In preclinical models, gold nanoparticles have been investigated as promising contrast agents across several imaging modalities, with reported improvements in tumor visualization and treatment planning [1]. Gold nanoparticles have been investigated as alternative contrast agents to traditional iodine-based contrast agents used in radiation therapy and computed tomography (CT)-based imaging modalities, which are associated with potential side effects and limitations despite their widespread use [3]-[5]. Traditional iodine-based contrast agents have been found to be limited in their usage due to its “fast clearance, short imaging times, requirement for high doses of radiation exposure from CT, and insufficient contrast resolution” [8]. Gold’s higher atomic number (Au, 79) than iodine (I, 53) permits higher absorption and augmentation of ionization radiation and better X-ray attenuation for diagnostics and imaging [8]. At typical energy ranges used for clinical CT imaging, gold nanoparticles have a higher mass-energy X-ray absorption coefficient than traditional iodine, demonstrating 2.7 times greater attenuation per unit weight (Figure 3) [8]. Gold particles have also been demonstrated to serve as superior contrast agents in higher X-ray/photon energies (80 - 100 keV) [8]. With its ability to attenuate X-ray through its higher weight, gold prevents soft tissues from absorbing radiation, lowering patient radiation exposure levels. Simultaneously, gold’s physical properties permit increasing image quality at lower radiation doses [9]. The decrease in imaging time, stability, and circulation time can be explained by the higher molecular weight of gold nanoparticles and the various ways they can be functionalized by conjugation to numerous biological surface molecules [2][3]. Gold nanoparticles are intravenously injected into tumor tissue either by passive enhanced permeability and retention (EPR)-assisted accumulation or target delivery, and prior preclinical studies have reported significant CT contrast enhancement [10][11].

Figure 3. Mass-energy absorption coefficient of gold versus iodine. This figure demonstrates that gold’s mass-energy absorption coefficient is greater in comparison to iodine, the traditional base for CT contrast agents, indicating gold’s superior X-ray attenuation and contrast. This image was taken from Dorsey et al., “Gold nanoparticles in radiation research: potential applications for imaging and radiosensitization”, Translational Cancer Research, 2013 [Vol 2] [No 4].

Gold nanoparticles demonstrate adjustable optical properties due to their surface plasmon resonance, which lies in the visible range of the spectrum [1][4][5]. The localized surface plasmons (LSP) can be observed at the interface between gold and a dielectric when a photon interacts with the nanoparticle, which results in absorption (electron-hole excitations) [4]. Gold nanoparticles demonstrate enhanced light absorption at their plasmon resonance and highly efficiently convert this light into heat, which is constricted to the direct area of the nanoparticle. As a result, nanoparticles can be used in local applications targeting specific tumor tissues.

Gold contrast agents are seen as “molecular CT imaging platforms for tumors that are undetectable by structural and anatomical imaging modalities” [8]. According to Popvetzer et al., the gold nanoparticles coated with tumor-selective antibodies bind to carcinoma cells, leading to the accumulation of attenuation coefficient [10]. The accumulation leads to five times greater CT attenuation compared to non-targeted cancer cells and normal cells. The technique is advantageous because of its ability to target antigens of cells that are metastasizing [8]. In murine studies, Reuveni et al. showed this ability when nude mice were injected with EGF-conjugated gold nanoparticles. The head and neck cancers of these mice showed contrast enhancement that were not detected under conventional CT [11]. Additionally, anti-CD4-target gold nanoparticles have been shown to enhance X-ray contrast of peripheral lymph nodes, which can help with radiation treatment planning for targeting tumors and normal organs [12].

In addition to enhancing CT imaging, gold nanoparticles have also been investigated as magnetic resonance imaging (MRI) contrast agents. Gold nanoparticles have also been investigated as MRI-related contrast platforms for two main reasons: 1) “improved sensitivity” relative to CT at low concentrations (the sensitivity of CT imaging of AuNPs tends to fall off at a concentration of about 0.5 mg/mL), and 2) the potential to provide complementary pathological or molecular information when combined with other imaging modalities [13]. Currently, gold nanoparticles are still being investigated in many different imaging methods. For example, researchers are currently exploring gold-iron oxide micellar formulation as a contrasting agent for CT and MRI imaging of tumors in mice. Choi et al. demonstrated gold-iron oxide micellar formulation through the use of hybrid FePt-Au nanoparticles in molecular MR imaging and other biological detection modalities and of dumbbell-shaped Au-Fe₃O₄ nanoparticles as MR imaging agents [14]. Collectively, these studies suggest that GNPs can improve contrast performance under selected experimental conditions; however, the evidence remains dominated by preclinical imaging models, and comparative human data remain sparse. Human clinical evidence remains limited.

