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.
High-precision radiotherapy with proton beams is frequently used in the management of aggressive soft tissue sarcoma (STS) and is often combined with doxorubicin (Dox), the first-line chemotherapy for STS. However, current treatment approaches continue to result in high local recurrence rates often occurring within the treatment field. This strongly indicates the need of optimized treatment protocols taking the vast heterogeneity of STS into account, thereby fostering personalized treatment approaches. Here, we used preclinical STS models to investigate the radiation response following photon (X) or proton (H) irradiation alone and in combination with different treatment schedules of Dox. As preclinical models, fibrosarcoma (HT-1080), undifferentiated pleiomorphic sarcoma (GCT), and embryonal rhabdomyosarcoma (RD) cell lines were used; the latter two are mutated for TP53. The cellular response regarding clonogenic survival, apoptosis, cell-cycle distribution, proliferation, viability, morphology, and motility was investigated. The different STS cell types revealed a dose-dependent radiation response with reduced survival, proliferation, viability, and motility whereas G2/M phase arrest as well as apoptosis were induced. RD cells showed the most radiosensitive phenotype; the linear quadratic model fit could not be applied. In combined treatment schedules, Dox showed the highest efficiency when applied after or before and after radiation; Dox treatment only before radiation was less efficient. GCT cells were the most chemoresistant cell line in this study most probably due to their TP53 mutation status. Interestingly, similar additive effects could be observed for X or H irradiation in combination with Dox treatment. However, the additive effects were determined more frequently for X than for H irradiation. Thus, further investigations are needed to specify alternative drug therapies that display superior efficacy when combined with H therapy.
Sterilization is a major prerequisite for the utilization of nanoparticle colloids in biomedicine, a process well examined for particles derived from chemical synthesis although highly underexplored for electrostatically stabilized ligand-free gold nanoparticles (AuNPs). Hence, in this work, we comprehensively examined and compared the physicochemical characteristics of laser-generated ligand-free colloidal AuNPs exposed to steam sterilization and sterile filtration as a function of particle size and mass concentration and obtained physicochemical insight into particle growth processes. These particles exhibit long-term colloidal stability (up to 3 months) derived from electrostatic stabilization without using any ligands or surfactants. We show that particle growth attributed to cluster-based ripening occurs in smaller AuNPs (∼5 nm) following autoclaving, while larger particles (∼10 and ∼30 nm) remain stable. Sterile filtration, as an alternative effective sterilizing approach, has no substantial impact on the colloidal stability of AuNPs, regardless of particle size, although a mass loss of 5–10% is observed. Finally, we evaluated the impact of the sterilization procedures on potential particle functionality in proton therapy, using the formation of reactive oxygen species (ROS) as a readout. In particular, 5 nm AuNPs exhibit a significant loss in activity upon autoclaving, probably dedicated to specific surface area reduction and surface restructuring during particle growth. The filtered analog enhanced the ROS release by up to a factor of ∼2.0, at 30 ppm gold concentration. Our findings highlight the need for carefully adapting the sterilization procedure of ligand-free NPs to the desired biomedical application with special emphasis on particle size and concentration.
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