Research Article Nanoparticle augmented radiation treatment decreases cancer cell proliferation Helen E. Townley, PhD a, * , Elizabeth Rapa, PhD b , Gareth Wakefield, PhD c , Peter J. Dobson, PhD a a Department of Engineering, Oxford University, Oxford, United Kingdom b Department of Obstetrics & Gynaecology, Oxford University, John Radcliffe Hospital, Oxford, United Kingdom c Oxford Advanced Surfaces, Oxford, United Kingdom Received 13 December 2010; accepted 4 August 2011 Abstract We report significant and controlled cell death using novel x-ray-activatable titania nanoparticles (NPs) doped with lanthanides. Preferential incorporation of such materials into tumor tissue can enhance the effect of radiation therapy. Herein, the incorporation of gadolinium into the NPs is designed to optimize localized energy absorption from a conventional medical x-ray. This result is further optimized by the addition of other rare earth elements. Upon irradiation, energy is transferred to the titania crystal structure, resulting in the generation of reactive oxygen species (ROS). From the Clinical Editor: The authors report significant and controlled cell death using x-ray-activated titania nanoparticles doped with lanthanides as enhancers. Upon irradiation X-ray energy is transferred to the titania crystal structure, resulting in the generation of reactive oxygen species. © 2012 Elsevier Inc. All rights reserved. Key words: Cancer; Nanoparticles; Titania; Radiotherapy Despite surgery, radiation and chemotherapy treatments, cancer is one of the principal causes of death in developed countries and is responsible for 25% of mortalities in the United Kingdom. 1 Nanoscale structures have the potential to radically change cancer therapies, providing noninvasive access to the interior of a living cell. Studies have shown that nanoparticles (NPs) of titania can be stimulated by ultraviolet (UV) light to produce reactive oxygen species (ROS) for photodynamic therapy. 2 Titania is a wide bandgap semiconductor that is known to exhibit a high photoactivity and generate ROS following excitation of valence band electrons to the conduction band by absorbed photons. Although it is effective, this technique is limited to tumors on or just under the skin, or on the lining of internal organs or cavities due to the limited penetration depth of UV light; consequently deep tissue or large tumors cannot be treated by this method. 3 It is known that the same photoelectrochemical reactions observed under UV irradiation are also promoted under x-ray irradiation. 4 The key advantage of x-ray activation is its ability to penetrate the human body and thus achieve noninvasive photocatalytic treatments. It is hypothesized that the interaction of titania NPs with x-rays could be optimized by the addition of rare earth (RE) elements as dopants. The probability of an x-ray photon being absorbed or scattered by a particular material is a function of its photon interaction cross-section. A greatly enhanced photoelectric cross- section can be derived from the introduction of a material with a high atomic number (Z) as the cross-section scales as Z. 4 If a high Z element could be readily and specifically incorporated into cells and then exposed to photons of energy just above the binding energy of the innermost orbital (K edge), a selective absorption might be induced when the differential cross-section peaks sharply in comparison with tissue. 5 One such element that has precedent in medical diagnostics is gadolinium (for a review see Villaraza et al 6 ), which has an x-ray photon interaction cross-section significantly greater than the elements that comprise biological tissue. For example, the photoelectric cross-section for gadolinium at 51 keV is 4500 barns in comparison with 0.19 barns for carbon. 7 Furthermore, gadolinium has been shown to protect excited electrons from rapid recombination when incorporated BASIC SCIENCE Nanomedicine: Nanotechnology, Biology, and Medicine 8 (2012) 526 – 536 nanomedjournal.com Helen Townley was supported by the South East England Development Agency. Elizabeth Rapa was supported by the Camilla Samuel Fund. ⁎ Corresponding author: Tel.: +44 01865 283792; fax: +44 01865 374992. E-mail address: helen.townley@eng.ox.ac.uk (H.E. Townley). 1549-9634/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.nano.2011.08.003 Please cite this article as: H.E. Townley, E. Rapa, G. Wakefield, P.J. Dobson, Nanoparticle augmented radiation treatment decreases cancer cell proliferation. Nanomedicine: NBM 2012;8:526-535, doi:10.1016/j.nano.2011.08.003