title: Laser-induced drug release for local tumor control--a proof of concept.
abstract: 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.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany. Electronic address: alambertz@ukaachen.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lambertz
authors.affiliation: Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klink
authors.affiliation: Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Anjali
authors.initials: A
authors.lastname: Röth
authors.affiliation: Leibniz Institute of Interactive Materials and RWTH Aachen University, Aachen, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schmitz
authors.affiliation: Leibniz Institute of Interactive Materials and RWTH Aachen University, Aachen, Germany.
authors.forename: Andrij
authors.initials: A
authors.lastname: Pich
authors.affiliation: Institute of Textile Technology, (ITA), RWTH Aachen, Aachen, Germany.
authors.forename: Katalin
authors.initials: K
authors.lastname: Feher
authors.affiliation: Fraunhofer Institute for Laser Technology, (ILT), RWTH Aachen, Aachen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Bremus-Köbberling
authors.affiliation: Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Ulf P
authors.initials: UP
authors.lastname: Neumann
authors.affiliation: Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Junge
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics; D001973:Bromodeoxyuridine / Q000378:metabolism; D045744:Cell Line, Tumor; D019281:Dimerization; D016503:Drug Delivery Systems / Q000379:methods*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000737:chemistry / Q000493:pharmacokinetics*; D057927:Hydrophobic and Hydrophilic Interactions; D007834:Lasers; D010166:Palliative Care / Q000379:methods; D010190:Pancreatic Neoplasms / Q000473:pathology*; D012995:Solubility; D015607:Stents; D047392:beta-Cyclodextrins / Q000493:pharmacokinetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D047392:beta-Cyclodextrins; D001973:Bromodeoxyuridine; C031215:betadex; D005472:Fluorouracil
keywords: 5-FU dimer; Carcinoma cell lines; Cytotoxicity; Laser-induced drug release; Tumor reduction