Efficacy of radiosensitizing doped titania nanoparticles under hypoxia and preparation of an embolic microparticle

Abstract

The aim of this study was to develop a manufacturing protocol for large-scale production of doped titania radiosensitizing nanoparticles (NPs) to establish their activity under hypoxia and to produce a multimodal radiosensitizing embolic particle for cancer treatment. We have previously shown that radiosensitizing NPs can be synthesized from titania doped with rare earth elements, especially gadolinium. To translate this technology to the clinic, a crucial step is to find a suitable, scalable, high-throughput method. Herein, we have described the use of flame spray pyrolysis (FSP) to generate NPs from titanium and gadolinium precursors to produce titania NPs doped with 5 at% gadolinium. The NPs were fully characterized, and their capacity to act as radiosensitizers was confirmed by clonogenic assays. The integrity of the NPs in vitro was also ascertained due to the potentially adverse effects of free gadolinium in the body. The activity of the NPs was then studied under hypoxia since this is often a barrier to effective radiotherapy. In vitro radiosensitization experiments were performed with both the hypoxia mimetics deferoxamine and cobalt chloride and also under true hypoxia (oxygen concentration of 0.2%). It was shown that the radiosensitizing NPs were able to cause a significant increase in cell death even after irradiation under hypoxic conditions such as those found in tumors. Subsequently, the synthesized NPs were used to modify polystyrene embolization microparticles. The NPs were sintered to the surface of the microparticles by heating at 230°C for 15 minutes. This resulted in a good coverage of the surface and to generate embolization particles that were shown to be radiosensitizing. Such multimodal particles could therefore result in occlusion of the tumor blood vessels in conjunction with localized reactive oxygen species generation, even under hypoxic conditions such as those found in the center of tumors.

Chemical Mechanisms of Nanoparticle Radiosensitization and Radioprotection: A Review of Structure-Function Relationships Influencing Reactive Oxygen Species

“…Furthermore, iron can dissociate and further undergo Haber-Weiss and Fenton reactions to generate, and propagate, ROS [78]. Titanium and copper have also been shown to dissociate metal ions and interact with antioxidants and other enzymes within the cell, enhancing ROS [5,136]. Nanoparticles can also be designed to transport more oxygen to allow for higher ROS generation.…”

“…Modifying the nanoparticle's chemical and physical structure also has implications on ROS generation and can be demonstrated by comparing different crystal structures of titanium dioxide. Anatase titanium dioxide generates ROS more readily than a rutile structure due to an increased surface area to volume ratio and stability [5,113,119,149]. In another example, Seo et al used gadolinium oxide and gadolinium chelate nanoparticles to compare the difference in the atomic bonds and the effects of the "core-inner-valence excitation" under irradiation.…”

“…Hence, the inherently hypoxic microenvironment within many solid tumours leads to radioresistance. [1,2,[4][5][6]. While it is possible to deliver a radiation dose sufficient to overcome hypoxia and induce cancer cell death, in many instances this is practically not feasible due to dose limitations of normal tissues.…”

A comparison of the radiosensitisation ability of 22 different element metal oxide nanoparticles using clinical megavoltage X-rays

“…already been made using radiosensitisers based on TiO 2 NPs (Nakayama et al 2016;Morrison et al 2017;Townley et al 2012). We consider that the future of NP radiosensitisers most probably lies in the combination of high Z elements with catalytic oxides: using the photoelectric effect of high Z elements to feed secondary electrons into the catalyst.…”

“…However, NPs of many lower atomic number element oxides have been shown to be effective radiosensitisers, such as: Al (Roth et al 2011), Si (David Gara et al 2012;Generalov et al 2015;Zhao et al 2016), Ca (Chu et al 2013), Ti (Morrison et al 2017), Fe (Khoei et al 2014), Cu (Jiang et al 2019), Zn (Generalov et al 2015), Zr (Carrasco-Flores and LaVerne 2007). This suggests that other, physico-chemical and chemical processes, likely involving the nanoparticle surface, contribute to the overall pool of X-ray-induced radicals.…”