Activation of the Catalytic Activity of Thrombin for Fibrin Formation by Ultrasound

Abstract

The regulation of enzyme activity is a method to control biological function. We report two systems enabling the ultrasound‐induced activation of thrombin, which is vital for secondary hemostasis. First, we designed polyaptamers, which can specifically bind to thrombin, inhibiting its catalytic activity. With ultrasound generating inertial cavitation and therapeutic medical focused ultrasound, the interactions between polyaptamer and enzyme are cleaved, restoring the activity to catalyze the conversion of fibrinogen into fibrin. Second, we used split aptamers conjugated to the surface of gold nanoparticles (AuNPs). In the presence of thrombin, these assemble into an aptamer tertiary structure, induce AuNP aggregation, and deactivate the enzyme. By ultrasonication, the AuNP aggregates reversibly disassemble releasing and activating the enzyme. We envision that this approach will be a blueprint to control the function of other proteins by mechanical stimuli in the sonogenetics field.

Microgels as drug carriers for sonopharmacology

“…Firstly, the sonication time necessary to release a large fraction of the bound cargo was only 5 min, which compares favorably to linear polymer chains where multiple hours of sonication are required. 11 This is important to eventually enable the application of such platforms in combination with the effort to use higher, clinically relevant US frequencies 36,37 avoiding detrimental side effects of US. 57 Secondly, the covalent incorporation of the antibiotic within the microgel structure avoided drug leakage and screened the drugs efficiently as expressed in the lack of antimicrobial activity of the microgels.…”

“…The mechanochemical activity of a carrier‐payload construct can be tailored by the properties of the bound drug, 15,22 the force‐response of the mechanophore, 12,35 as well as power, frequency, and duration of US application 36,37 . In addition, polymer topology has a remarkable effect on the mechanochemical activity 38 and represents an important parameter to be investigated in the context of mechanochemical drug activation.…”

Ultrasound-Responsive Systems as Components for Smart Materials

“…This process proceeded through the reversible disassembly of gold (Au) nanoparticles bound by the aptamer, as depicted in Figure 20 b. 331 Under focused ultrasound at 5 MHz (MI = 0.38), they achieved 75% of catalytic activity in 6 min. Although 20 kHz ultrasound with 10 W cm –2 can reach 50% of the activity in 15 s, these results showed reasonable effect strengths at clinical frequencies.…”

Mechano‐Nanoswitches for Ultrasound‐Controlled Drug Activation

“…[18,19] Furthermore, the combination of nanoparticle systems with polymer mechanochemistry enabled increased drug loading efficiency and enhanced mechanical responses compared to systems relying exclusively on synthetic polymers. [20] To further expand the scope of the US-induced drug activation in nanosystems, herein we construct a mechano-nanoswitch for the selective activation of anticancer drug doxorubicin (DOX) through ultrasonication. Using the principle of mechanochemistry, two gold nanoparticles (AuNPs) act as a transmitter of the shear force.…”

“…[ 18 , 19 ] Furthermore, the combination of nanoparticle systems with polymer mechanochemistry enabled increased drug loading efficiency and enhanced mechanical responses compared to systems relying exclusively on synthetic polymers. [ 20 ]…”