Enhancing radiotherapy for melanoma: the promise of high-Z metal nanoparticles in radiosensitization

Abstract

Melanoma is a type of skin cancer that can be challenging to treat, especially in advanced stages. Radiotherapy is one of the main treatment modalities for melanoma, but its efficacy can be limited due to the radioresistance of melanoma cells. Recently, there has been growing interest in using high-Z metal nanoparticles (NPs) to enhance the effectiveness of radiotherapy for melanoma. This review provides an overview of the current state of radiotherapy for melanoma and discusses the physical and biological mechanisms of radiosensitization through high-Z metal NPs. Additionally, it summarizes the latest research on using high-Z metal NPs to sensitize melanoma cells to radiation, both in vitro and in vivo. By examining the available evidence, this review aims to shed light on the potential of high-Z metal NPs in improving radiotherapy outcomes for patients with melanoma.

Graphical Abstract

Plain language summary

Article highlights.

• Melanoma, a lethal skin cancer from melanocytes, causes 75% of skin cancer-related deaths worldwide. Rising incidence necessitates urgent interventions.

• Traditional treatments like surgery, chemotherapy, immunotherapy and radiotherapy (RT) have limitations. Nanomedicine, using nanoparticles (NPs) sized 1–100 nm, shows promise in enhancing cancer treatment, especially high-Z metal NPs (e.g., gold, platinum, gadolinium) in improving RT outcomes for melanoma.

Radiotherapy for melanoma

• RT is vital for melanoma management, especially when surgery is not viable or cancer has spread.

• Combining RT with immune checkpoint inhibitors (ICI) improves outcomes in brain metastases.

• Fractionated RT enhances T cell responses, similar to vaccines.

• Studies suggest higher radiation doses may be more effective, with clinical studies indicating a median total dose of 30 Gy and BED >39.0 Gy10.

• High-Z metal NPs can enhance RT by targeting cancer cells precisely while sparing healthy tissue.

High-Z metal NPs for radiotherapy of melanoma

• High-Z metal NPs like gold, magnetic iron oxide, gadolinium, copper-cysteamine and platinum enhance RT efficacy while preserving healthy tissue.

• Gold NPs enhance RT through unique properties like surface plasmon resonance.

• mIONs offer RT combined with hyperthermia, enhancing therapeutic outcomes.

• Gadolinium enhances MRI and RT, with AGuIX^® NPs allowing precise imaging and targeted therapy. Other high-Z metals like copper-cysteamine and platinum enhance ROS production, improving treatment outcomes.

Nanoparticle physicochemistry & radiosensitization

• Key design factors include material, size, shape, surface coating and charge. NP size affects biodistribution and clearance, with optimal sizes for tumor uptake being 20–60 nm.

• NP concentration and surface charge impact RT enhancement and cytocompatibility.

• Synthesis methods, including chemical, physical and green, ensure biocompatibility and reduced toxicity.

• Coatings improve stability and targeting, essential for passive and active strategies, enhancing treatment efficacy.

Mechanisms of High-Z Metal NPs radiosensitization

• Radiosensitization involves physical, chemical and biological phases.

• High-Z metal NPs enhance RT through the photoelectric effect and sary electron production, increasing local radiation doses. They modulate chemical reactions, enhancing DNA damage and ROS production.

• Biologically, NPs disrupt cell cycles, delay DNA repair and induce oxidative stress, increasing tumor cell radiosensitivity.

Conclusion

• High-Z metal nanoparticles show significant promise in enhancing radiotherapy for melanoma.

• Benefits include efficient x-ray absorption, targeted delivery and induction of oxidative stress.

• Key challenges like ensuring biocompatibility, understanding mechanisms and optimizing NP design need addressing before clinical translation. Continued research is essential for developing effective and safe NP-based therapies.

Future perspectives

• Future prospects include using NPs for targeted radiation doses to melanoma cells, optimizing delivery strategies and conducting preclinical and clinical studies to validate efficacy and safety.

• Continued innovations in nanomedicine could lead to more targeted, effective and personalized cancer treatments, transforming oncology.

1. Introduction

Melanoma is a fatal type of skin cancer that results from the uncontrolled growth of melanocytes, pigment-producing cells [1]. It accounts for approximately 75% of all skin cancer-related deaths globally and can affect individuals of any age and skin color [2]. However, it usually affects fair-skinned people with significant sun exposure [2,3]. The incidence of melanoma has been consistently increasing in recent decades, emphasizing its importance as an urgent public health concern [3]. Fortunately, numerous treatment options exist for melanoma, including surgery, chemotherapy, immunotherapy and radiation therapy (RT). However, each option has limitations and may not be suitable for every patient [4]. The selection of an appropriate treatment alternative is contingent on several factors, such as the cancer stage, tumor localization and overall health condition of the patient [5]. Surgery is typically the primary mode of treatment for melanoma, with additional therapies like chemotherapy, immunotherapy, or RT being utilized in some cases [5,6]. If surgery alone cannot remove melanoma that has spread to various body parts, radiotherapy can be a treatment option [2]. However, this approach may harm the healthy tissues surrounding the tumor site, causing negative effects [2]. To address this issue, scientists have been investigating nanomedicine's application in melanoma RT [4]. Nanomedicine employs small nanoparticles that measure between 1 and 100 nanometers [7]. These tiny particles can be intended to target specific cells or tissues in the body, making them a hopeful option for cancer treatment [7,8]. The utilization of nanomedicine in treating cancer provides several advantages including boosting drug delivery to the tumor location, reducing the required drug amount and lowering the risk of adverse effects [7,9–16]. Moreover, nanoparticles can act as radiation sensitizers, enhancing the effectiveness of RT. Radiation sensitizers are agents that amplify the sensitivity of cancer cells to radiation, thus allowing lower doses of radiation to be given while still achieving the desired treatment result [17,18]. In addition to high-Z metal nanoparticles, recent studies have demonstrated that non-metallic and low-Z nanoparticles can also produce a radiosensitizing effect. For example, carbon nanoparticles [19], titanium nanoparticles [20] and iron nanoparticles [21] have shown significant potential in enhancing the sensitivity of cancer cells to radiation. These findings suggest that a broader range of nanoparticles, beyond high-Z metals, could be explored for their radiosensitizing properties. However, using nanomedicine in cancer treatment has drawbacks. One major concern is the potential toxicity of nanoparticles because their small size enables them to penetrate cells and interact with cellular components, resulting in unfavorable effects [18]. Additionally, nanoparticles tend to accumulate in particular organs or tissues in the body, which poses a risk of long-term harm [22]. Researchers have been exploring the application of high-Z metal nanoparticles in nanomedicine to tackle these concerns. Platinum, gold and gadolinium are high-Z metal nanoparticles with unique chemical and physical properties, making them an excellent prospect for cancer treatment [23,24]. For instance, gold nanoparticles have biocompatibility and can efficiently absorb x-rays, making them a desirable option for radiation sensitization [17]. In this review, we aim to provide a comprehensive overview of the current state of research on the use of high-Z metal nanoparticles as radiation sensitizers for enhanced radiotherapy of melanoma. Specifically, we will examine the methods and findings of studies investigating the efficacy and safety of nanoparticle-enhanced RT for melanoma and highlight potential future directions for research in this field. By better understanding the benefits and limitations of nanomedicine in RT for melanoma, we may develop more effective and targeted treatments for this deadly disease.

