Exploring the Potential of Gold Nanoparticles in Proton Therapy: Mechanisms, Advances, and Clinical Horizons

Abstract

Proton therapy represents a groundbreaking advancement in cancer radiotherapy, leveraging the unique spatial energy distribution of protons to deliver precise, high-dose radiation to tumors while sparing surrounding healthy tissues. Despite its clinical success, proton therapy faces challenges in optimizing its therapeutic precision and efficacy. Recent research has highlighted the potential of gold nanoparticles to enhance proton therapy outcomes. Due to their high atomic number and favorable biological properties, gold nanoparticles act as radiosensitizers by amplifying the generation of secondary electrons and reactive oxygen species upon proton irradiation. This enhances DNA damage in tumor cells while preserving healthy tissues. Additionally, functionalization of gold nanoparticles with tumor-targeting ligands offers improved precision, making proton therapy more effective against a broader range of cancers. This review synthesizes current knowledge on the mechanisms of gold nanoparticle radiosensitization, preclinical evidence, and the technological hurdles that must be addressed to integrate this promising approach into clinical practice, aiming to advance the efficacy and accessibility of proton therapy in cancer therapy.

Keywords: cancer therapy; gold nanoparticles; precision medicine; proton therapy; radiosensitization; reactive oxygen species.

Figure 5

A diagram illustrates various ways AuNPs can be modified for use in developing miRNA-based therapies. AuNPs come in various shapes (such as spheres, rods, cages, and shells) and possess unique properties that can be customized by attaching different functional groups. These include oligonucleotides, like anti-miRNAs and synthetic miRNAs, which may themselves be modified with thiol groups or fluorescent tags. Additionally, the nanoparticles can be conjugated with polymers to enhance stability and biocompatibility, targeting ligands to increase specificity for cancer cells, chemotherapeutic drugs, or even other nanomaterials. Furthermore, many of these functional molecules can be designed to be released in response to specific external or internal triggers, such as light exposure or changes in pH. Reproduced with permission from Sousa and Conde, ACS, 2022, licensed under cc-by-nc-nd 4.0 [139].

Figure 1

Main biological barriers that NPs must overcome to enable precise drug delivery. More advanced NP designs, which enhance delivery efficiency, can substantially increase the effectiveness of precision medicines, thereby speeding up their transition to clinical use.

Figure 2

Scheme of different methods for synthesis of AuNPs. Created by BioRender.com.

Figure 3

Influence of the protein corona on particle–immune cell interactions. Reproduced from Sarma et al., 2022 [77], with permission from Elsevier.

Figure 4

Mechanisms of nanoparticle radiosensitization in PT. (a) Processes of ionization and emission of proton-induced X-rays and Auger electrons resulting from interactions between protons and target atoms. (b) Process of Auger cascade. (c) Illustration of increased physical dose deposition and enhanced radiolysis in cancer cell with presence of nanoparticles. Reproduced with permission from Ma et al., Cells, published by MDPI, 2024 [7].

Figure 6

Size distribution (A) and TEM micrograph (B) of AuNPs and related SAED pattern (C). TEM micrograph of U87MG glioblastoma cells incubated with AuNPs for 24 h. AuNPs are highlighted in an endosomal compartment, as indicated in the magnification (D). N = nucleus, M = mitochondria, E = endosomal compartment.