# Advances in Purpurin 18 Research: On Cancer Therapy
## 5 Sonodynamic Therapy and Sonophotodynamic Therapy  
Another noninvasive approach of cancer treatment is sonodynamic therapy (SDT). It is a method discovered and derived based on PDT. In PS evaluation, it was found that, for example, porphyrin [54; 55; 56; 57], pheophorbide [57; 58], and/or pu18 derivatives [59] used in PDT show similar effects and cell damage after ultrasound application as detected after photoactivation. The main principle of SDT is identical to PDT. The SDT method is based on a combination of low-intensity ultrasound and a sonosensitive agent (ST), which is activated by ultrasound (Figure 5). However, the mechanism of ST activation and ROS formation in SDT is not exactly known. The action of ultrasound generates heat in the target tissue and, also, acoustic cavities. These can occur in two states: stable cavities, which oscillate in an aqueous environment, leading to fluid flow, and inertial cavities, which are characterized by rapid enlargement and subsequent sharp collapse (implosion). During the collapse of these cavities, a large amount of heat (\(\geq\)5000 K) and pressure (\(\geq\)800 atm.) is released [60; 61]. This can lead to a series of chemical reactions inside, on, or around the collapsing cavitation bubble, which is often referred to as a sonochemical reactor [62]. Typically, pyrolysis or thermal dissociation of water may occur here, which may lead to ST activation and, also, to ROS production. However, some authors suggest that ST activation occurs differently due to sonoluminescence. Sonoluminescence is described as the emission of light that can occur when cavities collapse. This emitted light could thus activate the ST, similarly to that in PDT. However, scientists do not fully agree on this mechanism either [63]. It is, thus, likely that the mechanism of SDT action is a combination of several factors, which depend on the ST and the parameters of the ultrasound used. Although the exact mode of action of SDT  
Figure 5: General principles of sonodynamic therapy. The action of ultrasound activates the sonosensitive agent and its transition to a higher energy state. When returning to the basic energy state, the energy generated is transformed in the form of heat, acoustic cavities, or light (sonoluminescence). As a result of these processes, reactive oxygen species (ROS) are formed, which leads to damage of the mitochondrial membrane, the release of cytochrome c (cyt c), and triggering a cascade leading to cell death. has not been elucidated, SDT has tremendous potential in the treatment of cancers. An indisputable advantage of SDT over PDT is the deep penetration of ultrasound into soft tissues, which can be even more than 10 cm [64]. As some PSs can be used as STs, it is possible to combine both approaches as SDT-PDT. Recently, [PERSON] et al. [65] have described the development of a new tumor-specific and multi-activatable drug called nano-riceball that can be used in SDT. This is a multilayer micelle with a size of 96.8 nm, the core of which is constructed of amphipathic bottlebrush-like dextran-based polymer (DOS), which carries in its structure the anticancer drug DOX and pu18, as a potent ST. This construct is denoted as DDP. For specific tumor cell targeting, the upper layer of the DDP is covered by a bioengineered cell membrane [66], which carries the target motif of the Asn-Gly-Arg (NGR) peptide [67]. It is recognized by various isoforms of the CD13 receptor (aminopeptidase N), which occurs on the membrane of many types of tumor cells and, thus, it is a suitable target for the delivery of anticancer drugs (Figure 6). In this way-targeted drug nano-riceball (NGR\({}^{\text{\textregistered}}\) DDP) is preferentially captured on the surface of tumor cells, and is transported into the cells by endocytosis. [PERSON] et al. [68] found that NGR\({}^{\text{\textregistered}}\)DDP accumulates in HepG2 cells within 3 h of treatment.