Radiation oncology consists of multiple technologies delivering cytotoxic ionizing radiation to malignant tumors. These technologies have taken advantage of various particle types, dose fractionation, and radiation doses in order to most effectively increase therapeutic benefits while minimizing harm to nearby normal organs [2]. The main adverse effect of radiotherapy is unnecessary radiation delivered to surrounding tissues, which may induce toxicities, organ failure, and consequent complications [1]. Thus, researchers and physicians have been working to discover better ways to provide radiation therapy with increased cytotoxicity to cancerous cells while limiting dosage to normal organs. Since the past two decades researchers have found some potential of gold nanoparticles to target cancerous cells as radiosensitizers [3]-[5].

Radiation sensitization is a process of enhancing the susceptibility of tumor tissues to injury by radiation. Gold nanoparticles’ use as a radiosensitizer has received considerable interest from their ability to improve radiotherapeutic effects [6]. Gold nanoparticles are able to scatter and absorb high-energy photons, which leads to more accurate targeting of cellular components with tumor tissues to allow for more precise damage [15]. The goal is to maximize the tumor damage while limiting the amount of radiation doses to healthy tissue. Currently, usage of gold nanoparticles as a radiosensitizer is still being tested for effectiveness in cancer imaging and cancer treatment in mice and in human cells in vitro [3]. The theory behind how gold nanoparticles influence radiation is by locating the tumor cell and binding to it, improving local tumor imaging, hence better defining the target volume during the treatment planning process. Gold nanoparticles have a high atomic number (Z), resulting in more electrons and greater mass energy absorption of photons, which provides a much better contrast compared to soft tissue [3][5][6]. When combined with the idea that GNPs coalesce at the tumor site, imaging of cancer cells and their sites will improve. Additionally, gold nanoparticles have been shown to enhance radiation dosage to the cancer cells based on their properties in absorbing photons [2][3]. In murine studies, Hainfield et al. found that upon intravenous injection of 1.9 nanometer diameter gold particles into mice with breast cancer (mammary carcinomas), there was an 86% one-year survival rate as compared to 20% in the control arm when both study arms were given high energy x-ray treatment [1]. This positive finding is attributed to higher tumor-to-normal-tissue ratio of gold nanoparticle concentration, which was 8:1 (Figure 4). Specifically, “radiation alone induced tumour growth delay; however,

Figure 4. The graph depicts the photon mass energy absorption of gold compared to soft tissue. The ratio of mass energy absorption coefficients is shown as a function of photon energy. Image was taken from Butterworth et al., “Radiosensitization by gold nanoparticles: effective at megavoltage energies and potential role of oxidative stress”, Translational Cancer Research, 2013 [Vol 2] [No 4].

radiation and AuNPs actually led to a dramatic reduction in tumour growth when assessed 1 month after treatment” [15]. However, the mechanism for these results is still under investigation, as many factors such as gold nanoparticle shape, size, concentration and type of cell lines, and radiation energy and type may account for the uncertainty of gold nanoparticle effectiveness [6]. In vitro findings suggest similar positive effects in HeLa cells, although the results remain inconclusive [15][16]. Thus, although currently research is in support of the development of gold nanoparticles as dosage enhancers for radiation treatment, more information must be determined before clinical phase trials can begin.

In theory, the potential of gold nanoparticles for radiation dose enhancement exists, but there are realistic limitations that still need to be examined. While benefits in vitro and in vivo (in mice) have been determined, there are realistic procedural issues, including the ability of intravenous injection of AuNPs to access deeper tissue, even concentration of gold particles within the desired target, and the longevity of the AuNPs in the bloodstream [4]. In addition, the ideal radiation dosage and AuNP concentration within a tumor have yet been realized, as current testing of these variables provide inconsistent results [4][6]. Thus, in order for human effectiveness and efficacy trials to utilize this new approach to heavy-atom radiation therapy, more research must be done to make gold nanoparticles realizable in patient treatment.

