Nanomaterials as Ultrasound Theragnostic Tools for Heart Disease Treatment/Diagnosis

Abstract

A variety of different nanomaterials (NMs) such as microbubbles (MBs), nanobubbles (NBs), nanodroplets (NDs), and silica hollow meso-structures have been tested as ultrasound contrast agents for the detection of heart diseases. The inner part of these NMs is made gaseous to yield an ultrasound contrast, which arises from the difference in acoustic impedance between the interior and exterior of such a structure. Furthermore, to specifically achieve a contrast in the diseased heart region (DHR), NMs can be designed to target this region in essentially three different ways (i.e., passively when NMs are small enough to diffuse through the holes of the vessels supplying the DHR, actively by being associated with a ligand that recognizes a receptor of the DHR, or magnetically by applying a magnetic field orientated in the direction of the DHR on a NM responding to such stimulus). The localization and resolution of ultrasound imaging can be further improved by applying ultrasounds in the DHR, by increasing the ultrasound frequency, or by using harmonic, sub-harmonic, or super-resolution imaging. Local imaging can be achieved with other non-gaseous NMs of metallic composition (i.e., essentially made of Au) by using photoacoustic imaging, thus widening the range of NMs usable for cardiac applications. These contrast agents may also have a therapeutic efficacy by carrying/activating/releasing a heart disease drug, by triggering ultrasound targeted microbubble destruction or enhanced cavitation in the DHR, for example, resulting in thrombolysis or helping to prevent heart transplant rejection.

Keywords: cancer; contrast agent; high intensity ultrasounds; nano-oncology; nanomaterials; nanomedicine; nanotechnology; sonodynamic therapy; ultrasounds.

Figure 1

A schematic figure illustrating the large choice of methods used to treat or diagnose a cardiac disease by using a combination of contrast agents and ultrasounds. While gaseous nanomaterials can be used for ultrasound imaging, metallic ones can serve in photo-acoustic imaging. Targeting of the DHR to specifically image/treat this region can be achieved by designing NMs that target the DHR through passive, active, or magnetic targeting, and/or by applying ultrasound in this region. Therapeutic activity can be obtained through the release/activation of heart disease drugs under controlled conditions of ultrasound application and/or via ultrasound targeted microbubble destruction or cavitation, which can be enhanced in the presence of the contrast agent.

Figure 2

An illustration of the different ways in which a nanoscale contrast agent can target the DHR by relying on: (a) molecular/active targeting (i.e., a ligand is attached to the NM that specifically recognizes a receptor of the DHR), (b) passive targeting (i.e., NMs diffuse through the holes of the blood vessels irrigating the DHR), (c) magnetic targeting (i.e., a magnetic field is applied in the direction of the DHR, which attracts the magnetic NM toward the DHR).

Figure 3

A schematic presenting the different mechanisms for producing ultrasound contrast (i.e., through the emission of ultrasounds resulting from the thermal expansion of a metallic NM heated by a laser (photoacoustic imaging) or via the difference in acoustic impendence between the gaseous inner part and the solid surrounding tissue of NM such as microbubbles, nanobubbles, or hollow silica meso-structures).

Figure 4

A schematic summarizing the various mechanisms under which an ultrasound contrast agent can trigger a therapeutic activity (i.e., through cavitation, ultrasound targeted microbubble destruction, or the release/activation of a heart disease drug). The different heart conditions that can be treated with these methods are listed (i.e., the suppression of cardiac hypertrophy, the destruction/dissolution of thrombi leading to arteria recanalization, stem cell transplantation in the heart, prevention of heart transplantation acute rejection, promotion of heart angiogenesis, prevention/treatment of myocardial infarction, and treatment of atherosclerosis).

Figure 5

A list of advantageous features of nanosized contrast agents used with ultrasounds comprising: (i) the targeting of the diseased heart region resulting in the imaging/treatment of this region; (ii) the possibility to carry out multimodal imaging (US; PA; MPI; MRI; PL) and hence to benefit from the combined advantages of these different imaging methods; (iii) theragnostic properties (i.e., imaging and therapy can be combined); (iv) a wide choice of contrast agents is available including MBs, NBs, NDs, NCs, Silica NMs; Au NMs; (v) the efficacy of the treatment against heart diseases can be achieved at reduced drug concentration, hence minimizing the potential side effects of such drugs; (vi) the heart disease drug can be released/activated under the controlled condition by deciding to apply the ultrasound or not and by applying the ultrasound in the diseased heart region; (vi) the size of some NMs can be tuned (i.e., NDs can be transformed into MBs under acoustic droplet vaporization), hence enabling such system to benefit from the enhanced targeting efficacy of NDs (i.e., the EPR (enhanced permeability and retention) effect was improved for NDs of relatively small sizes and MBs yielded superior echogenicity).