Pancreatic cancer is a highly lethal disease that is often diagnosed only in the advanced stage. It is the fourth most common cause of cancer-related deaths in the United States, causing 40,560 deaths annually [
1]. Moreover, the 5-year survival rate of pancreatic cancer patients is approximately 3-7 % after diagnosis [
1,
2]. Locally advanced pancreatic cancer is also notoriously resistant to many types of cytotoxic chemotherapy and radiotherapy [
3]. As a result, there are currently no effective therapies for pancreatic cancer, and novel strategies need to be explored.
The biological application of nanoparticles (NPs) is rapidly increasing in nanotechnology and introduces new possibilities for the diagnosis and treatment of human cancers [
4‐
6]. NPs have been used in many different areas of radiation oncology, including radiosensitization [
7]. Nano-sized titanium dioxide (TiO
2) is one of the most widely produced nanoparticles. TiO
2 is poorly soluble and has been used in numerous applications as a food colorant, or as a white pigment in a number of products including cosmetics, medicines, and pharmaceutical products [
8,
9]. Rutile and anatase are the two major crystalline forms of TiO
2. The photocatalytic activity and cytotoxicity of anatase TiO
2 nanoparticles (TiO
2NPs) are higher than those of the rutile forms [
10,
11]. Recently, TiO
2NPs have been used in the phototherapy of malignant cells and are regarded as potential photosensitizing agents for photodynamic therapy because they exert unique phototoxic effects upon ultraviolet (UV) irradiation [
12‐
16]. Despite the promising effects of UV-activated TiO
2NPs, this strategy seems to be ineffective in treating many cancers and is difficult to apply clinically for two major reasons. First, UV light cannot penetrate the human body to reach internal organs such as the gastrointestinal system, liver, and pancreas, thus limiting the application of this technique to superficial tumors [
17]. Second, the UV-mediated production of reactive oxygen species (ROS) occurs for a very short duration and is insufficient to provide a continuous and prolonged cancer-killing effect [
18]. Radiotherapy using X-rays is known to be effective in various cancer treatments. However, to our knowledge, there are few reports investigating whether or not TiO
2NPs can enhance the effects of X-ray irradiation [
19]. In addition, the properties of TiO
2NPs seem to be insufficient to render them useful as radiosensitizers. Wang et al. demonstrated that the potential biological effects of TiO
2NPs depend on their size, crystal phase, surface coating, and chemical composition [
20]. Therefore, certain modifications may be necessary to make TiO
2NPs suitable for use as agents that enhance the effects of radiation.
Chemical reactions between hydrogen peroxide and TiO
2 have been widely investigated [
21,
22], but the effects of these reactions on the properties of TiO
2NPs in response to X-ray irradiation have not been clarified. In this study, we investigated the properties of titanium peroxide nanoparticles (TiOxNPs) to determine whether the TiOxNPs might be useful as potential agents to enhance the effects of radiation against a human pancreatic cancer model in vitro and in vivo.