Sonodynamic Antitumor Effect of Protoporphyrin IX Disodium Salt on S180 Solid Tumor

Abstract

Background: The sonodynamically induced antitumor effect of protoporphyrin IX (PPIX) disodium salt was studied in mice bearing sarcoma 180 solid tumors. Methods: In order to determine the optimum timing of ultrasound exposure after administration of PPIX, the PPIX concentrations in plasma, skin, muscle and tumor were estimated by measuring the fluorescence intensity of tissue extractions with a fluorescence photometer based on the standard curve. Antitumor effects were estimated by measuring tumor size and calculating the average survival time of tumor-bearing mice after sonodynamic therapy; additionally, the morphological changes of sarcoma 180 cells were evaluated by transmission electron microscope observation in vivo. Results: Our experiments suggested a time of 24 h after the administration of PPIX to be best for ultrasound exposure. At an ultrasound intensity ≧5 W/cm² and a PPIX dose ≧5 mg/kg, a significant synergistic effect of ultrasound combined with PPIX was observed, reducing tumor volume and increasing average animal survival time; this synergistic effect was obviously stronger than ultrasound treatment alone, while PPIX alone showed no significant effect. Transmission electron microscope observation indicated that changes in cell ultrastructure, such as cell membrane destruction, mitochondria swelling and chromatin condensation, were important factors that inhibited tumor growth and even induced cell death. Conclusion: The results implied that the antitumor effect of ultrasound could be enhanced in the presence of PPIX which might be involved in a sonochemical mechanism.

Sonodynamic therapy inhibits angiogenesis and tumor growth in a xenograft mouse model

“…In contrast, a long DUI allows diffusion of the sonosensitizer into the tissue, to be accumulated in the tumor cellular compartment, so that the subsequent sonication will generate more direct tumor cytotoxicity (i.e., cellular-targeting sonosensitization). SDT is usually thought to maximize its therapeutic effect on tumors and minimize side effects on the surrounding healthy tissues when the sonosensitizer ratio of tumor to normal tissue is maximal [8,11]. However, in recent years, increasing evidence in photodynamic therapy (PDT) accumulated suggests that plasma concentration (which reflects endothelial cell exposure) correlated better with the therapeutic effect than tumor concentration [38][39][40][41][42].…”

“…Furthermore, the energy of the ultrasound wave can be focused on sites of malignancy and, thus, locally activate sonosensitizers that have preferentially accumulated in tumor tissues, causing injuries to desired cells with minimal damage to peripheral healthy tissue. Currently, studies of SDT have mainly focused on its direct killing effects on tumor cells [8][9][10][11][12]. Many mechanisms had been proposed by different research groups, including apoptosis [13][14][15][16][17] and autophagy [18,19].…”

“…Protoporphyrin IX (PpIX), as a hematoporphyrin derivative, is one of the most commonly used sonosensitizers [8,11,13,16]. In addition to an exogenous supply of PpIX itself, the accumulation of PpIX in tissues or cells may be produced by administration of its precursors, such as 5-aminolevulinic acid (ALA) or ALA derivatives [20][21][22][23][24].…”

Bioeffects of Low-Energy Continuous Ultrasound on Isolated Sarcoma 180 Cells

“…These morphological cell changes occurring immediately after exposure may be due to an ultrasonic mechanical effect. The plasma membrane is a dynamic and complex structure which connects the cell with the environment and coordinates most intercellular communication; changes on the surface of the cell membrane will subsequently affect membrane functions and eventually lead to cell lysis, apopto- sis and necrosis [19][20][21] . In addition, membrane LPO and hydroxyl radicals were generated in the culture medium immediately after treatment, and results showed that the LPO levels and hydroxyl radicals in the cell suspensions were obviously increased after 30 s of ultrasound exposure (p !…”

A Review of Low-Intensity Ultrasound for Cancer Therapy

“…The therapy's effectiveness has also been demonstrated in more deeply located tumors including those of the central nervous system (Ohmura et al 2011; Gao et al 2013; Jeong et al 2012). Post-therapy histologic studies have consistently shown damage to the ultrastructure of the cancer cells including destruction of cell membranes, mitochondrial swelling and chromatin condensation (Liu et al 2006[b], 2007[a, b], 2008; Wang et al 2008[a], 2011[c], 2012[b]); it was considered that these changes induced by the therapy may have mediated cancer cell death. Combining photodynamic therapy with sonodynamic therapy had a synergistic effect in solid tumors with additional post-therapy tumor necrosis, inhibition of tumor growth and increased survival times (Jin et al 2000; Tserkovsky et al 2012).…”