2. Radiotherapy for melanoma

RT has proven essential in managing melanoma, especially in cases where surgical options are limited or when the cancer has spread to distant body regions [25]. RT operates on a core principle wherein it employs powerful ionizing radiation to disrupt the DNA of cancer cells, inhibiting their ability to multiply and ultimately causing their demise [26]. In contrast to healthy cells, cancer cells display heightened sensitivity to radiation due to their accelerated division and diminished DNA repair capabilities [27]. The combination of RT with other approaches, like surgery and immunotherapy, has demonstrated encouraging outcomes, resulting in enhanced clinical results in certain instances [6].

The results of a phase 2 trial involving 92 patients with melanoma brain metastases (MBM) further validate the importance of combining RT with immune checkpoint inhibitors (ICI). The study examined two treatment sequences: radiation followed by ICI treatment (Rad-ICI) or ICI treatment followed by radiation (ICI-Rad). The primary objective was to assess radiological and immunological responses in peripheral blood. Multivariate analysis revealed that patients who started with RT (Rad-ICI) had a significant advantage in terms of overall response rate (RR: p = 0.007; hazard ratio (HR): 7.88 (95% confidence interval (CI): 1.76–35.27)) and disease control rate (DCR: p = .036; HR: 6.26 (95% CI: 1.13–34.71)). There was also a trend toward improved progression-free survival (PFS: p = .162; HR: 1.64 (95% CI: 0.8–3.3)). Following RT and two cycles of ipilimumab-based ICI (ipi-based ICI) in both treatment sequences, peripheral blood showed increased frequencies of activated CD4 and CD8 T cells and melanoma-specific T cell responses. Lasso regression analysis further identified significant clinical benefits for patients treated with the Rad-ICI sequence, including specific immunological features such as high frequencies of memory T cells and activated CD8 T cells. These findings support the potential superiority of sequencing RT followed by ICI treatment in patients with MBM [28].

Chandra and colleagues conducted a study involving 47 consecutive metastatic melanoma patients treated with ipilimumab followed by radiotherapy. The analysis revealed that radiotherapy resulted in a 68% response rate in the main tumor sites, with two-thirds of these lesions showing progression prior to radiotherapy. Interestingly, the effectiveness of radiotherapy on the main tumor sites was not influenced by the time interval between immunotherapy administration and RT. The researchers also observed that fractions of radiation equal to or less than 3 Gy led to the highest response rate in the main tumor sites (81% compared with 52% for higher fractions). This difference was statistically significant in univariate analysis (p = 0.014) and multivariate analysis (p = 0.027). This finding suggests that fractionated radiation may stimulate the production of antigen-specific CD8⁺ T cells, similar to the effects of a vaccine [29].

A notable instance of RT influencing the immune system in melanoma is demonstrated by a case study involving a 67-year-old man. Following axillary irradiation, the patient experienced depigmentation within the intended treatment area. Subsequently, he developed brain metastases, and after receiving whole-brain radiation therapy, depigmentation occurred both within and outside the targeted region, including sites that were not previously exposed to radiation. Remarkably, during the last follow-up visit, which took place 3 years after the onset of brain metastases, no signs of melanoma were detected in the patient. Immunological analyses indicated the presence of specific CD8⁺ T-cell and B-cell responses against melanocyte differentiation antigens, suggesting an immune-mediated effect [30]. Determining the most effective radiation dose for treating melanoma is a difficult endeavor. The objective is to administer sufficient radiation to eliminate cancer cells while minimizing harm to nearby healthy tissues. Various factors, such as the size and location of the tumor, the patient's overall health condition and the specific type of RT employed, impact the selection of the ideal radiation dose. Achieving the correct equilibrium between successful tumor eradication and reducing adverse effects is essential to ensure optimal patient outcomes [31]. Interestingly, research has revealed that administering sublethal doses of radiation can paradoxically elevate the likelihood of metastases in melanoma. This occurrence may be linked to the emergence of heightened hypoxic conditions and the upregulation of certain proteins within regenerating primary tumors [32]. In theory, melanoma cells respond better to higher radiation doses per treatment session (hypofractionation) instead of lower doses (hyper fractionation). However, determining the most effective pattern of dose fractionation continues to be a persistent challenge, and a consensus has yet to be reached [32–34].

In a clinical study involving 84 patients who underwent palliative radiotherapy for 114 metastatic lesions, the median total dose administered was 30 Gy (ranging from 6 to 64.8 Gy) and the median dose per fraction was 3.0 Gy (ranging from 1.8 to 8 Gy). The study found that lesions receiving a biologic effective dose (BED) greater than 39.0 Gy10 had a longer period of freedom from symptomatic progression (FFP) compared with those receiving lower doses (p = 0.03). The median FFP for higher doses was 7 months. In comparison, it was 4 months for lower doses. Additionally, the median survival time after radiotherapy was 3.7 months, and this was significantly associated with both the total radiation dose (p < 0.0001) and BED (p < 0.0001). Patients who received higher doses (>30 Gy or >39.0 Gy10) had a median survival of 8 months, whereas those who received lower doses had a median survival of 2 months [35].

The response of melanoma cells to RT is a complex process that is affected by multiple factors. One important factor is the presence of intra-tumor variability, which leads to variations in radiosensitivity among different clonogenic subpopulations within the tumor [33,36]. Furthermore, the response to radiation is influenced by various tumor physiological factors, including but not limited to hypoxic regions present within the tumor, intracellular glutathione levels and the kinetics of tumor cells [31,33]. To summarize, RT remains a crucial aspect of melanoma treatment and ongoing research provides hope for advancements in this field. By synergizing RT with other treatments and addressing melanoma's specific challenges, progress is being made toward improved outcomes and patients' quality of life. In this context, the use of high-Z metal NPs holds significant promise. These nanoparticles possess unique properties that make them potential candidates for enhancing the effects of radiation therapy. By utilizing high-Z metal NPs in combination with radiation, researchers aim to increase the radiation dose delivered to cancer cells while minimizing damage to healthy tissue. This innovative approach may offer a more targeted and effective treatment option for melanoma patients, improving their chances of successful outcomes and long-term well-being.