Gold nanoparticles have been tested to see if they induce radiosensitization at megavoltage energy, despite previous research illustrating that radiosensitization occurs at kilovoltage energy [3] (Figure 5). As a result of modern testing, there has been more research that shows that radiosensitization has shown to occur at megavoltage energy, which is the typical energy used in current radiation therapy [1][2][3][13]. For example, Jain et al. showed similar radiosensitization in breast cancer when comparing dose enhancement of megavoltage energy with dose enhancement of kilovoltage energy [16]. Recently, research has demonstrated gold nanoparticles enhance tumor-killing efficiency at megavoltage and illustrate similar efficiency for kilovoltage and megavoltage [4]. Dorsey et al. reported that gold nanoparticles can exhibit radiosensitization at megavoltage radiation energies [15]. Studies are being conducted to analyze how gold nanoparticles can affect radiosensitization at different ranges of energy [15][16].

Another mechanism for gold nanoparticles in radiosensitization through enhancing “radiation damage by inducing cellular responses such as cell cycle acceleration, cytokinesis arrest, increased apoptosis, and reactive oxygen species (ROS)-induced DNA damage” [15][16]. In vitro findings suggest that gold nanoparticles can enhance radiosensitization through multiple biological mechanisms; however, the extent to which these effects translate to clinical radiation therapy remains uncertain. Across cell lines and animal studies, there are various degrees of radiosensitization and tumor cell killing [15][16]. In one example, Hainfield et al. demonstrated that injecting gold nanoparticles into mice caused accumulation, and mammary carcinoma killed through radiation [17]. In another example,

Figure 5. An image schematic of radiation interactions with gold nanoparticles relating to downstream applications in radiation research. Top, Compton scattering in which an incident photon is scattered by a weakly bound outer-shell electron. This process causes the photon to be deflected and lose energy, which is transferred to the electron which is ejected from the atom. Bottom: Photoelectric ionisation in which an incident photon is fully absorbed by an inner-shell electron, transferring energy to it and causing it to be ejected from the atom. Outer-shell electrons can fall into this vacancy, liberating further energy, often in the form of additional secondary Auger electrons. This image was taken from Butterworth et al., “Radiosensitization by gold nanoparticles: effective at megavoltage energies and potential role of oxidative stress”, Translational Cancer Research, 2013 [Vol 2] [No 4].

Chang et al. illustrated gold nanoparticles accumulation within melanoma cells, which then led to enhancing “the efficacy of ionizing radiation, inducing tumor cell apoptosis, retarding tumor growth, and resulting in significantly increased survival in tumor-bearing mice” [18]. There have been more results showing gold nanoparticles radio-enhancement for head and neck squamous cell carcinoma, prostate cancer, ovarian cancer, glioma cells, and brain tumors, leading to “enhanced DNA damage, tumor cell killing, and improved survival” [15][18][19]. The results from these studies suggest that gold nanoparticles cause higher efficacy in killing tumor cells, potentially leading to higher local control and survival rate. Importantly, reported radiosensitization is not uniform across studies and appears sensitive to nanoparticle design, intracellular localization, radiation energy, and tumor model, which limits straightforward clinical extrapolation. Human clinical evidence remains limited.

In preclinical studies, proton radiotherapy has been reported to show greater tumor-killing efficacy when tumors are loaded with gold nanoparticles. Polf et al. showed that loading gold nanoparticles into prostate cancer cells had an “increased ionization density and lower survival fraction when irradiated with proton beams compared to cells exposed to proton therapy alone” [20]. They discovered a significant increase of around 15% - 20% of proton therapy effectiveness when tumors are loaded with gold nanoparticles compared to proton therapy alone. They attribute this effect to “proton-Au scatter interactions and production of low energy delta-ray electrons, which result in lethal intracellular damage and lower cell survival for any given proton dose” [20]. In another recent study, Kim et al. demonstrated the irradiation of protons with injection of gold nanoparticles and discovered “significant dose enhancement with increased intracellular ROS generation in vitro as well as increased tumor regression and mouse survival in vivo, due to release of secondary electrons and particle-induced radiation” [15][19][21].

Chemotherapy treatment is used for many types of cancers. In many cases, chemotherapy is given with radiation, referred to as chemo-radiation therapy [22]. Chemo-radiation therapy has been shown to improve outcomes in selected cancer types and stages, although it may also increase toxicity compared with chemotherapy or radiation alone [22]. In preclinical models, gold nanoparticles are being examined for their potential to lower the levels of toxicity during chemoradiation therapy. Also, gold nanoparticles have been shown to improve the synergy between chemotherapy and radiotherapy, leading to more therapeutic efficacy [22][23].

