Laser-induced drug release for local tumor control--a proof of concept.

BACKGROUND: The systemic palliative chemotherapy of locally extended gastrointestinal and hepatobiliary tumors is associated with a considerable burden for the patient. The aim of this project was to develop a new drug release system to improve the local stent therapy in these patients as a proof of concept study. For this purpose, polymer filaments were modified with drug-loaded polymer microgels that allow selective release of the active substance by photochemical triggering using laser radiation. Integrated into a stent system, the better local tumor control could thus contribute to a significant increase in the quality of life of patients. METHODS: A standard mammalian cell line and two carcinoma cell lines were established. By Fluorescence activated cell sorting (FACS), the cytotoxicity of the different materials was determined in vitro before and after drug loading with the chemotherapeutic agent 5-Fluorouracil (5-FU). For this purpose, the locally applied 5-FU concentration was previously determined by Bromdesoxyuridin assay. 5-FU dimer was synthesized by photo-induced dimerization of 5-FU in the presence of benzophenone in methanol. The chemical structure of 5-FU dimer was confirmed with Hydrogen-1 nuclear magnetic resonance and Fluorine-19 nuclear magnetic resonance. 5-FU dimer is nonsoluble in water and can be easily incorporated in polymer microgels modified with hydrophobic binding domains (cyclodextrin). After laser irradiation, 5-FU dimer decomposes and 5-FU can be released from microgels. Finally, the measurements were repeated after this laser-induced drug release. RESULTS: In FACS analysis, neither the microgels nor the microgel cumarin complexes showed a significant difference in comparison with the negative control with H2O and therefore no toxic effect on the cell lines. After loading with the 5-FU dimer, there was no significant cell death (contrary to the pure 5-FU monomer, which dose had been previously tested as highly toxic). After laser-induced dissociation back to monomer and the associated drug release, FACS analysis showed cytotoxicity. CONCLUSIONS: It was possible to develop 5-FU dimerloaded microgels, which show no cytotoxic effect on cell lines before laser irradiation. After dissociation back to 5-FU monomer by selective photochemical triggering using laser irradiation, the active substance was released. Thus, a new drug release system has been created and tested in vitro. For further development, integration into a stent system and for in vivo follow-up evaluation more studies need to be conducted.

Photochemistry with laser radiation in condensed phase using miniaturized photoreactors.

Miniaturized microreactors enable photochemistry with laser irradiation in flow mode to convert azidobiphenyl into carbazole with high efficiency.

Local ultraviolet laser irradiation for gradients on biocompatible polymer surfaces.

Generation of supporting structures, which guide cell growth, is a challenging task in the field of tissue engineering. Cell guidance properties of a scaffold are important in the field of neuronal regeneration. Those guiding structures can provide guidance just by mechanical stimulus or by chemical stimuli like cell signaling molecules. For an enhanced guidance, chemical gradients are under investigation. With this study, we show that ultraviolet laser irradiation is a useful tool to activate polymer surfaces with a high temporal and spatial resolution. We demonstrated that poly(methyl methacrylate) (PMMA) and poly-ε-caprolactone (PCL) can be locally activated and functionalized with amine groups that can be used for immobilization of arginine-glycine-aspartic acid (RGD) peptide. The immobilized RGD was detected by neuronal B35 cells. By defined pulse accumulation functionalization density on the surface can be varied for the generation of gradients. We demonstrated that PMMA and PCL have different process windows for functionalization. Although PMMA has a very small process window for activation, PCL allows the generation of stepwise functionalization. The presented technology can help to develop assays for the analysis of cell migration and neuronal regeneration due to flexible patterning easily realized by changing the irradiation parameters.