Urea-Bond Scission Induced by Therapeutic Ultrasound for Biofunctional Molecule Release

Abstract

Ultrasound-triggered remote control of biomolecular functions in cells provides unique advantages for us to interrogate nature. However, strategies to design therapeutic ultrasound-responsive functional molecules remain elusive, and rare ultrasound-cleavable chemical bonds have been developed to date. Herein, therapeutic ultrasound (1 MHz)-induced scission of urea bonds for drug release is demonstrated for the first time. Such a transformation has been verified to be initiated by hydroxyl radicals generated in the interior of cavitation bubbles, occurring specifically at the cavitation bubble−liquid interface. A series of urea-bond-containing prodrugs based on methylene blue (MB), namely MBUs, are designed. Upon sonication with low-intensity therapeutic ultrasound, the urea bonds linked with primary amines can be selectively cleaved, and free MB is released in a physiologically relevant environment, accompanied by recovered absorbance, fluorescence, and photosensitivity. Moreover, an FDAapproved alkylating agent (i.e., melphalan) bearing urea bond is also developed (MBU-Mel), successfully achieving ultrasoundtriggered drug release in deep-seated cancer cells (mimic with 1 cm pigskin), showing the scalability of our ultrasound-responsive molecule platform in bioactive molecules release. This may set the starting point for therapeutic ultrasound-induced drug release, making a forward step in "sonopharmacology".

A Space‐Dependent ‘Enzyme‐Substrate’ Type Probe based on ‘Carboxylesterase‐Amide Group’ for Ultrafast Fluorescent Imaging Orthotopic Hepatocellular Carcinoma

“…As we know, fluorescence imaging based on fluorescent probes is allowed to perform in vitro, ex vivo, and in vivo images and provide an analysis with higher sensitivity. [11][12][13][14][15][16][17][18][19] It has surfaced as a powerful tool for visualizing target analytes in complicated biological specimens owing to its real-time detection, non-destructive analysis and, especially, excellent sensitivity.…”

Fluorescence-based chemical tools for monitoring ultrasound-induced hydroxyl radical production in aqueous solution and in cells

“…[10][11][12] In a recent report by Peng and co-workers, ultrasound-induced cavitation effectively generated OH radicals by sonolysis 13 to activate methylene blue-based urea conjugates for both imaging and therapeutic applications. 14 Inspired by this strategy, we rationalised the recently reported OH radical responsive unit, 3,5-dihydroxylbenzyl (DHB) 4 may afford a general ''sonocaging'' unit that is selectively removed by OH radicals generated from ultrasound irradiation. It is proposed OH radical-mediated aromatic hydroxylation results in self-immolation releasing the active molecule (Scheme 1).…”

Ultrasound-Activated NIR Chemiluminescence for Deep Tissue and Tumor Foci Imaging

“…To overcome these limitations, Peng et al developed a US-activatable molecule, and the •OH produced by cavitation bubbles acted as an "intermediary" to trigger the urea bond cleavage for drug release (demonstrating excellent •OH responsiveness) under therapeutic US conditions (1 MHz). 11 This new way of bridging US chemistry with bond scission via an "intermediary" is novel and meaningful with wide application prospects.…”

“…As a promising alternative, ultrasound (US) not only exhibits noninvasiveness and high spatiotemporal control similar to light but also has the advantages of deep penetrability (up to 10 cm), minimal side effects, precise localization of lesions, and low cost. − Recent studies have shown that the US cavitation effect-driven mechanical force can act as an energy stimulus, triggering specific chemical reactions. , Herrmann’s group designed a disulfide-centered polymer carrying camptothecin anticancer drugs. The disulfide was transformed to thiols under US radiation, achieving efficient drug release and activation .…”

“…Such US-cleavable chemical bonds are only demonstrated in macromolecular polymers under high-intensity US radiations; besides, the disulfide bond is also easily reduced by GSH, releasing the nonspecific drug molecules. To overcome these limitations, Peng et al developed a US-activatable molecule, and the •OH produced by cavitation bubbles acted as an “intermediary” to trigger the urea bond cleavage for drug release (demonstrating excellent •OH responsiveness) under therapeutic US conditions (1 MHz) . This new way of bridging US chemistry with bond scission via an “intermediary” is novel and meaningful with wide application prospects.…”