Photochemische Linkerstrukturen zur laserinduzierten Wirkstofffreisetzung aus polymeren Intraokularlinsen
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Philipps-Universität Marburg
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Abstract
Cataract is a disease caused by a dysfunction of the metabolism in the eye which leads
to an opacification of the natural ophthalmic lens. About 18 million people worldwide
have already lost their vision by cataract and 2 millions new incidences are estimated
per year. The course of the disease leads to a painless loss of sight, decreasing of the
acuity and higher sensitivities towards glares. In the progression, a gray or brown
discolouration of the lens develops and the patient may loose his vision completely.
The reasons for the opacification vary and they are still under extensive research, but
most cases of cataract are related to the aging process. The sole treatment of cataract is
replacing the opacified natural lens with a polymer intraocular lens (IOL) via surgery.
A typical complication of this treatment is secondary cataract or posterior capsule
opacification (PCO), occuring in almost 50 % of all cases within 5 years. Retained
ephitelical cells migrate onto the IOL and the anterior and posterior capsule bag and
cause a progressive deterioration of the visual acuity. The state-of-the-art treatment
for PCO is Nd:YAG laser capsulotomy where the posterior capsule bag is destroyed
to improve the transparency of the field of vision. However, this treatment has several
drawbacks. The high energy beams may damage the IOL, the intraocular pressure
is increased, which leads to glaucoma, and the retina can be damaged. Therefore another
approach to treat PCO is investigated at present, which targets the epithelial cells
via a photo-induced drug delivery system in the IOL.
A cytotoxic drug is covalently bound to the polymer backbone of the IOL, which
may be released via photochemical excitation when required. The linker cleavage occurs
via a cyclobutane moiety which needs excitation at wavelengths below 300 nm,
which are absorbed by the cornea. Therefore the required energy must be applied via
a two-photon-processes (TPA) at wavelengths of 512 nm. This process guarantees a
high selectivity for the linker and excellent spatial control of the drug release.
This thesis describes the synthetical development of a new drug-linker-conjugate
for the immobilisation of 5-fluorouracile as cycotoxic drug and the effectivities of
photochemical cleavage and drug releases from functionalized polymer materials.
5-Fluorouracile (5FU) has already been proven as a suitable drug for opthalmic applications.
Coumarin and another six other potential linker molecules were examined
for the application as linker for 5FU.
Coumarin was the first molecule tested for this application, but showed several disadvantages.
The lactone ring in the dimer is very vulnerable towards hydrolysis, which
cannot be excluded in aqueous surroundings in the eye and leads to undesired reactions
upon irradiation. Alternatively, several other molecules were examined, which
were 1,1-dimethylnaphtalenone, 1,2-dihydronaphtalene, stilbene, cinnamic acid,
1,4-naphtoquinone and chalcone. In the course of the synthesis coumarin-, cinnamic
acid-, 1,2-dihydronaphtalene- and especially 1,1-dimethylnaphtalenone-5FU dimers
showed an unexpected [2+2]-cycloreversion reaction at higher temperatures. These
temperatures are required for autoclaving the polymer material before insertion into
the eye, the sole sterilisation method for hydrogels.
According toWoodward-Hoffmann a thermal [2+2]-cycloreversion of the 5FU-linkerconjugate
is not allowed under these conditions. This interesting finding was thoroughly
investigated and the reaction successfully elucidated via radical scavenging
reactions and ESR measurements. The reaction does not occur via a concerted mechanism,
but via radicals, which may undergo several different following reaction
pathways. Although these kind of reactions have already been noticed in the past,
the radical mechanism was experimentally proven for the first time in this work.
However, this thermal instability of the dimers is unfavourable for the application
as a drug delivery device. Therefore, two molecules from the remaining three stable
dimers were chosen for further examination. New polymers were synthesized with
1,4-naphtoquinone and chalcone as linkers for 5FU and proved the desired stability
against higher temperatures and drug release via TPA processes.
A general procedure for the synthesis of 5FU loaded polymers was developed in
this thesis and successfully carried out with small modifications for coumarin, 1,1-
dimethylnaphtalenone, 1,4-naphtoquinone and chalcone. The last three were further
examined regarding photochemical properties, drug release and diffusion rates from
the polymer material.
Drug release was successfully carried out for all three of them, but only 1,4-naphtoquinone
and chalcone have the desired thermal stability, which makes them suitable linkers
for 5FU. Both have efficient TPA-cross sections which is advantageous for the application
due to the possibility of using lower energies and/or shorter irradiation times
in the eye.
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Dates
Created: 2011Issued: 2011-12-21Updated: 2011-12-21
Faculty
Fachbereich Chemie
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Two-photon-absorptionZwei-Photonen-Absorption
DFG-subjects
WirkstofffreisetzungFluorouracilKontrollierte WirkstofffreisetzungCataracta secundariaGrauer StarNichtlineare AbsorpNeodym-YAG-Laser
DDC-Numbers
540
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Liese, Julia: Photochemische Linkerstrukturen zur laserinduzierten Wirkstofffreisetzung aus polymeren Intraokularlinsen. : Philipps-Universität Marburg 2011-12-21. DOI: https://doi.org/10.17192/z2011.0664.
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This item has been published with the following license: In Copyright