2.1. Triple combination therapy: enhancing melanoma treatment with radiotherapy, immunotherapy & nanoparticles

Recent research suggests that a promising approach for melanoma treatment involves a triple combination of radiotherapy, immunotherapy and nanoparticles. This integrative strategy aims to improve therapeutic outcomes, minimize side effects and potentially overcome resistance associated with conventional therapies. Peltek et al. demonstrated the enhanced efficiency of 188Re-labeled gold nanorods combined with laser irradiation and paclitaxel, compared with single therapies, underscoring the potential of local triple-combination therapy [37]. Zhang et al. showed significant tumor growth inhibition with Cu-Cy nanoparticles and x-ray irradiation. Apoptosis rates soared from 24.1% to 84.7% when combined, with animal studies confirming these results [38].

Sang et al. addressed tumor resistance by combining radiotherapy with anti-CTLA-4 therapy and metal-phenolic networks, showing improved efficacy with hafnium-based nanopumps (AHSC NPs) containing atovaquone and sabutoclax [39]. Xue et al. engineered rough-surface nanoparticles (JQ-1@PSNs-R), combining photothermal and immune therapies. These nanoparticles eradicated melanoma in animal models and prevented metastasis and recurrence [40]. Zhu et al. introduced NIA-D1@R848 nanoparticles, combining a radio-sensitizer, a peptide substrate and a PD-L1 antagonist with a TLR7/8 agonist, which promoted apoptosis and enhanced the antitumor immune response [41]. Chen et al. developed polydopamine-coated Al2O3 nanoparticles for combined photothermal therapy and CpG adjuvant therapy, achieving tumor eradication in 50% of treated mice [42]. Li et al. used platinum@polymer-catechol nanobrakers to enhance radio-immunotherapy, effectively modifying the tumor microenvironment and improving treatment outcomes [43].

Collectively, these studies highlight that the triple combination of radiotherapy, immunotherapy and nanoparticles not only enhances therapeutic efficacy and tumor response in melanoma treatment but also reduces therapeutic resistance and minimizes side effects associated with single therapies. This promising approach in melanoma treatment necessitates further research to determine optimal clinical protocols and assess long-term effects.

3. High-Z metal NPs for radiotherapy of melanoma

The quest to conquer melanoma has propelled researchers into an innovative realm where nanotechnology holds tremendous promise. Among the most compelling advancements are nanoparticles, with gold and magnetic iron oxide nanoparticles (mIONs) leading the charge. These minuscule marvels exhibit remarkable radiosensitizing capabilities, augmenting the potency of RT while preserving healthy tissues. In parallel, gadolinium-based contrast agents have redefined medical imaging, enabling real-time monitoring and targeted therapeutic interventions. Additionally, high-Z metals, including copper-cysteamine and platinum nanoparticles, have emerged as captivating players, employing synergistic strategies for combating cancer. This section delves into the exciting research underpinning these pioneering nanotechnological breakthroughs, offering a glimpse into the future landscape of melanoma treatment. While our review focuses on high-Z metal nanoparticles, it is important to acknowledge that non-metallic and low-Z nanoparticles, referred to as ‘Radiation-activated NPs’, also contribute significantly to radiosensitization. Recent studies have shown that carbon, titanium and iron nanoparticles exhibit remarkable radiosensitizing effects, providing a broader understanding of the potential for various types of nanoparticles to enhance radiotherapy [19–21]. Supplementary Table S1 provides a concise summary of the radiosensitization observed in melanoma by applying high-Z metal nanoparticles.

3.1. Gold nanoparticles

The irradiation of gold nanoparticles with a wavelength greater than their sizes caused the polarization of d electrons through oscillation, leading to surface plasmon resonance [44]. Active research is underway on cancer imaging and diagnostic biosensors that utilize this property [45,46]. The size and shape of gold nanoparticles can alter their distinct optical properties. When the size is approximately 25 nm, spherical gold nanoparticles demonstrate a unique ultraviolet absorption at 540 nm. Additionally, the absorption tendency of these nanoparticles shifts toward red as their size increases [47]. Gold nanoparticles can be utilized for photothermal therapy if their absorption band is adjusted to near-infrared. In a study conducted by Trinidad et al., they synthesized gold nanoshells that could produce combined photothermal and photodynamic effects, ultimately eliminating cancer cells through the generation of ROS and induced oxidative stress [48]. Gold microsphere solution was utilized by Herold et al. in 2000 to test for x-ray dose enhancement effects on Chinese hamster ovary cells (CHO-K1), mouse breast cancer cells (EMT-6) and human prostate cancer cells (DU-145) [49]. Following this, several studies were conducted to assess the radiosensitizing impact of gold nanoparticles and other high-Z metal nanoparticles in various kinds of cancer, including melanoma. Gold nanoparticles have been investigated as radiation sensitizers since the early 2000s when researchers started exploring the potential of nanotechnology in cancer treatment. The unique physicochemical properties, biocompatibility and ease of functionalization of gold NPs made them promising candidates. Early studies primarily focused on determining their ability to augment the effects of radiation therapy, which led to a growing interest in using gold NPs as radiosensitizers for treating melanoma [50,51]. Various methods have been used to utilize them. The following section will highlight several important studies implemented in this field. In some studies, gold nanorods conjugated with arginine-glycine-aspartate peptides (RGD-GNRs) were used as radiation sensitizers in combination with photothermal therapy [52,53]. The αvβ3 receptor is highly expressed on the surface of A375 melanoma cells. RGD-GNRs bind to these receptors, which increases the concentration of RGD-GNRs on the surface and cytoplasm of these cancer cells. According to the study conducted by Li et al., exposing A375 cells to RGD-GNRs increased their sensitivity to radiation, resulting in a dose-modifying factor (DMFSF2) of 1.28. However, no significant effect was observed when NIR (near-infrared radiation) was used alone as a treatment (DMFSF2 = 1.02). Nonetheless, the combination therapy of RGD-GNRs and NIR resulted in an amplification of the radiosensitizing impact, with a DMFSF2 of 1.41 [52]. Therefore, using gold nanoparticles in radiotherapy combined with photothermal therapy holds promise as an effective therapeutic method for melanoma. A comparative study was performed by Mohammadi et al. that focused on the Mel-Rm melanoma cell line to evaluate and contrast the efficacy of radiotherapy and photodynamic therapy (PDT) utilizing 5-aminolevulinic acid (5-ALA) conjugated gold nanoparticles. The ED50 value, which represents the dose required to achieve 50% cell death, was lower for photodynamic therapy (56.2 J/cm2) than for x-ray treatment. The study suggests that photodynamic therapy was more effective than x-ray treatment in killing melanoma cells. The transport of 5-ALA into cells was enhanced by utilizing GNPs as a delivery agent. This increased the formation of protoporphyrin IX (PpIX), which generates reactive oxygen species upon exposure to light and selectively destroys cancer cells due to its higher accumulation in cancerous tissues. However, despite its effectiveness, PDT has limitations in managing large or metastatic tumors and pain during treatment, which were observed in this study that suggested PDT was more effective than traditional x-ray treatment [54]. In some other methods, carriers such as liposomes are used to deliver gold nanoparticles to cancer cells. In one study, lipid nanocapsules were used to transport amphiphilic gold nanoparticles into tumor cells, potentially enhancing the effectiveness of radiotherapy [55]. A study by Bemidinezhad et al. investigated the impact of liposomes containing gold ions and glucose-coated gold nanoparticles on melanoma cell radiation sensitivity. Gold-Lips performed better than gold nanoparticles with their larger size, better stability and higher biocompatibility. They increased gene expression related to apoptosis, reduced cell survival gene expression and enhanced DNA damage and cell death. These findings suggest that gold-containing liposomes can serve as effective radiosensitizers for treating melanoma [56]. So, the use of liposomes as carriers show promise in enhancing radiotherapy's effectiveness and as effective radiosensitizers for treating melanoma, offering potential advancements in cancer treatment.

