Photochemische Linkerstrukturen zur laserinduzierten Wirkstofffreisetzung aus polymeren Intraokularlinsen

Der Katarakt oder auch Grauer Star genannt, ist eine Erkankung des Auges, in deren Verlauf sich durch verschiedene Faktoren die ursprünglich klare Augenlinse trübt. Schätzungen gehen davon aus, dass etwa 18 Millionen Menschen ihr Sehvermögen durch Katarakt verloren haben und jährlich etwa 2 Milli...

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Bibliographic Details
Main Author: Liese, Julia
Contributors: Hampp, Norbert (Prof.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2011
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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.