Porphyrins and their derivatives

Porphyrins and their derivatives are the most widely studied organic sonosensitizers with excellent sonosensitizers efficiency and catalytic properties. Porphyrins and their derivatives have no anti-tumor activity but show sonodynamic activity when subjected to ultrasound. For example, HP, HP methyl ether, ATX-70, PpIX, etc [ ]. Porphyrins, as first-generation photosensitizers, are widely used in PDT, and they are also the first generation of sonosensitizers [ ]. In 1990, Umemura et al. confirmed that ultrasound combined with HP could enhance the killing effect on cells through in vivo and in vitro experiments. They proposed the anti-tumor mechanism of HP activated by ultrasound to produce ROS for the first time [ ]. HP monomethyl ether (HMME) is a second-generation HP-related sensitizer of two porphyrins. Sun et al. investigated the anti-tumor effect of HMME-mediated SDT on endometrial cancer cells. SDT promotes ROS production, decreases MMP, and increases intra-cellular Ca ²⁺ concentration. This induces apoptosis in endometrial cancer cells [ ]. PpIX, a protoporphyrin derivative, is an essential representative of carboxy-modified porphyrin. Wang et al. examined the effect of PpIX on hepatoma cell line H22 in the presence of low-intensity ultrasound. The results confirmed that SDT using PpIX combined with ultrasound successfully induced apoptosis of H22 cells, and a series of events occurred in the mitochondria during the death process, including the release of mitochondrial protein cytochrome c, the redistribution of Bcl-2 family proteins Bid and Bax, and the reduction of mitochondrial membrane potential [ ].

However, aggregation of conventional sonosensitizers occurs under physiological conditions, resulting in poor water solubility and pharmacokinetic performance. Moreover, the accumulation of porphyrin molecules can affect the energy transfer between porphyrin and oxygen molecules, resulting in low ROS production, which needs to be solved urgently. Zinc phthalocyanine (ZnPcs) as photosensitizers exhibit high photodynamic ROS production due to their high conversion efficiency from singlet to triplet states. According to these unique properties, ZnPcs are promising sonosensitizers. Recently, artemisinin derivatives have been found to have sonodynamic activity. Zhao et al. [ ] designed a phthalocyanine artesunate conjugate (ZnPcT4A) that produces twice as much ROS as porphyrin IX. Biological studies have shown that ZnPcT4A has high anti-cancer activity and biological safety, which opens up a new way to develop efficient organic sonosensitizers.

Non-porphyrin derivatives

Some dye-based compounds have also been used in SDT, such as fluorescein, bamboo erythromycin B, eosin, erythropoietin, etc. RB B is a basic fluorescent dye that was once used as a food additive. Umemura et al. [ ] treated sarcoma cells with rose red B under ultrasound and found significant damage to sarcoma cells, deducing that rose red produced singlet oxygen under ultrasound. Zou et al. [ ] investigated the sonodynamic damage of BSA induced by fluorescein and its derivatives. The UV spectrum showed a noticeable hyperchromic effect, and the fluorescence spectrum showed quenching. This indicates that BSA is significantly damaged, disulfide bonds are broken, and tryptophan and tyrosine are exposed. Eosin B red powder is easily soluble in water, the solution has green fluorescence, and it is soluble in ethanol. Biostain and histology were used to stain epithelial cells, muscle fibers and nuclei. He et al. [ ] also demonstrated the sonodynamic activity of eosin B by the method described above, and an increase in the concentration of eosin B led to a greater degree of cell damage. Wang et al. [ ] The bacterial family unit formation and viability tests were used to observe the changes in Staphylococcus aureus after sonication and hypoxia-erythromycin B. The permeability and DNA fragmentation of the CM were also studied. The results showed that when the concentration of hypocretin was 500 μM and the ultrasonic irradiation time was 50 minutes, the S. aureus was significantly destroyed. At the same time, it was found that the DNA was not broken, and the integrity of the CM was lost. It was concluded that hypoxigenin caused the death of S. aureus by damaging the CM and increasing the membrane permeability under ultrasound.

The killing ability of some anti-tumor drugs, such as cisplatin, daunorubicin and adriamycin, is significantly enhanced when combined with ultrasound. Cisplatin has cytotoxicity, inhibiting the DNA replication process of cancer cells and damaging their CM structures. It is clinically used in ovarian cancer, prostate cancer and so on. Irajira et al. [ ] A sonosensitive nanoplatform (ACA) consisting of alginate coloaded with cisplatin and gold nanoparticles (AuNPs) was constructed. When stimulated with ultrasound, cisplatin showed a solid ability to induce cancer cell death, demonstrating the anti-tumor effect of the ACA nanoplatform in combination with ultrasound. The thermal and mechanical effects of ultrasound can enhance the therapeutic effect of conventional chemotherapy methods. Doxorubicin (DOX), a commonly used anthracycline anti-biotic used to treat a variety of cancers, causes DNA damage, apoptosis, production of oxygen and hydroxyl radicals, and enhances cavitation effects. An et al. [ ] prepared a degradable hollow polydopamine nanoparticle (P@HP) by co-loading DOX and Ce6 and modified by mitochondrial triphenylphosphonium (TPP) to encapsulate platinum nanoparticles (Pt). Under ultrasound, the nanocomposite enriches the tumor site by enhancing the permeability and retention effect of solid tumors, followed by killing tumor cells by releasing DOX to inhibit cellular DNA replication.

Some natural products can produce sonosensitivity under ultrasound due to their unique properties. CUR, the main component of curcuma longa, has anti-tumor effects and low toxicity to normal cells. In addition, CUR can also induce tumor cell apoptosis as a sonosensitizer. To introduce more functions and prepare more efficient sonosensitizers, Zhu et al. [ ] prepared CUR-loaded poly ( l -lactic-co-glycolic acid) microbubble (CUR-PLGA-MB). They found that CUR-PLGA-MB had a more significant anti-tumor effect in PDT compared to SDT or PDT and that CUR-PLGA-MB was a promising sound/photosensitizer.

Although these sonosensitizers all have strong sonodynamic effects, most organic sonosensitizers have poor water solubility, unstable properties in the microenvironment and short blood circulation time, which cannot accumulate in large amounts at the tumor site to produce enhanced EPR effect [ ]. Therefore, finding new science and technology to effectively improve the defects of existing sonosensitizers and exploring new sonosensitizers are urgent problems to be solved in SDT.