Remote control of mechanochemical reactions under physiological conditions using biocompatible focused ultrasound

Creators: Yao, Yuxing; McFadden, Molly E.; Luo, Stella M.; Barber, Ross W.; Kang, Elin; Bar-Zion, Avinoam; Smith, Cameron A. B.; Jin, Zhiyang; Legendre, Mark; Ling, Bill; Malounda, Dina; Torres, Andrea; Hamza, Tiba; Edwards, Chelsea E. R.; Shapiro, Mikhail G.¹; Robb, Maxwell J.¹

1. California Institute of Technology

Abstract

External control of chemical reactions in biological settings with spatial and temporal precision is a grand challenge for noninvasive diagnostic and therapeutic applications. While light is a conventional stimulus for remote chemical activation, its penetration is severely attenuated in tissues, which limits biological applicability. On the other hand, ultrasound is a biocompatible remote energy source that is highly penetrant and offers a wide range of functional tunability. Coupling ultrasound to the activation of specific chemical reactions under physiological conditions, however, remains a challenge. Here, we describe a synergistic platform that couples the selective mechanochemical activation of mechanophore-functionalized polymers with biocompatible focused ultrasound (FUS) by leveraging pressure-sensitive gas vesicles (GVs) as acousto-mechanical transducers. The power of this approach is illustrated through the mechanically triggered release of covalently bound fluorogenic and therapeutic cargo molecules from polymers containing a masked 2-furylcarbinol mechanophore. Molecular release occurs selectively in the presence of GVs upon exposure to FUS under physiological conditions. These results showcase the viability of this system for enabling remote control of specific mechanochemical reactions with spatiotemporal precision in biologically relevant settings and demonstrate the translational potential of polymer mechanochemistry.

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Acknowledgement

We gratefully acknowledge financial support from the Division of Chemistry and Chemical Engineering (CCE) at Caltech through a CCE Innovation Grant (M.G.S. and M.J.R.), the Arnold and Mabel Beckman Foundation through a Beckman Young Investigator Award (M.J.R.), the David and Lucille Packard Foundation (M.G.S.), the Resnick Sustainability Institute (M.G.S.), the Institute for Collaborative Biotechnologies (W911NF-19-D-0001 to M.G.S.), and the National Institute of General Medical Sciences of the NIH (R35GM150988 to M.J.R.). M.E.M. was supported by an NSF Graduate Research Fellowship (DGE-1745301) and a Barbara J. Burger Fellowship from Caltech. A.B.-Z. was supported by the Lester Deutsch Fellowship and the Marie Skłodowska-Curie Postdoctoral Fellowship. C.A.B.S. was supported by the Human Frontiers Science Program Cross-Disciplinary Fellowship. We thank Dr. Scott Virgil for technical assistance and the Center for Catalysis and Chemical Synthesis of the Beckman Institute at Caltech for access to equipment. We gratefully acknowledge the Alfred P. Sloan Foundation for a Sloan Research Fellowship (M.J.R.) and the Camille and Henry Dreyfus Foundation for Camille Dreyfus Teacher-Scholar Awards (M.J.R. and M.G.S.). We thank the Kornfield group at Caltech for use of their GPC. M.J.R. thanks Prof. Peter Dervan for helpful discussions.

Contributions

Y.Y., M.E.M., M.G.S., and M.J.R. designed research; Y.Y., M.E.M., S.M.L., R.W.B., E.K., A.B.-Z., C.A.B.S., Z.J., M.L., B.L., D.M., A.T., T.H., and C.E.R.E. performed research; Y.Y., M.E.M., S.M.L., R.W.B., A.B.-Z., C.A.B.S., Z.J., M.G.S., and M.J.R. analyzed data; and Y.Y., M.E.M., M.G.S., and M.J.R. wrote the paper.

Data Availability

All study data are included in the article and/or SI Appendix.

Conflict of Interest

M.G.S. is an Investigator of the Howard Hughes Medical Institute. Y.Y., M.E.M., M.G.S., and M.J.R. are inventors on a US provisional patent application submitted by California Institute of Technology (CIT 9023-P) covering the method disclosed herein. M.J.R. is an inventor on a US patent issued to California Institute of Technology (11,584,752) covering the chemistry for mechanically triggered release employed in this study.

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