These approaches offer potential advancements in cancer treatment that could improve outcomes for patients with melanoma. Although further research is needed to understand these methods' efficacy and safety fully, the findings thus far suggest that they hold great promise for the future of melanoma treatment.

3.2. Magnetic iron oxide nanoparticles

mIONs offer an exciting opportunity to combine radiotherapy and hyperthermia for enhanced cancer treatment. When exposed to an external magnetic field, these nanoparticles possess magnetic properties that enable targeted heat generation within tumor tissues. When combined with radiotherapy, the localized heating effect of mION-based hyperthermia sensitizes cancer cells to radiation-induced damage, leading to improved therapeutic outcomes. This dual approach enhances the efficacy of radiation treatment and provides a synergistic effect that selectively targets tumor cells while minimizing harm to healthy tissue. Integrating mIONs with radiotherapy and hyperthermia holds great promise for advancing cancer therapy and improving patient outcomes [57,58]. In recent studies, the radiosensitizing effects of iron oxide nanoparticles (IONPs) have been further explored. One study highlighted the radiosensitizing effect of two formulations of IONPs (7 nm carboxylated IONPs and PEG5000-IONPs) on A549 lung carcinoma cells. This study revealed that these nanoparticles enhance radiation effects not solely through physical mechanisms but also by inhibiting detoxification enzymes such as thioredoxin reductase. The correlation between radiation amplification at 2 Gy and the residual activity of thioredoxin reductase emphasized the biological impact of these nanoparticles [21].

Another significant study assessed the in vitro radiosensitizing effect of citrate-coated superparamagnetic iron oxide nanoparticles (SPIONs) at 6 MV energies. This research demonstrated that the highest radiosensitization occurred in radiosensitive cell lines MCF-7 and MDAH-2447 at a dose of 2 Gy, and in relatively radioresistant MDA-MB-231 cells at 4 Gy. The study concluded that SPIONs exhibit dose-dependent and cell-line specific radiosensitization, possibly through synergistic effects [59]. A study was carried out by Duval et al. to investigate the effects of low thermal doses generated by magnetic nanoparticle hyperthermia (mNPH) on gene and protein expression in melanoma cells; researchers demonstrated that mNPH increased the expression of genes and proteins associated with anti-cancer immune responses and cell death pathways. This included the activation of cytokine–cytokine receptor pathways, toll-like receptor signaling pathways and apoptosis pathways. These findings suggest that mNPH can stimulate immune cell recruitment and inflammatory responses, potentially augmenting cancer therapy [60]. Hoopes and colleagues conducted a research study that explored the combination of mNPH with radiotherapy in treating canine oral melanoma in dog models. The study incorporated mNPH alongside virus-like nanoparticles (VLPs) as immune adjuvants during RT. The results revealed that incorporating mNPH in the RT regimen led to increased infiltration of immune cells. in the tumor and extended control over tumor growth. High-frequency RT combined with mNPH showed the highest level of immune cell infiltration. Higher concentrations of immune cells, particularly leukocytes, within the tumor, were associated with improved clinical outcomes [58]. These studies collectively highlight the potential of mION-based hyperthermia in treating melanoma. By leveraging the unique properties of mIONs, such as targeted heat generation and enhanced radiation sensitivity, this approach offers the possibility of more effective therapies while minimizing damage to healthy tissues [58,60]. Furthermore, mIONs offer imaging capabilities that enable real-time monitoring of their distribution within the tumor using techniques like MRI. This provides healthcare professionals valuable insights into treatment response during hyperthermia and radiotherapy sessions, facilitating personalized therapeutic strategies [61]. While further research is needed to optimize treatment protocols and ensure long-term safety, the potential benefits of mION-based hyperthermia in combination with radiotherapy for melanoma treatment are significant. Continued advancements in this field may lead to more effective and precise therapies for melanoma patients, improving outcomes and quality of life.