Studies have shown that the effects of gold nanoparticles on lowering toxicity for chemoradiation can be attributed to their molecular size. Because of their bigger size, gold nanoparticles have unique biodistribution when bound to chemo drugs [22]. Nanoparticles are unable to fit into the smaller vessels of normal vasculature and capillaries, and therefore travel into tumor vasculature [24][25]. The lower drug concentration in normal vasculature results in reduced treatment toxicity [22]. Also, gold nanoparticles’ larger size allows for it to be removed from circulation in two ways; through the mononuclear phagocytic system (MPS) and hepatic excretion [24]. The systematic clearance of nanoparticle-bound-chemo drugs will decrease the duration and area of exposure when compared to smaller molecules chemotherapeutics, which have multiple secretion routes in the body [22][24]. Although nanoparticle-mediated delivery may reduce systemic exposure in some models, these benefits should be interpreted cautiously because biodistribution and tumor uptake remain highly context dependent. Human clinical evidence remains limited, and the magnitude of benefit in patients remains uncertain.

Gold nanoparticles have been shown to improve chemoradiotherapy through the enhanced permeability and retention (EPR) effect. Tumor angiogenesis causes rapid proliferation of endothelial cells that are poorly aligned, which leads to pores and leaky blood vessels [23] (Figure 6). Nanoparticles travel through these pores and blood vessels to reach the tumor. Unlike normal cells where the lymphatic system is able to clear out macromolecules, the irregular and rapid proliferation of tumor cells leads to defective lymphatic system. A defective lymphatic system allows for the nanoparticles to accumulate within the tumor by prevention of excretion of the nanoparticles [22][26]. The buildup of nanoparticles then leads to the enhancement of “irregular tumor vasculature structure, high vascular density within the tumor, increased tumor vessel permeability, and defective lymphatic drainage”, creating the EPR effect [25][27]-[29]. Radiotherapy further enhances the target of tumors with the nanoparticles and drug concentrations accumulated at the tumor location because of the EPR effect (Figure 7). Studies have shown that accumulated nanoparticles can irradiate tumors better than non-irradiated tumors [30][31]. In selected preclinical models, gold nanoparticles may improve therapeutic efficacy by allowing lower chemotherapy dosing and potentially reduced toxicity [30].

Despite substantial interest in gold nanoparticles for oncologic imaging and therapy,

Figure 6. A diagram representing how differences in tumor vessel tissue can influence the localization of chemotherapy. This image is from Upreti et al. “Tumor microenvironment and nanotherapeutics”, Translational Cancer Research, 2013 [Vol 2] [No 4].

Figure 7. Diagram of lung cancer chemotherapy delivery comparing small molecule drugs (a) to nanoparticles (b). This image was taken from Eblan et al., improving chemoradiotherapy with nanoparticle therapeutics, Translational Cancer Research, 2013 [Vol 2] [No 4].

clinical translation remains limited. Most published evidence remains preclinical, and comparisons across studies are complicated by major differences in particle size, shape, surface coating, tumor model, delivery route, and radiation energy [8][15][23]. As a result, findings from one platform cannot be assumed to generalize across all GNP formulations.

Safety also remains an important limitation. Although bulk gold has a history of medical use, nanoparticle formulations should not be broadly described as uniformly safe or non-toxic. Their biological effects depend on physicochemical properties such as size, coating, dose, route of administration, circulation time, organ accumulation, and clearance. Concerns remain regarding persistence in the reticuloendothelial system, delayed hepatic clearance, and possible renal or off-target tissue effects [32].

Another major translational challenge is tumor delivery [25][29]. Many studies rely on the enhanced permeability and retention (EPR) effect to explain nanoparticle accumulation; however, EPR-based delivery is heterogeneous across tumor types and is not uniformly reliable in human tumors [25][29]. This limits the predictability of intratumoral uptake and may reduce the consistency of therapeutic benefit in clinical settings [8][25][29][33].

The current clinical evidence base is also narrow. Only a limited number of nanoparticle-based formulations have advanced to early-phase clinical evaluation, and these examples should be interpreted carefully. Gold-based platforms such as CYT-6091 and AuroShell particles illustrate translational efforts involving gold-containing systems, whereas NBTXR3 is a hafnium oxide nanoparticle and should be considered a non-gold comparator rather than a gold nanoparticle clinical example [23][34].

Finally, large-scale clinical implementation will require improved manufacturing reproducibility, tighter control of nanoparticle size and surface functionalization, standardized characterization methods, and clearer regulatory pathways. Until these issues are addressed, gold nanoparticles should be viewed as promising but still investigational tools in cancer imaging and treatment [35]-[37].