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Ultrasound

Ultrasound or sonography is a diagnostic imaging technique similar to the technique applied in oceanographic studies. Ultrasound produces higher frequency sound waves that are pulsed into the tissue with a probe. These pulses are reflected or absorbed (echos) at varying degrees depending on the tissue. Such pulses are recorded as electrical impulses and images [36]. Ultrasound is the most common, noninvasive, and safest way of examining internal organs without the use of harmful radiation [56]. It is widely applied in pregnancy to determine the growth and development of a fetus. Other than pregnancy, ultrasound is applied to detect tumors, congenital vascular malformations, and organs like pelvis, abdomen, heart, thyroid, kidneys, liver, uterus, ovaries, and blood vessels [36]. Over the last decade, insoluble gas microbubbles encapsulated in protein/liposomal shell had been clinically indicated as contrast agents [56]. These commercially available microbubbles are in the micrometer range with poor circulation half-lives that limit tumor penetration and targetability [57]. Moreover, these microsized contrast agents are unstable during sonication. These molecules generate low endothelial layer permeability, rendering them unfavorable for tumor permeation and targeting. In case of ultrasound contrast agents, nanoparticles overcome most of the limitations with their physicochemical properties (mainly nanosize) and ease of surface functionalization. Popularity ofnano- systems as carriers for ultrasonication contrast agents stems from their enhanced stability, tumor targeting, and application in multiplex imaging modality. However, in this scenario nanosized gas-filled vesicles enhance contrast to noise ratio because of their hollow inner shell echogenicity [44]. Various types of nanosystems have been studied as nanocarriers including liposomes, dendrimers, nanomicelles, quantum dots, emulsions, polymers, and silica nanoparticles.

Mesoporous silica nanoparticles (MSNs) are inorganic, porous solid nanoparticles with high circulation half-life than traditional microbubbles. MSN is amenable to conjugation with tumor overexpressing receptor antibody (such as Herceptin). It allows the conjugate to increase tumor cell accumulation and selectivity for contrast enhancement with real-time imaging [58].

Poly(lactic acid) nanoparticles encapsulating ultrasound contrast agents such as SF6 gas improves weak echogenicity of dense hydrophobic gases. The particle size in these nanosystems (~ 200 nm) is crucial for passive tumor accumulation via enhanced permeability and retention (EPR effect) of tumor cells [59,60]. Advancements in the development of contrast-enhancing nanosystems have also advanced dual imaging system with multimodal contrast agents. Copper oxide nanoparticles are proven to demonstrate magnetic, acoustic, and high thermal conductivity [61]. The multifunctional nanoparticles reduce Tj relaxation times for MRI and enhance attenuation coefficient for ultrasound imaging. Moreover, simple surface modification of these nanoparticles enables target-specific visualization and simultaneous thermal ablation of tumor cells [44,61].

 
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