High-Intensity Focused Ultrasound-Induced Disulfide Mechanophore Activation in Polymeric Nanostructures for Molecule Release

Ultrasound(US)activation of mechanophores in polymers that initiates cascade chemical reactions is a promising strategy for on-demand molecule release.However,the typical US frequency used for mechanochemistry is around 20 kHz,producing inertial cavitation that exceeds the tolerance threshold of biological systems.Here,high-intensity focused US(HIFU)as a mechanical stimulus is introduced to drive the activation of disulfide mechanophores in hyperbranched star polymers(HBSPs)and microgels(MGLs).The mechanism of molecular release is attributed to the thiol-disulfide exchange reaction and subsequent intramolecular cyclization.We reveal that HBSPs and MGLs effectively transduce HIFU as mechanical input to chemical output,demonstrated by the quantification of the release of fluorescent umbelliferone(UMB).Moreover,an in vitro study of drug release is carried out using camptothecin as the model drug,which is covalently loaded in MGLs,demonstrating the potential of our system for controlled drug delivery to cancer cells.

Ultrasound responsive microcapsules for antibacterial nanodrug delivery

The development of ultrasound-responsive microcapsule structures has resulted in several spatiotemporally controlled drug delivery systems for macromolecular cargoes,including proteins,nucleic acids,and even cells for biomedical applications.However,utilizing microcapsules to transport small molecular cargoes remains a challenge,because the leakage of drugs before ultrasound irradiation might cause side effects such as the undesired toxicity and the decrease of effective drug concentration at the target site.Herein,we present a novel strategy to tackle these shortcomings by employing nanodrugs which refers to nanoparticles coated with small molecule drugs.We showed that the drug leakage was prevented when encapsulating the nanodrug in microcapsules.Moreover,the fabricated drug delivery system was responsive not only to unfocused high-intensity ultrasound but also to the clinically relevant high-intensity focused ultrasound.Finally,as a proof of concept,we showed that the antibacterial activity of the nanodrug@Microcapsules could be activated by applying ultrasound in situ.These results may provide new insights into the development of ultrasound triggered small molecule drug delivery assisted by metallic nanoparticles.

The Mechanochemical Release of Naphthalimide Fluorophores fromβ-Carbonate andβ-Carbamate Disulfide-Centered Polymers

The covalent attachment of cargo molecules(e.g.,drugs and fluorophores)inβ-position to a disulfide moiety through carbamate and carbonate bonds finds many applications in responsive release systems.Recently,we showed that the combination of this release process with polymer mechanochemistry-induced disulfide scission enabled the remote-controlled release of small molecule drugs and fluorophores from their inactive parent macromolecules using ultrasound.The nature of the linker bond largely governed the subsequent release kinetics,an aspect that has not been investigated so far.To compare the differences,we here employ disulfide-centered polymers releasing either hydroxyl-or amino-naphthalimides from their respectiveβ-carbonate or-carbamate linkers by forceinduced intramolecular 5-exo-trig cyclization.We present the synthesis,characterization,and cell imaging evaluation of three naphthalimides featuring colorimetric and green fluorescence turn-on upon release,allowing monitoring of the release process.We believe that the insights gained from these experiments would advance the tailoring of release rates for force-induced pharmacotherapy.