Mechano-Nanoswitches for Ultrasound-Controlled Drug Activation 

Cancer encompasses a variety of diseases that result from the deregulated growth and spread of malignant cells. Chemotherapy drugs primarily interfere with DNA synthesis, targeting rapidly dividing cancer cells. These agents, whilst effective, are nonspecific, leading to healthy tissue damage and subsequent side effects that can contribute to the high mortality rates of cancer patients. An additional issue with chemotherapy drugs is the increased incidence of drug resistance. Hence, the ability to develop chemotherapeutics that actively target cancer cells is highly desirable.

Nanocarriers are now established as materials that can be increasingly utilized in cancer therapeutics. In particular, stimuli-responsive and surface-engineered targeted nanocarriers that release their payloads at the tumor site are of particular interest to cancer therapy. Recent advances in the field of pharmaceutical nanotechnology have led formulation and nanotechnology scientists to develop smart nanocarrier-based targeted delivery systems for effective treatment and management of various cancers. Although many challenges complicate nanodrug development, it may only be a matter of time until these agents offer unique solutions for unmet clinical needs. It has recently been demonstrated that sonomechanical bond scission permits remote-controlled medication release from inert parent macromolecules using ultrasound. In a new study published in the journal Advanced Science, Xiamen University scientists: Professor Shuaidong Huo and Zhihuan Liao in collaboration with Dr. Pengkun Zhao, Yu Zhou, Dr. Robert Göstl and Professor Andreas Herrmann from Leibniz Institute for Interactive Materials and RWTH Aachen University in Germany developed a new Au-DOX-Au system sensitive to ultrasonication and applied sonomechanical force to stretch the Au-DNA dimer structures to induce drug release and activation.

In their study, the research team synthesized citrate-protected 15 nm gold nanoparticles (AuNPs), which they subsequently modified with terminally double thiolated ssDNA. The drug loading of the Au-DNA dimer architecture was then measured. The authors showed that DNA_DOX sequence’s drug payload capacity may be enhanced and adjusted by varying the sequence length and number of drug intercalation sites. The drug loading capacity of Au-Au nanoswitches was demonstrated and quantified. The acquired fluorescence spectra confirmed the drug payload capacity of the Au-Au nanoswitches, and the drug loading efficiency was determined to be 64%. After 10 minutes of ultrasonication, a portion of the initially closed dimer converted to an open state with a significant interparticle gap, demonstrating the dimer structure’s force-response capabilities.

Further, the research team used MTT cell proliferation to compare the activity of US-responsive nanoswitches to a range of controls, they showed improved IC50 values of Au-DOX-Au compared to DOX, suggesting that DOX intercalation inside DNA_DOX lowered pharmacological action. As a result, findings showed that the pharmacological activity of nanoswitches might be activated and regulated spatiotemporally by varying the ultrasonication exposure period for selective cancer cell inhibition.

In summary, the new study used ultrasound as an external stimulus for the first time to regulate drug release and activation utilizing a sonomechanical responsive Au-DNA nanoswitch. According to the researchers, this new technique provides a roadmap for building and designing drug activation nanoparticle systems with external ultrasonic control. Moreover, this strategy envisioned a future medication with well-regulated action that may prevent systemic adverse effects.