3.3. Gadolinium

Gadolinium (Gd) is a special element with a preferred oxidation state of +3. It has a unique arrangement of electrons, with eight unpaired ones [62]. In the field of medical imaging called MRI, Gadolinium has a bigger effect on how quickly water molecules in our bodies relax and return to their normal state (called longitudinal relaxation) compared with how quickly they lose their phase coherence (called transverse relaxation) [63,64]. The ‘relaxivity’ of Gadolinium refers to its ability to change the relaxation rate of nearby water molecules. We calculate the relaxivity by comparing the differences in relaxation rates and adjusting for the concentration of the contrast agent. Gadolinium chelates are compounds that bind to Gadolinium ions. They are used as contrast agents in MRI scans to make certain tissues stand out more in images [63]. Scientists have been studying different structures of Gadolinium complexes, like polymers, dendrimers and liposomes, to improve relaxivity. They consider factors such as how these structures move, how water molecules exchange around them, the distance between the Gadolinium and the water and the relaxation rate. By optimizing these factors, they can enhance the effects of Gadolinium-based contrast agents in MRI [63]. Theranostics is an exciting field that combines therapy and diagnostics. It allows doctors to treat and monitor diseases at the same time. Gadolinium is crucial in theranostics because it is a powerful contrast agent for accurate imaging. This helps guide targeted therapies and improves treatment outcomes [65]. AGuIX^® is an advanced nanoparticle technology that combines Gd with radiotherapy and MRI, representing a cutting-edge approach in the field [66]. These nanoparticles have a core made of gadolinium, which acts as a highly potent contrast agent for MRI scans. By leveraging the unique properties of AGuIX^®, the nanoparticles accumulate specifically in tumor tissues, enabling precise imaging of the tumor site. When used in conjunction with radiotherapy, AGuIX^® nanoparticles enhance treatment outcomes significantly [67]. The presence of gadolinium within the nanoparticles amplifies the energy deposition within the tumor when exposed to ionizing radiation, thereby improving the destruction of cancer cells during radiotherapy [67]. This integration of AGuIX^® nanoparticles with radiotherapy and MRI offers numerous benefits. First and foremost, it allows for real-time monitoring of treatment response through MRI, facilitating timely adjustments to the therapy plan. Furthermore, these nanoparticles serve as targeted imaging agents and greatly improve the accuracy of tumor visualization. Additionally, AGuIX^® nanoparticles enhance the sensitivity of cancer cells to radiation, potentially leading to improved therapeutic outcomes [68,69]. A study was conducted by Kotb et al. to investigate the potential of AGuIX^® nanoparticles as radiosensitizers in melanoma treatment. These nanoparticles, composed of high-Z elements, demonstrated excellent radiosensitization capabilities due to their superior cross-section for high atomic number elements when exposed to photon irradiation. In both in vitro and in vivo experiments, the nanoparticles were found to accumulate in tumors through the enhanced permeability and retention effect. They were also internalized into cells in small vesicles. In vitro experiments revealed a dose enhancement fraction of 1.3, indicating increased sensitivity to radiation. Similarly, in vivo studies showed increased animal lifespan when AGuIX^® was combined with radiotherapy. Moreover, AGuIX^® nanoparticles can serve as T1-positive MRI contrast agents, enhancing imaging quality for treatment planning and real-time guidance [70]. These promising results strongly support the potential clinical applications of AGuIX^® in improving RT outcomes while minimizing damage to healthy tissues. Another promising approach for the targeted treatment of solid tumors using gadolinium is Gadolinium neutron-capture therapy (Gd-NCT). This strategy involves the selective distribution of gadolinium-loaded nanoparticles within tumor tissues, followed by thermal neutron irradiation [71]. Gadolinium can capture neutrons and emit destructive photons and/or electrons, facilitating localized tumor destruction while minimizing harm to surrounding healthy tissue [71,72]. The study conducted by Tokumitsu and colleagues aimed to assess tumor growth suppression; researchers evaluated the efficacy of intra-tumoral (i.t.) injection of gadolinium-loaded nanoparticles combined with neutron irradiation. The study employed chitosan nanoparticles as a novel gadolinium delivery system. These nanoparticles incorporated 1200 μg of natural gadolinium and were administered i.t. twice in mice with subcutaneous B16F10 melanoma. Thermal neutron irradiation was performed at the tumor site, using a fluence of 6.32 × 1012 neutrons/cm2, eight h after the s gadolinium administration. Remarkably, despite the radioresistance typically associated with melanoma, the group treated with gadolinium-loaded nanoparticles exhibited significant suppression of tumor growth [73]. This study provides compelling evidence for the potential effectiveness of Gd-NCT utilizing gadolinium-loaded nanoparticles as a promising therapeutic option for cancer treatment.

3.4. Other high-Z metals

In the following, we will highlight fascinating research regarding other high-Z metals in melanoma treatment:

A study by Zhang et al. highlights the remarkable effectiveness of copper-cysteamine (Cu-Cy) nanoparticles as a radiosensitizer for treating melanoma [38]. These nanoparticles can generate reactive oxygen species (ROS) upon exposure to x-rays, significantly inhibiting melanoma growth. Moreover, when combined with x-ray treatment, Cu-Cy nanoparticles enhance cell death and stimulate a robust antitumor immune response within the tumor microenvironment. This immune response involves several key mechanisms, including the maturation of dendritic cells, activation of CD4⁺ and CD8⁺ T cells and suppression of M2 macrophages. Consequently, the combined approach of Cu-Cy-based oxidative therapy proves highly successful in effectively suppressing tumor growth without causing substantial adverse effects. These findings firmly establish Cu-Cy-based oxidative therapy as a promising and multifaceted strategy that seamlessly integrates radiotherapy, oxidative therapy and immunotherapy [38].

In another fascinating study, Daneshvar et al. showcased the significant potential for treating melanoma by combining platinum nanoparticles (PtNPs) with photothermal therapy (PTT) and radiotherapy (RT) [74]. PtNPs possess unique properties that enhance RT and PTT, making them ideal candidates for improving tumor therapy. In a study conducted on B16/F10 melanoma cells, the investigation focused on the efficacy of PtNPs as a sensitizer when combined with 808-nm laser light and 6-MV x-ray radiation. The combination treatment of PTT and RT displayed superior efficacy compared with individual treatments. Intracellular production of reactive oxygen species (ROS) was assessed, and PtNPs, in conjunction with laser and x-ray radiation, induced higher ROS levels compared with other treatment groups, enhanced cell killing and mitigated concerns associated with RT, such as hypoxia and tissue damage [74]. These results highlight the potential of PtNPs in improving the outcomes of RT and PTT, providing a promising strategy for enhancing cancer therapy (Supplementary Table S1).

4. Nanoparticle physicochemistry & radiosensitization

The development of new nanoparticles requires attention to various factors, including the choice of material, shape and size, surface coating and net charge on the particles. These parameters affect the nanoparticles' cellular uptake, biological response and radiation interaction. Since numerous adjustable parameters are involved, discovering the ideal design poses a challenging task. Hence, we will provide an overview of some critical parameters.

4.1. Size

The interaction of NPs with the biological system and radiation depends on the size of the NPs used for radiosensitization. The size of NPs significantly influences their biodistribution and elimination pathway from the body. Metal NPs should be eliminated from the body within a few days to prevent their accumulation in organs like the heart and liver, which could lead to long-term side effects. This timeframe still allows for the presence of NPs during radiotherapy. The most effective way to achieve this is through renal clearance, which is influenced by the size of the NPs [75–77]. NPs with a hydrodynamic diameter of over 10 nm are more likely to be captured by the liver. In comparison, those smaller than 6 nm are typically eliminated via renal clearance regardless of their charge [78–82]. While the existing data suggest that NPs are most effectively taken up by cells when their size is between 20 and 60 nm [83,84], smaller NPs can still accumulate in tumors due to the Enhanced Permeability and Retention (EPR) effect. Smaller NPs tend to diffuse more extensively into tumor tissue from the bloodstream, resulting in a more uniform distribution within larger tumors than larger NPs. This characteristic may offset the lower active uptake and faster elimination of small NPs from the bloodstream [83,85]. Studies on the toxicity of AuNPs have suggested that NPs smaller than 5 nm or larger than 50 nm exhibit minimal toxicity, whereas those with intermediate sizes display severe toxicity [86]. Vijayakumar and Ganesan found that toxicity was observed in AuNPs with diameters of 3, 8 and 30 nm but not in those of 5, 6, 10, 17 or 48 nm [87]. Defining the mechanisms of toxicity of NPs is a complex issue, and further research is required. The size of NPs is a crucial factor to consider when examining the interaction between NPs and radiation. As the size of AuNPs increases, more ionizing events resulting from interactions with sary electrons and radiation occur within the bulk of the NPs, leading to reduced dose deposition in the surrounding medium [88]. In a study by Carter et al. (2007), it was observed that the generation of low-energy electrons was greater for 3 nm NPs than for 6 nm NPs [89].

