Cyclodextrin-based supramolecular systems of emerging guests with pharmaceutical and environmental interest

Abstract

The aim of the present thesis is to study and characterize the molecular interactions between cyclodextrins (CDs) or cyclodextrin-based materials with emerging guest molecules such as drugs or toxins for potential pharmaceutical and environmental applications. Chapter 1 is a wide introduction to the topics that will be discussed in this thesis. It covers the general information about CDs, its applications in different industries and takes a special focus on cyclodextrin nanosponges (CD-NS) as well as the characterization techniques of CD-guest inclusion complexes in solution and using in-silico methods. Chapter 2 covers the systematic studies of the formation of an inclusion complex between serine protease inhibitor nafamostat mesylate (NM) with different neutrally charged and anionic CDs. The mechanism of action of CDs in the drug is unveiled to be a protection against hydrolysis which depends both on the CD concentration and type. Finally, enzymatic assays confirm that the inclusion complex of NM-CD correctly inhibits the reaction of trypsin as a model enzyme thus being a proof-of-concept for further pharmaceutical research in new administration ways for NM. Chapter 3 explores the molecular interactions of the neurotoxin veratridine (VTD) with different CDs. Subsequently, with an interest in understanding the effects of the VTD-CD inclusion complex, cell-based assays (CBAs) were performed on neuroblastoma-2a cells. Our findings reveal that the use of different amounts of CDs has an antidote-like concentration-dependent effect on the cells, significantly increasing cell viability and thus opening opportunities for novel research on applications of CDs and VTD. Chapter 4 is dedicated to the synthesis characterization a new family of and CD-nanosponges (CD-NS) crosslinked with anhydride molecules of different lengths. The synthesized CD-NS were used in a proof-of-concept ELISA experiment as potential passive adsorption materials for the monitorization of lipid-soluble marine toxins brevetoxin and okadaic acid. Overall, the presented thesis has contributed to expand the current knowledge on the use of CDs for pharmaceutical and environmental applications. The studies of characterization and understanding the mechanisms of CD inclusion complexes with serine protease inhibitor nafamostat mesylate and veratridine neurotoxin constitute the first reports in the literature of CD interactions with these guests. Furthermore, the synthesis and characterization of CD-NS with different anhydride crosslinkers broadens the current state of the art on CD-based polymeric materials and represents a potential novel use of CD-NS as passive adsorbers for marine toxins.