Comprehensive review on ultrasound-responsive theranostic nanomaterials: mechanisms, structures and medical applications

Abstract

The field of theranostics has been rapidly growing in recent years and nanotechnology has played a major role in this growth. Nanomaterials can be constructed to respond to a variety of different stimuli which can be internal (enzyme activity, redox potential, pH changes, temperature changes) or external (light, heat, magnetic fields, ultrasound). Theranostic nanomaterials can respond by producing an imaging signal and/or a therapeutic effect, which frequently involves cell death. Since ultrasound (US) is already well established as a clinical imaging modality, it is attractive to combine it with rationally designed nanoparticles for theranostics. The mechanisms of US interactions include cavitation microbubbles (MBs), acoustic droplet vaporization, acoustic radiation force, localized thermal effects, reactive oxygen species generation, sonoluminescence, and sonoporation. These effects can result in the release of encapsulated drugs or genes at the site of interest as well as cell death and considerable image enhancement. The present review discusses US-responsive theranostic nanomaterials under the following categories: MBs, micelles, liposomes (conventional and echogenic), niosomes, nanoemulsions, polymeric nanoparticles, chitosan nanocapsules, dendrimers, hydrogels, nanogels, gold nanoparticles, titania nanostructures, carbon nanostructures, mesoporous silica nanoparticles, fuel-free nano/micromotors.

Keywords: smart nanomaterials; sonodynamic therapy; sonoporation; theranostics; ultrasound; ultrasound responsive nanomaterials.

Figure 1

Schematic illustration of the contents.

Figure 2

Mechanism of US in synergism with nanomaterials. Generally, the effects of US can be explained by five mechanisms, including cavitation, ARF, acoustic droplet vaporization (ADV), hyperthermia, and free radical species generation. In some conditions, these mechanisms occur at the same time and cannot be studied separately. In this sense, free radical generation is related to cavitation and thermal processes and ADV is integrated with cavitation. As a result of these mechanisms, cargo carriers can release their contents and some drugs become activated. Free radicals cause intrinsic tissue damage, tissue ablation occurs, particles pass through barriers and accumulate in the desired location, and image contrast is enhanced due to the increased backscattered signal.

Figure 3

MB structure and mechanism of action. (a) MBs are gas-filled shell-coated particles that can be decorated with ligands or loaded with cargos. The cargo can also be loaded in the core of the structure. (b) MBs undergo inertial or stable cavitation under US irradiation, each of which can be used for specific applications. MB formation can enhance image contrast, facilitate cargo release, or cause tissue damage through different pathways.

Figure 4

US-triggered liposomes. (a) Liposomal structure with phospholipid bilayer membrane and an aqueous core. Liposome surface can be modified with different ligands for more biological functions and the desired cargo can be loaded into the core of the structure. (b) Mechanism of action of cargo release from liposomes under US irradiation. Cavitation in the lipid bilayer or near the liposome, hyperthermia, and ARF are possible mechanisms that could cause a decrease in membrane integrity and lead to cargo release.

Figure 5

Structure and mechanism of action of NEs. (a) Nanoemulsions are composed of a core of hydrophobic liquid, stabilized via an emulsifier in an aqueous medium, which can be coated with a shell decorated with ligands. (b) Nanoemulsions are related to MBs and could be considered as a precursor of MBs. Under US irradiation, NEs can transform into bubbles. This phenomenon is explained by cavitation and ADV. The acoustic radiation force explains some of the biological effects of these particles.

Figure 6

Mechanism of polymeric nanostructures in combination with US.

Figure 7

Mechanisms of action of (a) gold, (b) titania, (c) silica, and (d) carbon nanostructures plus US irradiation. Hyperthermia, cavitation, and free radical species generation can occur alone or in combination.