Ultrasound-mediated activation of drugs

• Ultraschall-vermittelte Aktivierung von Medikamenten

Shi, Zhiyuan; Herrmann, Andreas (Thesis advisor); Schwaneberg, Ulrich (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021

Abstract

Treatment using pharmaceutical drugs is arguably the most important medical therapy warranting the health of every human. However, the systemic application of drugs often has severe side effects due to the intrinsic lack of drug selectivity. It is thus desirable and necessary to develop control mechanisms gating where and when drugs exhibit activity, regardless of the selected target, and yield a more effective and accurate treatment. Ultrasound as a stimulus with high spatiotemporal and energetic resolution together with its non-invasive character outperforms the physicochemical stimuli for controlled drug release, such as light, temperature, pH or redox reactions. In this work, we present two individual approaches, both culminating in the release of small drug molecules from their respective inactive precursors by ultrasound-induced site-specific scission of disulfide bonds. The first example is the intermolecular disulfide bond scission induced drug release system, capable of successively releasing furan-containing small molecules by ultrasound-induced selective scission of a disulfide mechanophore embedded at the center of a polymer chain. Upon disulfide scission, thiyl radicals were generated and protonated in aqueous media yielding thiols. These, in turn, underwent a Michael-type addition to Diels-Alder (DA) adducts of furylated drugs and acetylenedicarboxylate, which ultimately induced a retro DA reaction releasing the corresponding small molecule. To outline the conceptual scope of this system, we successively released the furylated fluorophore dansyl and the drugs furosemide as well as furylated doxorubicin. The second example is the intramolecular mechanochemical disulfide bond scission induced drug release system. Here, we employ a disulfide-centered polymer carrying the drug bound via a carbonate/carbamate linker on the β-carbon. These polymers were designed such that ultrasonication induced central bond scission in aqueous medium would lead to the generation of free thiols and subsequently a kinetically favored 5-exo-trig cyclization would extrude the target molecule from the carbonate/carbamate linker. The results for this intramolecular drug release system were then split into three subchapters, and we describe the unprecedented use of mechanical force for the activation of seven different prodrugs along with three reference molecules. To prove the concept, we first activated the latent fluorophore umbelliferone to optimize the experimental conditions. Afterward, we successfully activated a pharmacologically relevant drug molecule camptothecin. Subsequently, the intramolecular drug release was extended for the mechanochemical activation of disulfide-based multifunctional constructs for theranostic drug release, which allows direct and fluorescence-based monitoring of the released drugs. We show two ultrasound-responsive multifunctional constructs capable of releasing either naphthalimide or coumarin as the fluorescent reporter and camptothecin or gemcitabine as the anticancer agent from its disulfide polymer. In principle, this theranostic approach would allow the drug delivery and release to be monitored directly in a non-invasive manner with sub-molecular precision. Furthermore, we systematically investigated the effects of linkage bond on the release kinetics of the disulfide polymer for the development of novel mechanochemically sensitive disulfide conjugates to achieve tailored and controllable release. For this purpose, we employed three naphthalimides to display colorimetric and green fluorescence off-on changes upon release, which allow the analytical description of the release process. We believe that this work may serve as a novel blueprint for many more approaches employing ultrasound to release different functional molecules for a manifold of other applications in the field of medicine and beyond.

Institutions

• DWI - Leibniz-Institut für Interaktive Materialien e.V. [052200]
• Department of Chemistry [150000]
• Institute of Technical and Macromolecular Chemistry [154005]
• Chair of Macromolecular Materials and Systems [155910]