Enhancement of Proton Therapy Efficiency by Noble Metal Nanoparticles Is Driven by the Number and Chemical Activity of Surface Atoms

Abstract

Proton‐based radiotherapy is a modern technique for the treatment of solid tumors with significantly reduced side effects to adjacent tissues. Biocompatible nanoparticles (NPs) with high atomic numbers are known to serve as sensitizers and to enhance treatment efficacy, which is commonly believed to be attributed to the generation of reactive oxygen species (ROS). However, little systematic knowledge is available on how either physical effects due to secondary electron generation or the particle surface chemistry affect ROS production. Thereto, ligand‐free colloidal platinum (Pt) and gold (Au) NPs with well‐controlled particle size distributions and defined total surface area are proton‐irradiated. A fluorescence‐based assay is developed to monitor the formation of ROS using terephthalic acid as a cross‐effect‐free dye. The findings indicate that proton irradiation (PI)‐induced ROS formation sensitized by noble metal NPs is driven by the total available particle surface area rather than particle size or mass. Furthermore, a distinctive material effect with Pt being more active than Au is observed which clearly indicates that the chemical reactivity of the NP surface is a main contributor to ROS generation upon PI. These results pave the way towards an in‐depth understanding of the NP‐induced sensitizing effects upon PI and hence a well‐controlled enhanced therapy.

Catalytic activity imperative for nanoparticle dose enhancement in photon and proton therapy

“…We thus concluded that (i) proton irradiation led to lower nanoparticle excitation compared to X-rays, and (ii) the energy spectrum (150 kVp vs. 6 MV) of the X-rays had an influence on the electron–hole pair generation for high- Z nanoparticles (HfO 2 and WO 3 ) but not for TiO 2 nanoparticles. Au nanoparticles also possess the ability to generate ROS under X-ray 41 , 47 , 48 or proton 49 irradiation. Using 150 kVp X-rays and acellular ROS assays, Au NPs were found to generate additional •OH radicals 48 .…”

Disproportional surface segregation in ligand-free gold–silver alloy solid solution nanoparticles, and its implication for catalysis and biomedicine

“…Next to these unintended use scenarios, nanoparticle-induced ROS is further discussed as one of the most critical pathways in the anti-tumor efficiency of sensitizers in irradiation therapy 3 . Here, a recent study suggested a correlation between therapy-enhancing effects of Pt and Au nanoparticles in proton therapy and catalytic surface reactions 4 . Another important research field is single atom catalysts which are discussed as relevant materials for biomedical applications 5 .…”

Impact of Sterilization on the Colloidal Stability of Ligand-Free Gold Nanoparticles for Biomedical Applications

“…As we have already demonstrated that different sterilization methods have a significant impact on the stability of colloidal AuNPs, it is critical to investigate how different NP sterilization methods affect PT enhancement, as a case study. According to a recent report, 16 both the surface dose and surface chemistry of the NPs play an inevitable role in ROS production in NP-assisted irradiation therapy, and hence any processing of the particles that may hamper the surface properties should be excluded. Here, particle growth may reduce the specific surface area, thus decreasing the expected boosting effects of NPs in proton treatment.…”

“…This again underlines that for smaller AuNPs, sterile filtration is more effective than the steam sterilization technique from the application point of view, considering the scaling of ROS generation with the available particle surface area. 16 A decrease in the ROS generation could also be attributed to defect healing through the surface restructuring through coalescence, 101 as defects are known for their enhancing effect in, for example, the oxygen evolution reaction, which leads to the generation of ROS. 102 The immediate cooling of generated particles in LAL due to the surrounding liquid often leads to the kinetic stabilization of defect-rich and metastable phases.…”

“…It has been previously shown in many studies that metallic NPs can enhance the efficacy of PT 13−15 via specific mechanisms, e.g., secondary electron emission or catalytic reactions occurring at the NP− water interface. 16 Although the underlying mechanism is yet to be fully understood, most studies point toward the generation of reactive oxygen species (ROS) in the presence of metallic NPs, which leads to higher death rates of the targeted tumor cells in PT. 17 Because of its high atomic number, density, biocompatibility, and chemical inertness, Au is one of the most studied elements in NP-assisted PT.…”