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Biomedical application of mechanophores is the next frontier in polymer mechanochemistry. We report the concept, mechanochemical dynamic therapy (MDT), that utilizes remote, ultrasound-triggered mechanophore activation to enable anticancer activities. We selected an azo-based mechanophore to generate reactive free radicals (FRs) under the control of high-intensity focused ultrasound (HIFU), which subsequently produced ROS. We investigated two sets of invitro mouse cancer models: 1) melanoma (B16F10) and 2) breast cancer (E0771). Inhibition of growth and decreases in viabilities of both B16F10 and E0771 were observed in correlation to the release of ROS by mechanophore activation. By circumventing the known issues in photodynamic therapy and sonodynamic therapy, we anticipate MDT to be a powerful anticancer tool complementary to other existing cancer treatments.

Mechanophores are molecular motifs that respond to mechanical perturbance with targeted chemical reactions toward desirable changes in material properties. A large variety of mechanophores have been investigated, with applications focusing on functional materials, such as strain/stress sensors, nanolithography, and self-healing polymers, among others. The responses of engineered mechanophores, such as light emittance, change in fluorescence, and generation of free radicals (FRs), have potential for bioimaging and therapy. However, the biomedical applications of mechanophores are not well explored. Herein, we report an invitro demonstration of an FR-generating mechanophore embedded in biocompatible hydrogels for noninvasive cancer therapy. Controlled by high-intensity focused ultrasound (HIFU), a clinically proven therapeutic technique, mechanophores were activated with spatiotemporal precision to generate FRs that converted to reactive oxygen species (ROS) to effectively kill tumor cells. The mechanophore hydrogels exhibited no cytotoxicity under physiological conditions. Upon activation with HIFU sonication, the therapeutic efficacies in killing invitro murine melanoma and breast cancer tumor cells were comparable with lethal doses of H2O2. This process demonstrated the potential for mechanophore-integrated HIFU combination as a noninvasive cancer treatment platform, named mechanochemical dynamic therapy (MDT). MDT has two distinct advantages over other noninvasive cancer treatments, such as photodynamic therapy (PDT) and sonodynamic therapy (SDT). 1) MDT is ultrasound based, with larger penetration depth than PDT. 2) MDT does not rely on sonosensitizers or the acoustic cavitation effect, both of which are necessary for SDT. Taking advantage of the strengths of mechanophores and HIFU, MDT can provide noninvasive treatments for diverse cancer types.

Author contributions: G.K., Q.W., M.L.O., J.S.M., and K.C.L. designed research; G.K., Q.W., and J.L.C. performed research; G.K., Q.W., E.J.S., and M.L.O. analyzed data; M.L.O., J.S.M., and K.C.L. supervised the study; and G.K., Q.W., J.L.C., and M.L.O. wrote the paper.

Reviewers: A.B., University of WisconsinMadison; K.B.P., Stanford University; and Y.X., Stanford University.

The authors declare no competing interest.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2109791119/-/DCSupplemental.

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Ultrasound controlled mechanophore activation in hydrogels for cancer therapy - pnas.org