Radiosensitization Effect of Gold Nanoparticles in Proton Therapy

Abstract

The number of proton therapy facilities and the clinical usage of high energy proton beams for cancer treatment has substantially increased over the last decade. This is mainly due to the superior dose distribution of proton beams resulting in a reduction of side effects and a lower integral dose compared to conventional X-ray radiotherapy. More recently, the usage of metallic nanoparticles as radiosensitizers to enhance radiotherapy is receiving growing attention. While this strategy was originally intended for X-ray radiotherapy, there is currently a small number of experimental studies indicating promising results for proton therapy. However, most of these studies used low proton energies, which are less applicable to clinical practice; and very small gold nanoparticles (AuNPs). Therefore, this proof of principle study evaluates the radiosensitization effect of larger AuNPs in combination with a 200 MeV proton beam. CHO-K1 cells were exposed to a concentration of 10 μg/ml of 50 nm AuNPs for 4 hours before irradiation with a clinical proton beam at NRF iThemba LABS. AuNP internalization was confirmed by inductively coupled mass spectrometry and transmission electron microscopy, showing a random distribution of AuNPs throughout the cytoplasm of the cells and even some close localization to the nuclear membrane. The combined exposure to AuNPs and protons resulted in an increase in cell killing, which was 27.1% at 2 Gy and 43.8% at 6 Gy, compared to proton irradiation alone, illustrating the radiosensitizing potential of AuNPs. Additionally, cells were irradiated at different positions along the proton depth-dose curve to investigate the LET-dependence of AuNP radiosensitization. An increase in cytogenetic damage was observed at all depths for the combined treatment compared to protons alone, but no incremental increase with LET could be determined. In conclusion, this study confirms the potential of 50 nm AuNPs to increase the therapeutic efficacy of proton therapy.

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

“…Gold nanoparticles (AuNPs) have been widely utilized in biomedicine due to their biocompatibility, nontoxicity, size, shape-controlled optical and electronic properties, and suitability for bioconjugation. , These unique features also make AuNPs promising candidates in different applications including drug delivery, imaging, and sensing . Recently, AuNPs are also emerging as nanosensitizers in radiation therapy using X-rays , and protons, while particularly proton therapy (PT) with NPs as sensitizers is a hot topic for tumor treatment. , PT has recently received a lot of attention due to a more conformal absorbed dose delivery to the tumor cells with a much lower adverse effect on healthy tissues in comparison to conventional X-ray (photon) therapy. − PT is hence highly relevant in treating tumors near sensitive organs such as the brain, especially in children. It has been previously shown in many studies that metallic NPs can enhance the efficacy of PT − via specific mechanisms, e.g., secondary electron emission or catalytic reactions occurring at the NP–water interface .…”

Biodegradable Ultrasmall-in-Nano Architectures Loaded with Cisplatin Prodrug in Combination with Ionizing Radiation Induces DNA Damage and Apoptosis in Pancreatic Ductal Adenocarcinoma

“…Although a few studies have investigated the effect of gold USNPs in combination with radiation, it remains difficult to compare the results as size, shape, surface charge and coating can influence the effect in biological systems [ 32 , 33 ]. Therefore, we also investigated the effect of our gold USNPs at a diameter of 3 nm with and without radiation.…”

“…Of note, GNP-associated toxicity has been reported previously in both normal and tumor cells, as they can be chemically reactive to other vital cellular structures, including the membrane and mitochondria and accumulate in organs such as the spleen, liver and kidney in rats [ 45 , 46 , 47 ]. While our gold USNP-loaded NAs did not induce significant alterations in reproductive functions nor toxic side effects in zebrafish larvae, further investigation and monitoring for long-term periods are of importance, in particular when combining with IR [ 32 ]. Furthermore, the choice to encapsulate gold USNPs instead of using itself as a vehicle such as our NAs, could improve unspecific binding in various tissues.…”

Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy

“…It is important to highlight that some nanocarriers themselves, such as high atomic number nanoparticles (mainly gold nanoparticles), act as radiosensitizers by enhancing radiation energy deposition in the cells. This strategy has been recently reviewed elsewhere [103,104] and is not the focus of the present review. Herein, we describe nanocarriers designed to encapsulate and deliver radiosensitizing molecules.…”