Ultrasound-mediated nano drug delivery for treating cancer: Fundamental physics to future directions

The application of biocompatible nanocarriers in medicine has provided several benefits over conventional treatment methods. However, achieving high treatment efficacy and deep penetration of nanocarriers in tumor tissue is still challenging. To address this, stimuli-responsive nano-sized drug delivery systems (DDSs) are an active area of investigation in delivering anticancer drugs. While ultrasound is mainly used for diagnostic purposes, it can also be applied to affect cellular function and the delivery/release of anticancer drugs. Therapeutic ultrasound (TUS) has shown potential as both a stand-alone anticancer treatment and a method to induce targeted drug release from nanocarrier systems. TUS approaches have been used to overcome various physiological obstacles, including endothelial barriers, the tumor microenvironment (TME), and immunological hurdles. Combining nanomedicine and ultrasound as a smart DDS can increase in situ drug delivery and improve access to impermeable tissues. Furthermore, smart DDSs can perform targeted drug release in response to distinctive TMEs, external triggers, or dual/multi-stimulus. This results in enhanced treatment efficacy and reduced damage to surrounding healthy tissue or organs at risk. Integrating DDSs and ultrasound is still in its early stages. More research and clinical trials are required to fully understand ultrasound's underlying physical mechanisms and interactions with various types of nanocarriers and different types of cells and tissues. In the present review, ultrasound-mediated nano-sized DDS, specifically focused on cancer treatment, is presented and discussed. Ultrasound interaction with nanoparticles (NPs), drug release mechanisms, and various types of ultrasound-sensitive NPs are examined. Additionally, in vitro, in vivo, and clinical applications of TUS are reviewed in light of the critical challenges that need to be considered to advance TUS toward an efficient, secure, straightforward, and accessible cancer treatment. This study also presents effective TUS parameters and safety considerations for this treatment modality and gives recommendations about system design and operation. Finally, future perspectives are considered, and different TUS approaches are examined and discussed in detail. This review investigates drug release and delivery through ultrasound-mediated nano-sized cancer treatment, both pre-clinically and clinically.