Ultrasound controlled mechanophore activation in hydrogels for cancer therapy.

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 in vitro 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 in vitro 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.

Noninvasive and Spatiotemporal Control of DNAzyme-Based Imaging of Metal Ions In Vivo Using High-Intensity Focused Ultrasound.

Detecting metal ions in vivo with a high spatiotemporal resolution is critical to understanding the roles of the metal ions in both healthy and disease states. Although spatiotemporal controls of metal-ion sensors using light have been demonstrated, the lack of penetration depth in tissue and in vivo has limited their application. To overcome this limitation, we herein report the use of high-intensity focused ultrasound (HIFU) to remotely deliver on-demand, spatiotemporally resolved thermal energy to activate the DNAzyme sensors at the targeted region both in vitro and in vivo. A Zn2+-selective DNAzyme probe is inactivated by a protector strand to block the formation of catalytic enzyme structure, which can then be activated by an HIFU-induced increase in the local temperature. With this design, Zn2+-specific fluorescent resonance energy transfer (FRET) imaging has been demonstrated by the new DNAzyme-HIFU probes in both HeLa cells and mice. The current method can be applied to monitor many other metal ions for in vivo imaging and medical diagnosis using metal-specific DNAzymes that have either been obtained or can be selected using in vitro selection.

Dopamine-modified TiO2 monolith-assisted LDI MS imaging for simultaneous localization of small metabolites and lipids in mouse brain tissue with enhanced detection selectivity and sensitivity.

Localization of metabolites using multiplexed mass spectrometry imaging (MSI) provides important chemical information for biological research. In contrast to matrix-assisted laser desorption/ionization (MALDI), TiO2-assisted laser desorption/ionization (LDI) for MSI improves detection of low molecular mass metabolites (<500 Da) by reducing matrix background. However, the low UV absorption of TiO2 nanoparticles and their ester hydrolysis catalytic activity hinder the detection of phospholipids and many low-abundance molecules. To address these challenges, we evaluated and optimized the material morphology and composition of TiO2. Dopamine (DA) was found to be an efficient ligand for TiO2, resulting in increased UV light absorption, higher surface pH, and formation of monolithic TiO2-DA structures. The sub-micron scale and higher surface pH of the TiO2 particle sizes led to improved detection of phospholipid signals. Compared to unmodified TiO2 sub-micron particles, the DA-modified TiO2 monolith led to 10- to 30-fold increases in the signal-to-noise ratios of a number of compound peaks. The TiO2-DA monolith-assisted LDI MSI approach has higher selectivity and sensitivity for Lewis basic compounds, such as fatty acids, cholesterols, ceramides, diacylglycerols, and phosphatidylethanolamine, when analyzed in positive mode, than traditional MALDI MS. Using this new method, over 100 molecules, including amino acids, alkaloids, free fatty acids, peptides, and lipids, were localized in mouse brain sections. By comparing the presence and localization of those molecules in young and old mouse brains, the approach demonstrated good performance in the determination of aging-related neurochemical changes in the brain.