CCS Chemistry, Ahead of Print.
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.
The use of three-dimensional self-assembled metallacages (MCgs) as multimodal drug platforms holds great promise. However, the synthesis of MCgs with increased complexity and functionality is a great challenge since understanding of the interaction of MCgs with biological targets is still limited. In this context, this work reports on the integration of a gold(III) porphyrin scaffold into a prismatic MCg structure and explores its application for multimodal therapy of cancer in vitro, namely enabling both photodynamic therapy and chemotherapy. Combining experimental approaches with a state-of-the-art metadynamics theoretical study, we discovered that the gold cage shows unprecedented host–guest interaction-driven selective stabilization of guanine-quadruplex (G4) structures – validated anticancer drug targets – disclosing a new mechanism to pursue in the design of supramolecular drugs.
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