Design, Synthesis and Characterization of Novel Bioactive Rotaxanes for Theranostic Applications

Currently, many smart materials as well as molecular and nano-machines employ molecular switches that can be activated by specific stimuli. In order to suit the needs in the future’s development in smart materials for biomedical purposes, three major characteristics in combining molecular switches and bioactive molecules should be considered, they are: (1) ability to activate in vitro and in vivo, (2) specificity, and (3) toxicity. In this proposal, we intend to construct novel bioactive rotaxane systems derived from (1) mechanically interlocked macrolide rotaxanes — [n]rotaxanes containing bioactive macrolide molecules as the rings which could be activated by stimuli to dethread from a backbone molecule, and (2) magnetic nanoparticles based on MRI-active superparamagnetic iron oxide nanoparticles with suitable porous surface for covalent attachment or physical trapping of the macrolide rotaxanes. In particular, selected antibiotic or immunosuppressive macrolide molecules with suitable ring size, e.g., rifampicin, rapamycin (sirolimus), and cyclosporine A, will be mixed and matched with polyamine/polyammonium (e.g., spermine and chlorhexidine) or polyamide (e.g., deferoxamine) compounds to obtain the most-proper binding situation followed by stoppering reactions to yield the designed bioactive macrolide rotaxanes. For characterization, first, the binding affinity based on molecular recognition between macrolides and the threads would be characterized by isothermal titration calorimetry (ITC), standard NMR, and UV/visible absorption spectroscopies. Secondly, the structure of macrolide rotaxanes would be characterized by NMR spectroscopy and mass spectrometry. Third, the thermally, ultrasound- or enzyme-triggered dethreading rates of macrolide molecules would be characterized using HPLC, UV/visible absorption spectroscopy, light scattering (LS) and advanced nanopore technology with temperature-controlled modules. For further applications, the macrolide rotaxanes would be modified and coupled with superparamagnetic iron oxide nanospheres or other nanostructures to facilitate magnetic recycling after coupling, MRI contrasting, as well as selective delivery and release of macrolides to specifically infected organs. To reduce the macrolide toxicity and resistance for in vivo applications are main concerns and addressed in this proposal. The development of our proposed and ground-breaking macrolide rotaxane nanoparticles with the abilities to be triggered for specific macrolide release therapy and act as MRI diagnostic contrast agent would certainly give insights on the design of more sophisticated smart theranostic nanomaterials for antibiotic and immunosuppresant purposes with macrolide therapy.