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At present, ultrasound radiation is broadly employed in medicine for both diagnostic and therapeutic purposes at various frequencies and intensities. In this review article, we focus on therapeutically-active nanoparticles NPs when stimulated by ultrasound. We therefore focus on the sonodynamic therapy and on the possible working mechanisms under debate of NPs-assisted sonodynamic treatments.

We support the idea that various, complex and synergistics physical—chemical processes take place during acoustic cavitation and NP activation. Different mechanisms are therefore responsible for the final cancer cell death and strongly depends not only on the type and structure of NPs or nanocarriers, but also on the way they interact with the ultrasonic pressure waves. We conclude with a brief overview of the clinical applications of the various ultrasound therapies and the related use of NPs-assisted ultrasound in clinics, showing that this very innovative and promising approach is however still at its infancy in the clinical cancer treatment.

Ultrasound is defined as a type of mechanical sound wave with a periodic vibration at frequencies higher than the human hearing 20 kHz. It is generated by exciting at a proper frequency an ultrasonic transducer usually based on a piezoelectric component or on an electromagnetic inductor able to convert the electrical signal into a mechanical displacement [ 1 , 2 ]. Ultrasound devices are usually composed by a generator, a compensating amplifier and a transducer [ 3 , 4 ].

It is already known that ultrasonic waves cause thermal and nonthermal effects. In particular, thermal effects refer to an increase in temperature due to the absorption of the ultrasonic waves through a tissue creating mechanical compression and decompression. Part of this mechanical energy is lost due to friction effects and it is converted to heat.

As a consequence, in biological systems [ 5 ] the liquidity of the phospholipid bilayer, composing the cell membranes, changes and the membrane permeability can alter [ 6 ].

The non-thermal effect of ultrasound is a complex and various set of mechanisms, comprising stable and inertial cavitation, microstreaming and radiation forces [ 7 ].

These events are able to induce both temperature increase and mechanical stresses, those in particular known as microjets and microstreams [ 8 ]. More in details, during non-inertial cavitation also called stable cavitation the gas pockets present in the liquid oscillate around an equilibrium radius and can persist for many acoustic compression and decompression cycles. These oscillations generate fluid streaming and the mechanical stresses create mixing of the medium [ 9 ].

On the other hand, the inertial cavitation is the process by which the gas bubbles trapped in a fluid are subjected by a rapid growth and violent collapse during exposure to ultrasound.

During such collapse, high temperatures higher than K and pressures more than atm are produced, releasing a high amount of energy [ 9 ]. The inertial cavitation is able to induce water thermal dissociation and thus reactive oxygen species ROS. Furthermore, cavitation generates flashes of light, a phenomenon called sonoluminescence SL [ 9 ].

Ultrasound is largely employed at present in medicine for diagnostic and therapeutic purposes. The produced biological effects are related both to the intensity and frequency of the ultrasound wave used [ 1 ]. Compared to other external stimuli, it has good tissue penetration capability, it is quite safe to human health and shows low operation and instrumental costs [ 9 , 10 ].

Ultrasound represents an important tool for imaging and diagnosis, in a technique called sonography. In particular, the ultrasonic waves are focalized at a particular depth of diagnostic interest.

Owing to the different acoustic resistances of the various tissues, the scattered signal is recovered, allowing to the imaging reconstruction of the different tissues.

To enhance the echogenicity and ultrasound responsiveness of certain tissues, microbubbles were developed as contrast agents. They basically consists of various gases enhancing echogenicity stabilized within a lipid or protein shell [ 11 , 12 ]. It is thus possible to obtain 2D and 3D images of tissues and organs [ 3 ]. Furthermore ultrasound was used for the treatment of numerous pathologies [ 13 ], such as a remedy of soft tissue injuries, for the acceleration of wound healing, for the resolution of edema, or for the softening of scar tissues [ 14 ].

Lithotripsy procedures were applied for stones removal in urology [ 15 ]; low-intensity pulsed ultrasound found therapeutic applications for bone growth stimulation [ 16 ]. Ultrasound-assisted lipolysis and liposuction are conventional practices in cosmetic surgery for fat tissue removal [ 17 ]. However, these topics are out of the interest of the present work and the reader could refer to recent gold reviews elsewhere [ 18 , 19 ].

This review will focus on the use of ultrasound in the presence of both soft and solid-state nanoparticles NPs against tumor cells or tissues and with a special emphasis on the sonodynamic treatment SDT.