In a theoretical study conducted by Lin et al., it was discovered that using 2 nm AuNPs resulted in better cell killing than larger NPs up to 50 nm. This is because sary electrons generated within larger NPs are more likely to lose their energy within the NP before reaching its surface [90]. A study investigated gadolinium-loaded nanoparticles with a size of 430 nm for tumor suppression and gadolinium-neutron capture in a melanoma model. Despite their larger size, the nanoparticles demonstrated significant effectiveness in suppressing tumor growth. Compared with administering a dimeglumine gadopentetate solution, the nanoparticles exhibited enhanced gadolinium retention in the tumor tissue. This superior retention could be attributed to their larger size, which facilitated passive accumulation in tumors through the enhanced permeability and retention (EPR) effect [73]. A study investigated a platinum@polymer-catechol nanobraker system with a hydrodynamic size of 105.7 ± 6.5 nm for melanoma treatment. Combining nanoparticles with radiotherapy, the nanobraker efficiently targeted melanoma cells and inhibited tumor growth by regulating metabolic and growth signaling pathways, such as mTOR/cMYC and mTORC1/HIF-1α/VEGF axes. It induced cell cycle arrest, apoptosis and promoted antitumor immunity. The nanobraker's larger size allowed for enhanced drug delivery and tumor retention due to its platinum content, leading to significant tumor suppression [43]. In another study, novel PMAA-AuNPs with a hydrodynamic size of 3 nm demonstrated remarkable stability in various aqueous solutions, even with high salt and protein concentrations. The nanoparticle size proved pivotal in efficiently targeting melanoma cells expressing NIS, enhancing iodine uptake. Furthermore, the smaller size played a crucial role in enhancing the therapeutic efficacy of PMAA-AuNPs when combined with radioiodine treatment. This combination led to notable reductions in tumor growth and induced extensive necrosis [91].

4.2. Concentration & surface charge of NPs

In the initial studies of nanoparticles (NPs) as a radiotherapy agent, Hainfield et al. (2004) discovered that the amount of NPs present in tumor tissue is a critical factor in their ability to enhance radiation sensitivity [50]. Subsequent research has revealed that the concentration of nanoparticles (NPs) has a greater impact on enhancing radiation dose than their size [17,92]. The study conducted by Daneshvar et al. reveals that platinum nanoparticles (PtNPs) demonstrated cytocompatibility up to a concentration of 250 μg ml^-1, with cell viability above 80% at concentrations lower than 100 μg ml^-1. This suggests that PtNPs can be safely utilized at these concentrations without inducing significant cell toxicity. Furthermore, the cytotoxicity of PtNPs in combination with x-ray radiation exhibited a concentration-dependent pattern. After 24 h, higher PtNPs concentrations increased cytotoxicity at x-ray doses of 2, 4 and 6 Gy. The effect was more pronounced 72 h post-treatment, indicating a deeper and prolonged impact with higher PtNPs concentrations [74]. A positive charge on the surface of nanoparticles is believed to enhance their cellular uptake by interacting with the negatively charged lipid membrane [83,93]. Nanoparticles with a positive charge may have the ability to selectively target cancer cells as they can interact with the glycocalyx structure of cancer cells, which is often larger and more negatively charged [94,95]. The glycocalyx structure comprises various glycoproteins and glycosaminoglycans that can impact the organization of the cell membrane, signaling pathways and potentially facilitate endocytosis [96]. While the quantity of charge on nanoparticles is related to their ability to penetrate the cell membrane, the precise optimal charge level remains uncertain [93,97]. Through computational analysis, it was revealed that the uptake mechanism of nanoparticles is contingent upon the charge level. Neutral or moderately cationic nanoparticles preferred passive membrane translocation, whereas highly cationic nanoparticles were inclined toward endocytosis-mediated uptake. Positively charged nanoparticles have a stronger interaction with the cell membrane, leading to greater local distortion and potential disruption of transmembrane function. This can impact ion transport and increase the likelihood of pore formation in the membrane [83,93]. Upon introducing a foreign object into the bloodstream, opsonins, which are specialized serum proteins, adsorb onto the object's surface and label it for removal from the body [98]. As these proteins carry a negative charge, positively charged nanoparticles tend to be eliminated more rapidly in vivo when compared with neutral or negatively charged nanoparticles [75,81]. In a mouse model investigating melanoma radiotherapy, the slightly negative surface charge of Au@IONPs (-3.8 mV) influenced their interactions with the biological environment, including blood proteins. Despite repulsion from cell membranes and blood proteins, the nanoparticles preferentially accumulate in the tumor and spleen tissues. This accumulation can be attributed to tumors' enhanced permeability and retention (EPR) effect, enhancing radiation delivery to cancer cells while sparing healthy tissues. The observed lower brain deposition indicates limited blood-brain barrier crossing, promising safety. The biodistribution results emphasize the significance of surface charge in directing Au@IONPs to specific tissues for effective therapeutic outcomes in melanoma radiotherapy [99].

4.3. Synthesis methods

Various methods are available for synthesizing high-Z metal nanoparticles for radiation sensitization, including physical and chemical methods [100,101]. Physical methods include techniques such as laser ablation, electron beam evaporation and sputtering, which involve using high-energy sources to produce nanoparticles [102,103]. Chemical methods, on the other hand, involve the reduction of metal ions using chemicals such as sodium borohydride or hydrazine [104,105]. A study by Mohamadkazem et al. focuses on the chemical synthesis of gold-coated iron oxide nanoparticles (Au@IONPs). The method involves co-precipitating iron oxide nanoparticles from iron chloride solutions with NH₄OH and functionalization using (3-aminopropyl) triethoxysilane. Gold seed solution is separately synthesized and immobilized onto the amine-functionalized iron oxide nanoparticles. The gold coating is achieved by reducing HAuCl₄·3H₂O and ascorbic acid under sonication [99]. In a recent study, platinum@polymer-catechol nanobraker nanoparticles (NPs) were synthesized primarily using chemical methods. The synthesis process involved several key steps, including the chemical reaction to produce the monomer N-Boc-ethylenediamine and the macromolecular initiator PEG-chain transfer agent (CTA). Controlled polymer growth was achieved through reversible addition-fragmentation chain transfer (RAFT) polymerization, resulting in PEG-b-PNHBoc. By removing protecting groups using chemical manipulation, amino-functionalized polymer PEG-b-NH2 was obtained. The final NPs, platinum@polymer-catechol nanobraker, were formed through a chemical reaction between PEG-b-NH2 and 3,4-dihydroxybenzaldehyde. To concentrate the NPs and optimize their properties, solvent evaporation, a physical method, was employed. During this process, a suitable solvent was carefully removed, leading to the formation of a more concentrated and stable nanoparticle dispersion [43]. Based on these studies, the chemical approach offers significant advantages in synthesizing high-Z metal nanoparticles for melanoma treatment when combined with radiotherapy, as it ensures precise control over the composition and structure of the nanoparticles, resulting in their uniformity and stability.

