20.500.12556/RUL-152237 Kovinsko-organski materiali kot dostavni sistem biološko aktivnih molekul Metal-organic frameworks as delivery system for biologically active molecules Raziskovanje in uporaba kovinsko organskih materialov (ang. metal-organic frameworks - MOF) na področju biomedicine (in ostalih bio-aplikacij) vzbuja čedalje več raziskovalne pozornosti. Pa vendar, so biokompatibilni MOFi s konstantno poroznostjo še vedno redkost na tem področju. Prav tako je biokompatibilnost posameznih gradnikov MOFov, načrtovanih z namenom uporabe kot dostavni sistem, pogosto spregledana. V doktorskem delu sem načrtovala in sintetizirala nov bioMOF material, ga podrobno okarakterizirala in preučila vpliv različnih sinteznih parametrov na lastnosti materiala, ter dokazala ustreznost materiala za namen dostavnega sistema biološko aktivnih molekul. V Raziskavi I sem se posvetila načrtovanju in sintezi novega bioMOF materiala, ki v svoji strukturi vsebuje biokompatibilne gradnike, pri sintezi pa ne uporabljamo toksičnih topil. Po uspešni sintezi sem se posvetila reševanju kristalne strukture materiala in karakterizaciji osnovnih lastnosti. Uspešno sem sintetizirala in preučila nov bioMOF material, ki nosi ime bioNICS-1 (National Institute of Chemistry, Slovenia), saj gre za prvi takšen material razvit na Kemijskem Inštitutu. bioNICS-1 je prvi material na področju MOFov, ki v svoji strukturi vsebuje askorbinsko kislino (vitamin C) kot samostojen ligand, »kovinski del« pa predstavljajo $Zn^{2+}$ kationi, ki se nahajajo v treh različnih koordinacijah in tvorijo 3D enoto s konstantno poroznostjo – kar je prav tako novost na področju. V Raziskavi II sem preučevala vpliv kompozicijskih in procesnih parametrov, ter pogojev aktivacije na nastavljivost lastnosti materiala. Z uporabo enostavnih monokarboksilnih kislin lahko kontroliram velikost kristalov po nihajnem modelu, pod različnimi pogoji sinteze. Ugotovila sem tudi, da se z uporabo propionske kisline med ali po sintezi (tekom aktivacije) v strukturo lahko vnese točkovne defekte, ki materialu celokupno povečajo število prostih kovinskih mest – le ta so ključnega pomena za adsorpcijo terapevtskega plina. V Raziskavi III sem z namenom dokazovanja uporabnosti materiala v strukturo bioNICS-1 uspešno vgradila molekularni donor dušikovega oksida – hidroksiureo in prikazala njeno sproščanje. Prav tako, sem v material uspešno vgradila 5,14 mmol/g dušikovega oksida (NO(g)), kar je – trenutno – ena izmed najvišjih poročanih vrednosti. Preliminarni in vitro test na človeških keratinocitih je pokazal od koncentracije odvisen toksičen učinek, a material kljub temu lahko uvrstimo med bolj varne bioMOFe na osnovi Zn2+. Rezultati vgrajevanja in kinetike sproščanja NO, skupaj z in vitro toksičnostjo dokazujejo, da lahko v toksikološko sprejemljive količine bioNICS-1 vgradimo in z njim dostavimo zadovoljivo količino NO za terapevtski učinek. Bioapplication is an emerging field of metal-organic frameworks (MOF) utilization, but bio-compatible MOFs with permanent porosity are still a rarity in the field. In addition, biocompatibility of MOF constituents is often overlooked when designing bioMOF systems intended for drug delivery. In my research, I designed and synthesised a new bioMOF material which was characterized in detail, investigated the influence of various synthetic parameters on its properties, and demonstrated the suitability of the material for use as a delivery system for biologically active molecules. Research I is focused on design and synthesis of a new bioMOF material with biocompatible constituents and no use of toxic solvents. After successful synthesis solving the crystal structure and a thorough characterization of its properties took place. I successfully synthesised and characterized a new bioMOF material, denoted bioNICS-1 (National Institute of Chemistry, Slovenia), since it is the first material of its kind developed at the Chemical Institute of Ljubljana. bioNICS-1 is a first MOF that utilizes ascorbic acid (Vitamin C) as an independent linker, while the »metal part« represents $Zn^{2+}$ cations, which are located in three different coordinations and form a 3D unit with constant porosity - another novelty in the field. In the second part of this research (Research II), the influence of compositional and process parameters, as well as activation conditions were studied in regards to the tunability of the material. By using simple monocarboxylic acids, size of the crystals could be controlled according to seesaw model, under different synthesis conditions. I also found that using propionic acid, either during or after synthesis (during the activation), can introduce point defects in the structure, which causes an overall increase in the amount of available acid metal sites – crucial feature for adsorption of therapeutic gas. The final part – Research III was dedicated to demonstration of usability of the material. I have successfully encapsulated a molecular donor of nitrogen oxide - hydroxyurea and showed its release. Additionally, I have successfully incorporated 5,14 mmol/g of nitrogen oxide (NO(g)) into the material, which is currently one of the highest reported values. Preliminary in vitro tests on human keratinocytes showed a concentration-dependent toxic effect, yet the material can still be classified as one of the safest bioMOFs based on Zn2+. Results of NO loading and release kinetics, together with in vitro assay, demonstrate that toxicologically acceptable amounts of bioNICS-1 can be used to deliver a satisfactory amount of NO suitable for a therapeutic effect. kovinsko-organski materiali nastavljivost lastnosti bioaplikacija dostavni sistem dušikov oksid metal-organic frameworks tunability of structure bioaplication drug delivery nitric oxide true false false Slovenski jezik Angleški jezik Doktorsko delo/naloga 2023-11-13 15:40:13 2023-11-13 15:40:14 2023-12-15 09:54:18 0000-00-00 00:00:00 2023 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 12902 177610755 Tajnsek_Tia_kristian_-_Kovinsko-organski_materiali_kot_dostavni_sistem_biolosko_aktivnih_molekul.pdf Tajnsek_Tia_kristian_-_Kovinsko-organski_materiali_kot_dostavni_sistem_biolosko_aktivnih_molekul.pdf 1 71ED6F3EF04CAF1E6AEDD39F450A00CA 0ce8e16de5e6978466031d17242c7cbaecbaa5753459ba92fe646331a98d71de 93e3dda7-8232-11ee-a249-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=177605 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0