A very recent review in the field related either to NPs and nanomaterials used for SDT was reported [ 20 ]. A second review more focused on the mechanisms of SDT related to experimental medicine and biology was also recently written [ 21 ]. Here our aim is to propose an update of the most recent advances in the field focusing on the mechanisms underlying the synergistic effect of NPs and acoustic fields toward the improved sonodynamic therapeutic outcome.

With respect to other routes of administration, transdermal drug delivery has potential advantages since it reduces the first-pass metabolism associated with oral delivery and is less painful than parenteral administrations [ 22 ]. However, the stratum corneum limits passive diffusion to small lipophilic molecules and methods to safely render it permeable to ionic and larger molecules are needed [ 13 ]. The sonophoresis technique is based on the ability of ultrasound radiation to increase the permeability of the stratum corneum, which is considered a primary barrier to protein and drug diffusion [ 23 ].

Once a drug has traversed the stratum corneum, the next layer is easier to perfuse, and subsequently the drug can reach the capillary vessels to be absorbed [ 13 ].

While ultrasound over all the frequency ranges can enhance skin permeability, the physical mechanisms responsible for enhanced permeation are different in each regime. Initial studies focused on High Frequency ultraSound HFS as the first use of ultrasound to deliver therapeutics across the skin in Because the skin penetration depth of the ultrasound waves is inversely dependent to the frequency of the pressure wave, thereby its effect are limited on the stratum corneum at high frequencies [ 24 , 25 ].

The characteristic permeation enhancement achieved with HFS is one to ten-fold more with respect to the absence of ultrasound [ 26 ]. Mitragotri et al. There are several mechanisms to enhance skin permeability in sonophoresis. Among these, the acoustic cavitation [ 29 , 30 ], the thermal effects [ 27 , 31 ], the radiation forces and convection acoustic streaming and the resulting boundary-layer reduction [ 32 ], as well as the lipid extraction [ 33 ] were investigated.

One of the dominating mechanism for the enhancement of skin permeability is acoustic cavitation [ 26 , 34 ]. With respect to stable cavitation, the inertial cavitation results in higher permeability enhancement of the stratum corneum in ultrasound-assisted skin permeabilization [ 26 ].

The bubbles diameter that initially nucleate is inversely proportional on ultrasound frequency. Using LFS, the large bubbles form outside the skin, become unstable and implode powerfully near the solid stratum corneum surface resulting in a jet of fluid, referred to microjet. When these microjets affect the stratum corneum, they erode the dead cells and help to permeate the membrane [ 35 — 37 ].

Tang et al. They reported that cavitation, occurring outside the skin, plays the pivotal role in the skin permeation effect, while internal cavitation has no effect in the skin permeability [ 38 ]. Focusing on the NPs-assisted ultrasound as the aim of this review, a first study supporting the delivery of oligonucleotides by the application of LFS 20 kHz, 2.

Similarly, Tran et al. High intensity focused ultrasound HIFU , also called focused ultrasound surgery FUS [ 5 ], is a non-invasive method where high intensity ultrasonic waves are applied locally in a focal zone. This increment results in a complete and irreversible cell death through coagulative necrosis in the focal region, minimizing the possibility of thermal damages to the tissues outside the irradiated region [ 1 ]. Non-thermal effects as acoustic cavitation, microstreaming and radiation forces also occur [ 8 ] inducing shear stress causing membrane damage and cell death [ 7 ].

With a different modulation of exposure time, number of pulses and duty cycles it is possible to obtain predominantly thermal or non-thermal effects in the focal region [ 41 ], limiting i.

HIFU was investigated for the treatment of various types of primary solid tumors and metastasis, including prostate, breast, kidney and liver.

Moreover, HIFU was also proposed as a novel approach capable to ablate heart ectopic foci and to obtain hemostasis in acute traumatic injuries [ 7 ] and for the treatment of Alzheimer disease [ 43 ]. HIFU was also successfully used to promote the uptake of various molecules, as antineoplastic drugs, antibodies, genes and others [ 44 ], increasing temporarily the cell permeability, thanks to the capability of ultrasound to temporarily increase the cell permeability [ 8 , 45 ], as described more in details below.

Moreover, a possibility is to enhance the drug release in a target region using HIFU by disrupting the drug trapping vesicles [ 46 ]. Despite of many promising outcomes, there are some limitations to this therapeutic approach. In particular, the achievement of elevated temperatures when the region of interest is deep or hypervascularized can be problematic. Actually, a solution could be to enhance the acoustic power or the exposition time, however it would increase the risk of side effects, as skin burns and nerve injury [ 47 , 48 ].

