Photoinduzierte Wirkstoff- und Farbstofffreisetzung aus hydrophilen Polymeren

Katarakt (Grauer Star) ist eine Erkrankung, die durch eine Dysfunktion des Metabolismus im Auge hervorgerufen wird und in Folge dessen zu einer Trübung der Linse führt [1, 2]. Über 20 Millionen Menschen haben durch diese Erkrankung ihre Sehkraft verloren [3, 4]. Die wesentlichste Behandlungsmeth...

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Bibliographic Details
Main Author: Busch, Annegret Philippine
Contributors: Hampp, N. (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Published: Philipps-Universität Marburg 2015
Online Access:PDF Full Text
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Table of Contents: 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.