Green synthesis is a relatively new approach involving using natural sources such as plant extracts, microorganisms and biomolecules to synthesize nanoparticles. This method has gained popularity due to its simplicity, lower cost and higher biocompatibility than traditional methods [106,107]. In green synthesis, natural sources' reducing and stabilizing agents convert metal ions into nanoparticles. For example, plant extracts contain various phytochemicals that act as reducing agents and stabilize the formed nanoparticles [107,108]. These phytochemicals may include flavonoids, terpenoids, alkaloids and phenolic compounds [108,109]. The green synthesis method has successfully synthesized various high-Z metal nanoparticles such as gold, silver, platinum and palladium [109,110]. These nanoparticles have shown promising results in RT by enhancing the cellular uptake of radiation and increasing the production of reactive oxygen species (ROS), leading to improved cancer cell killing [110,111]. In the study led by Bemidinezhad et al., a green synthesis method was employed to create Glu-GNPs by reducing Au³⁺ ions in a β-D-glucose solution. This environmentally friendly approach resulted in Glu-GNPs with lower toxicity than GNPs synthesized through the chemical Thio-glucose-assisted covalent functionalization method. Remarkably, the Glu-GNPs displayed enhanced uptake by the B16F0 cell line, indicating their potential as a targeted therapy for melanoma. Moreover, the study demonstrated that these Glu-GNPs could act as radiosensitizers, effectively increasing the sensitivity of melanoma cells to radiation treatment through the increase in apoptosis and ROS generation. These findings underscore the importance of green synthesis for producing biocompatible nanoparticles, holding promise for various biomedical applications, particularly in targeted cancer therapy [56].

4.4. Nanoparticle coating & targeting strategies

Applying a coating to NPs can help manage the interaction between NPs and proteins in the bloodstream [112,113]. The NP coating can target tumor cells within the body specifically. In order to achieve a high concentration of NPs in tumor cells, targeting strategies can be classified into passive and active [86]. As evident from Figure 1, Passive targeting involves utilizing the fact that cancer cells have a higher rate of endocytic uptake and the vasculature around tumors is more permeable, which results in a greater uptake of NPs compared with healthy tissues [76]. Active targeting involves modifying the NPs by attaching specific molecules that can interact with selectively present receptors in tumor cells. This allows for targeted delivery of NPs to the tumor cells, increasing their effectiveness while minimizing damage to healthy tissues [114]. By applying a coating to the surface of the NPs, it becomes possible to control their surface charge. This surface charge is important for maintaining the stability of the NPs, preventing them from aggregating both in the body and aqueous solutions [115]. Furthermore, the surface charge also affects how the NPs interact with opsonin proteins [114]. Coating the NPs enables some level of regulation on the lifespan and uptake behavior of the NPs [111]. When coating NPs to use them as Radiosensitizing agents, there is a potential concern that the coating may absorb sary electrons emitted from the metal core. Although previous studies have demonstrated radiosensitization using coated NPs [116,117], it is possible that the coating may decrease the number of radicals generated during the process, as indicated by Gilles et al. [118] (Figure 1).

Figure 1.

Passive, active and combination targeting at the tumor microenvironment. Passive targeting uses stealth-coated NPs, which induce a repulsive effect in opsonins. This effect stops opsonins from attaching to and marking the NPs' surface, preventing their removal from the organism. Tumor tissue has an undeveloped lymphatic system and defective blood vessel walls, causing the enhanced EPR effects. This causes NPs to accumulate in tumor tissue. Specific compounds conjugated onto NPs have a particular affinity for cancerous tissues in active targeting. The main goal is to avoid passive uptake via the EPR effect. Opsonins bind to NPs' surfaces in the circulatory system, allowing macrophages to recognize and remove them. Combining targeting techniques requires stealth coating and targeting ligand optimization to maximize circulation time. Combination coatings repel opsonins, preventing them from binding to and marking NPs. Biocompatibility, stability, passive tumor targeting and therapeutic cargo delivery to the tumor location are improved by this coating.

4.4.1. Active, passive & combination targeting strategies

As illustrated in Figure 1, Specialized serum proteins known as opsonins bind to the surface of foreign bodies in the bloodstream, marking them for elimination from the organism's system. This recognition process aids in the immune system's swift identification and clearance of foreign substances [98]. Studies have demonstrated that attaching specific molecules, such as polyethylene glycol (PEG), to the surface of nanoparticles can prevent this from occurring [81,119]. The prevailing theory is that coating nanoparticles with PEG create a repulsive effect on opsonins, effectively preventing them from binding to and labeling the surface of the NPs for elimination from the organism's system [120]. Due to the abnormal formation of blood vessel walls around tumor tissue and the underdeveloped lymphatic system that impairs the drainage of macromolecules from such tissue, nanoparticles (NPs) tend to accumulate in tumor tissue [121]. The enhanced permeability and retention effect (EPR) are observed in tumor tissue due to the abnormal formation of blood vessel walls and an underdeveloped lymphatic system, causing nanoparticles (NPs) to accumulate in such tissue preferentially. To take advantage of this effect and increase passive NP uptake, the circulation time of NPs can be increased by coating them with PEG. The efficiency of the coating layer's ability to facilitate passive targeting depends on various factors, including the size of the NP core and the length and surface density of capping molecules, which have been studied both computationally and experimentally [119,122,123]. Apart from PEG, numerous other materials and molecules have been investigated for their potential application in passive targeting during melanoma radiotherapy. This area of research includes substances like silica, PVP (polyvinylpyrrolidone), Chitosan, dextran, PVA (polyvinyl alcohol) and even gold. For comprehensive results, refer to Supplementary Table S1 in the supplementary materials. Dextran is a commonly used coating for magnetic nanoparticles in hyperthermia applications. Its biocompatibility, ease of functionalization and stability make it an ideal choice. In the study conducted by Duval et al., dextran-coated nanoparticles combined with radiotherapy showed increased expression of immune and cytotoxic genes, making them effective in anti-tumor responses for melanoma treatment [60]. Additionally, in the study conducted by Hoopes et al., dextran coating contributed to enhanced immune signaling, highlighting its potential for therapeutic applications in cancer treatment through magnetic nanoparticle hyperthermia combined with radiotherapy [58]. The technique of active targeting involves attaching specific molecules to NPs that have an affinity for cancer tissues [123]. The main goal is to avoid relying on passive uptake through the EPR effect. Various molecules have been successfully used, such as antibodies, peptides, folates, aptamers, hormones and glucose molecules [124–126]. A study investigated by Le Goas et al. explores the potential of utilizing poly (methacrylic acid)-grafted gold nanoparticles (PMAA-AuNPs) as a nanotherapeutic approach to enhance internal radioisotope therapy in melanoma and colorectal cancer. PMAA-AuNPs are functionalized with PMAA, serving as an active targeting moiety, which improves nanoparticle stability and enables specific uptake by cancer cells expressing the NIS symporter. By utilizing active targeting alone, PMAA-AuNPs demonstrate increased specificity for cancer cells and enhanced cellular uptake, potentially overcoming tumor heterogeneity. Combining PMAA-AuNPs with systemic radioiodine treatment effectively enhances the killing potential of radioiodine, offering a promising approach for reducing the required radioiodine dose and improving treatment efficacy [91].