Thus, various types of micro and nano—bubbles [ 49 ], as well as other particles [ 50 ], were proposed in combination with HIFU for therapy and diagnostic imaging. These structures are indeed able to enhance HIFU-associated mechanical effects, providing cavitation nuclei [ 48 ]. Furthermore, they increase the acoustic attenuation with a consequent temperature rise [ 51 ], reducing the ultrasound intensity and the exposure time required to obtain bioeffects [ 47 ].

This ultrasound-based permeation technique allows for the transfer of molecules between the intra- and extra-cellular medium [ 52 — 54 ]. Actually ultrasound can be used to temporarily render permeable the cell membrane allowing for the uptake of drugs, DNA and other therapeutic compounds from the extracellular environment [ 55 ].

Several sonoporation mechanisms were proposed and the main hypotheses of trapped microbubble interaction with cells are the push and pull mechanisms, micro-jetting, micro-streaming, and, more recently, translation of microbubbles through cells. Since the membrane alteration is transient, it leaves the drug trapped inside the treated cells after sonication.

Even if the biophysical mechanism that results in the enhancement of the cell membrane permeability under ultrasound needs further elucidation, it was reported that sonoporation is not due to inertial cavitation, but to micro-streaming and shear stresses related to stable oscillations [ 56 , 57 ].

In in-vitro experiments the dissolved gas in the culture medium is sufficient so that the sonication itself generates cavitation bubbles. Sonoporation is thus induced. In contrast, in in-vivo applications the lungs are very efficient at clearing out small bubbles from the circulatory system.

Therefore micro and nanobubbles have to be added to induce sonoporation through ultrasound irradiation [ 58 ]. In oncological research several in vitro studies have shown ultrasound-induced membrane permeability.

This mechanism has increased the uptake of anti-cancer drugs such as bleomycin, adriamycin, [ 59 , 60 ] and cisplatin both in-vitro and in-vivo [ 61 ]. Moreover, transcranial delivery by low-frequency ultrasound can be employed to temporarily disrupt the blood brain barrier BBB and thus enhance drug diffusion through microbubbles [ 62 ]. Administration of microbubbles further reduces the intensity threshold for temporarily BBB disruptions, thus allowing for much lower and safer frequencies to be applied than in their absence [ 63 ].

The targeted BBB disruption could also support the delivery of chemotherapeutic agents for brain tumors, which normally do not penetrate the BBB.

More specifically, the delivery of liposome-encapsulated doxorubicin to the BBB was first investigated. The treated regions showed significantly higher concentrations of doxorubicin than the contralateral side.

Moreover, the concentration of the drug in the brain tissue was observed to growth linearly with increasing the microbubble concentration [ 64 ]. Beside the use of sonoporation with chemotherapeutic molecules, this method is particularly suitable for the delivery of free nucleotides, which are otherwise prevented to cross the plasma membrane due to their negative charge and large size [ 57 , 65 ]. Efficient gene transfer by sonoporation was achieved when the applied ultrasound frequencies are close to those used clinically.

Typically they extend from 0. Significant results were obtained in-vitro as well as in-vivo with focused ultrasound [ 66 ]. The level of gene expression reported after sonoporation treatments is one or two orders of magnitude higher than the level obtained with plasmid DNA alone.

However, it remains lower than that obtained with chemical vectors [ 67 ]. This limitation is probably ascribable to the main difficulty in the field of ultrasound-assisted gene delivery. It consists in the lack of homogeneity both in the sonication set-up and of the acoustic conditions.

Biological systems have demonstrated very high spatiotemporal location and timing sensitivity to cues and drugs. Polymer-based drug delivery systems are able to achieve a constant rate of release.

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At present, ultrasound radiation is broadly employed in medicine for both diagnostic and therapeutic purposes at various frequencies and intensities. In this review article, we focus on therapeutically-active nanoparticles NPs when stimulated by ultrasound. We therefore focus on the sonodynamic therapy and on the possible working mechanisms under debate of NPs-assisted sonodynamic treatments. We support the idea that various, complex and synergistics physical—chemical processes take place during acoustic cavitation and NP activation. Different mechanisms are therefore responsible for the final cancer cell death and strongly depends not only on the type and structure of NPs or nanocarriers, but also on the way they interact with the ultrasonic pressure waves.

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