capsular bag
contraction. This depends on the proliferation and fibrous metaplasia of interior and
equatorial LECs [12, 13, 30].
In this work, we present a photochemically controlled drug release system of 5-FU homodimers
that are formed by a [2+2] Woodward-Hoffmann cycloaddition reaction. In other
studies [19, 31], coumarin was used as a linker molecule to attach to a polymer backbone.
Thermal and chemical instability of coumarine is the most challenging problem of this
linker molecule [20]. Because of the instability against hydrolysis, the purification of the
cross- and homodimers proved to be difficult; so the main object of this work was to
choose a linker that was chemically stable and had excellent photochemical properties.
The use of 5-FU as linker as well as a drug to be released solves both problems, allowing
its application. The system presented in this study is based on controlled drug release
upon activation. A photo-triggered drug delivery is based on a photo-cleavable linker
system consisting of a linker molecule and the cytotoxic active drug of 5-fluorouracil
(5-FU). This system may be activated by irradiation with wavelengths within a specific
range. The photo-triggered drug release is accomplished by a single-photon-absorption
(SPA) as well as by two-photon-absorption (TPA) triggered reaction. The drug linker
system is cleaved by UV-light in the range below 300 nm, but this wavelength is not
able to pass through the cornea. It is, therefore, necessary to deliver the required energy
for activation via two photons at higher wavelengths by 532nm.
With regard to the polymeric drug delivery systems, this study is focused on these
aspects:
1. The establishment of the synthesis of the cross- and homodimers.
2. Characterization of the SPA and TPA induced cycloreversion.
3. The design of a polymeric system consisting of each homo- or crossdimer, and
copolymerization with an UV-Absorber, in accordance with the DIN ISO Norm.
4. Characterization of the controlled drug release from the polymeric system.
5. Investigation into the light and thermal stability of these polymeric systems.
6. Reproducible light-induced drug release.
The utilization of polymer for medical applications loaded with fluorescent nanoparticles
or a fluorescent dye is a common method for the imaging of diffusion and delivery of a
drug [21, 22].
The system presented here follows the principle of photo-controlled triggered release of a
fluorescent dye after activation. This system is activated by irradiation with wavelengths
within a specific range; the release may be triggered by a single (SPA) or two-photonabsorption
process (TPA). Here, we demonstrate the synthesis and characterization of
polymer containing a new crossdimer, which consists of 4-tert-butyldimethylsilyloxychalcone
(COTBS) as photo-cleavable linker and 8-acetoxy-4-methyl-2H-Benzo[h]chromen-2-one (BCA) as a fluorescent dye. BCA was directly linked to the COTBS molecule via
[2+2]-cycloaddition. This study describes the development of a release system comparable
with future work [32, 33], containing a reversible crossdimer system. This showed high
sensitivity to activation done to visualize the release and diffusion out of a polymer after
irradiation by the single-photon and two-photon experiments. The release of the dye was
characterized with the help of several spectra methods with regard to diffusion time and
the ability to repeatedly activate this system, when required to show the ability of a
multi-dose application.
To demonstrate and visualize the activation of the system and the release of the dye,
a fluorescence camera was simultaneously used. In addition to the [2+2]-cycloaddition
according to the Woodward-Hoffmann rules, oxetanes are obtained, which are formed
by the well-known Paternò-Büchi reaction, between 5-FU and the photosensitizer Benzophenone.
The analytical experiments could verify this, and a photo-induced reaction
by the SPA process could prove the cycloreversion of this system.
Moreover, the application of another antiproliferative drug, Tranilast, was also investigated
in this study because of the fact that 5-FU also acts as a cyctotoxic drug against
healthy tissues. One of the benefits of Tranilast is the antiproliferative effect on highly
proliferative fibroblasts or scar tissues [34].
Tranilast was successfully used to prevent PCO [35, 36] and demonstrated good results
for the prevention with low negative side effects for the patient. Coumarine was used
as a linker molecule. Analytical tests proved that crossdimers occurred, showing good
photochemical properties created by the SPA-induced [2+2]-cycloreversion reaction.
Review
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Dates
Created: 2015Issued: 2016-04-14
Faculty
Fachbereich Chemie
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Zwei-Photonen-AbsorptionPolymeresPCOHydrophile Polymeredrug delivery
DFG-subjects
Grauer StarPolymere, Wirkstofffreisetzung
DDC-Numbers
540
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Busch, Annegret Philippine: Photoinduzierte Wirkstoff- und Farbstofffreisetzung aus hydrophilen Polymeren. : Philipps-Universität Marburg 2016-04-14. DOI: https://doi.org/10.17192/z2015.0387.
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This item has been published with the following license: In Copyright