Sonodynamic therapy

Currently, SDT does not have any clinical products and acts as an adjuvant for the aforementioned therapeutic methods, but it has been explored for use in atherosclerosis and cancer treatment to reduce tumor size in breast, pancreas, liver, and spinal sarcomas.

Cavitation occurs as a specific interaction between ultrasound and aqueous surroundings and causes gas bubbles to break upon exposure to particular ultrasonic parameters, thus promoting penetration of the therapeutic into the biological tissues by generating cavities near the edge of the membrane.

[1][19] Microbubbles are created by the acoustic waves from the ultrasound that expand and collapse, releasing energy, bringing the sonosensitizer into an excited state, and generating a ROS.

A study by Hachimine et al. highlights the use of SDT as a method to activate a low photosensitive sonosensitizer, DCPH-P-Na(I), for cancer that is too deep within the tissue to combat utilizing PDT without skin irritation.

[1] Single oxygen atoms or hydroxyl radicals are produced by porphyrin-based sensitizers upon exposure to ultrasound or light, providing the cytotoxic effects desired with sonodynamic and photodynamic therapies.

[1] Other sensitizers that have been investigated for their potential in sonodynamic therapy (and have also been used previously in PDT) include acridine orange, methylene blue, curcumin, and indocyanine green.

[36] As aforementioned, sonosensitizers are often used in conjunction with different drug carriers such as microbubbles, nanobubbles, liposomes, and exosomes to improve therapeutic agent concentration and penetration.

[38] Compared to the common cancer treatment chemotherapy, drugs loaded into liposomes allow for decreased systemic toxicity and a potential increase in the efficacy of targeted delivery.

[40] Another study by Ninomiya et al. utilized nanoemulsion droplets exposed to ultrasonic waves for the formation of larger gas bubbles to disrupt the liposome membrane for drug release.

Many properties and elements of liposomes can be altered for their specific purpose and to increase effectiveness, particularly their ability to travel in the blood and interact with cells and tissues in the body.

[43] Significantly increased reactive oxygen species generation was observed in breast cancer cells treated with folic acid-conjugated exosomes.

[44] Through SDT, these microbubbles could be selectively bursted at the tumor microenvironment in order to decrease systemic levels of the encapsulated drug and increase therapeutic efficacy.

[44] However, attaching the polymer poly lactic-co-glycolic acid (PLGA) to the shell resulted in increased stability compared to the lipid microbubbles without losing other desirable properties such as targeted delivery and selective cytotoxicity.

Another study performed by Nesbitt et al. has shown improved tumor reduction when gemcitabine was loaded into the microbubble and applied to a human pancreatic cancer xenograft model with SDT.

[51][50] One study by Nittayacharn et al. developed doxorubicin-loaded nanobubbles and paired them with porphyrin sensitizers to be used in SDT for treatment of breast and ovarian cancer cells in vitro.

In order to mitigate hypoxia of target tissue, Owen et al. used a pancreatic cancer rodent model to deliver phospholipid stabilized nanobubbles filled with oxygen.

[52] A statistically significant difference between the levels of oxygen in the tumors of the two groups was observed, indicating that nanobubbles could be an effective addition to SDT to treat cancers in a hypoxic environment.

[53] In another example of combining SDT with PDT, Borah et al. investigated the advantage of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HHPH), a photodynamic therapy drug, as a sonosensitizer and a photosensitizer for treating glioblastoma.

[54] The goal of a study by Browning et al. was to investigate the potential enhancement of chemoradiation efficacy through combining it with sonodynamic therapy in pancreatic cancer patients.

[1][20] Qu et al. aimed to develop an "all-in-one" nanosensitizer platform triggered by SDT that combines various diagnostic and therapeutic effects to treat glioblastoma.

Examples of sonosensitizers that have shown success in glioma treatment are hematopor-phyrin monomethyl ether (HMME), porfimer sodium (Photofrin), di-sulfo-di-phthalimidomethyl phthalolcyaninezinc (ZnPcS2P2), Photolon, 5-aminolevulinic acid (5-ALA), and rose bengal (RB).

They also showed that SDT could inhibit plaque inflammation in patients with peripheral artery disease and continue to promote positive results for longer than six months.

A study by Cheng et al. determined that THP-1 macrophage apoptosis is induced by an increase in PpiX concentration, leading to the production of large amounts of ROS.

[70][13][3] The use of SDT for AS treatment has also shown success in promoting the repopulation of vascular smooth muscle cells (VMSCs) through inducing further expression and autophagy to prevent VMSC evolution into plaque-holding macrophages.

[20][1][72] Some examples of in vitro work include initial studies that were performed by Yumita et al., 1989 who used haematoprophyrin and SDT for mouse sarcoma 180 and rat ascites hepatoma (AH) that showed a relationship between dosage and ultrasound, and microbubbles causing cavitation leading to cell damage without the use of drugs.

[21][1] Current research typically focuses on using tumor xenograft models to determine the effect of SDT on target cells and delivery efficacy.

In order to enhance the oftentimes low production of reactive oxygen species to address the hypoxic tumor environment, SDT can be combined with other therapies, such as PDT, chemotherapy, and immunotherapy to improve patient outcomes.

[2] Factors that limit the translation of organic sensitizers to clinical applications include low water solubility, sonotoxicity, and targetability as well as high phototoxiticty.

[1] Lastly, there are no current standardized computer simulations to predict the characteristics of different sonosenistizers within tissue, which would provide further insight into how sonosensitizers may behave.

Ultimately, the synergistic effects of combining SDT with other therapies would allow each to compensate for the limitations of the other, improving their therapeutic efficacy and increasing their ability to destroy tumors.