Melanoma-specific biological receptors that can be utilized for active targeting of nanoparticles include the melanocortin-1 receptor (MC1-R) [127], the anti-gp100/HLA-A2 T-cell receptor (TCR) [128] and the insulin-like growth factor 1 receptor (IGF1R) [129]. These receptors have been targeted in various studies to enhance the specificity and efficacy of nanoparticle-based therapies for melanoma. For instance, ultrasmall fluorescent silica nanoparticles conjugated with MC1-R targeting peptides demonstrated high affinity binding to MC1-R and selective targeting of melanoma cells in mouse models [127]. Additionally, T-cell membrane-coated nanoparticles loaded with Trametinib and engineered with anti-gp100 TCR showed increased cellular uptake and improved cancer killing efficiency, highlighting the potential of these nanoparticles for targeted therapy in melanoma [128]. Furthermore, nanoparticles designed with IGF1R targeting antibodies have shown promise in effectively targeting CD44-positive melanomas, emphasizing the significance of receptor-specific targeting strategies in nanoparticle-based melanoma therapies [129].

both targeting strategies mentioned earlier can be combined. However, optimizing the ratio of PEG and targeting ligands is necessary to utilize PEG for an increased circulation time. If there is an excess targeting ligand, the circulation time will be reduced. Conversely, if there is an excess of PEG, it will weaken the effect of the active targeting groups. According to Dai et al., when using combination coatings, the length of PEG molecules must not exceed the length of the targeting ligands to avoid blocking the receptor-ligand interaction caused by PEG molecules [130]. In a study by Li et al., PEG-coated nanoparticles (APTP NPs) were developed as an innovative nanobraker for melanoma treatment, incorporating both passive and active targeting strategies and radiotherapy. PEG played a crucial role by enhancing biocompatibility, stability and passive tumor targeting through the “stealth” effect, enabling prolonged circulation and effective delivery of therapeutic cargo to the tumor site. Additionally, PEG facilitated active tumor cell binding through aPD-L1 functionalization, promoting specific interaction with PD-L1-expressing melanoma cells and enhancing the anti-tumor immune response. The study by Li et al. demonstrated the promising potential of PEG-coated nanobrakers, combined with radiotherapy, for melanoma treatment and highlighted its significance in nanomedicine applications and cancer therapy [43].

5. Mechanisms of high-Z metal NPs radiosensitization

When biological systems are exposed to ionizing radiation (IR), they undergo a sequence of processes categorized into three phases: physical, chemical and biological. These phases differ in time scales [131,132]. The physical phase occurs within the initial nanoss of exposure, where IR interacts with biomolecules leading to ionization or excitation, which produces free radicals. Among the cellular components, DNA is the primary target that determines the effects of radiation. In this phase, the ejected electrons travel and collide with subsequent atoms, resulting in a cascade of ionization events [132]. In the chemical phase, the highly reactive radicals produced in the physical phase participate in rapid reactions to permanently fix the damage or engage in scavenging reactions to restore cellular charge equilibrium [132,133]. Studies involving gold nanoparticles (GNPs) have shown their potential to modify these chemical reactions, leading to enhanced radiosensitivity by affecting DNA damage and repair dynamics [133,134]. In the final biological phase, a series of cellular processes are activated to repair the damage caused by radiation. If the repair fails, it ultimately leads to cell death, occurring over ss to days or even years [135] (Figure 2).

Figure 2.

Mechanisms of high-Z NPs radiosensitization. High-Z NPs interact with IR at the physical, chemical and biological phases, enhancing radiation effects. Two interactions cause photoelectric and Compton effects in the physical phase. The photoelectric effect occurs when a bound electron disappears from the photon, emission characteristic radiation. Photons and free electrons interact in the Compton effect, causing scattering at an angle θ. Consequently, NPs induce cellular damage through the increasing production of photoelectrons. During the chemical phase, ROS were generated due to the interaction between NPs and radiolysis water molecules. ROS induce apoptosis, while extremely low energy electrons chemically sensitize DNA to IR damage. Finally, NPs increase IR through oxidative stress, DNA damage, G2/M cell cycle arrest and DNA repair inhibition during the biological phase.

5.1. Physical, chemical & biological phases

As can be observed from the information presented in Figure 2, the use of high-Z metal NPs in RT has gained considerable interest due to their ability to enhance the physical phase of radiosensitivity. This is primarily due to their high atomic number, which significantly increases the photoelectric effect [136]. When ionizing radiation interacts with matter, it can produce two types of interactions: the photoelectric effect and the Compton effect [51]. The photoelectric effect occurs when a photon (such as an x-ray photon) interacts with an atom and transfers all its energy to an inner-shell electron, leading to the emission of that electron from the atom [132]. On the other hand, the Compton effect occurs when a photon scatters off an outer-shell electron, transferring a fraction of its energy to the electron and causing a change in the photon's direction [136]. High-Z metal NPs have been found to preferentially absorb photons through the photoelectric effect when exposed to radiation, creating sary electrons and ionization events within proximity to the NP. This increased local dose of radiation can enhance cell killing in radiation therapy. Additionally, the high-Z metal NPs can generate sary electrons via the Compton effect, further contributing to their effectiveness in RT [132]. NPs can improve the cell's response to radiation damage. They do this by participating in chemical reactions that help repair the damage or make the DNA more vulnerable to radiation-induced damage. Depending on where NPs are located within cells, they may work through two mechanisms: by making DNA more sensitive to radiation damage and by increasing the formation of radicals that can react with other molecules. Although both mechanisms can enhance the effect of radiation therapy, the first mechanism requires NPs to be present inside the cell nucleus, which is only sometimes the case in most studies. Instead, NPs often get trapped within endosomes/lysosomes in the cytoplasm, limiting their ability to enter the nucleus [132]. The studies conducted so far have determined that three significant biological pathways contribute to radiosensitization. These include inducing oxidative stress, disrupting the normal cell cycle and inhibiting DNA repair mechanisms [135,137]. Radiation-induced cell killing primarily occurs via water radiolysis, which produces free radicals and reactive oxygen species (ROS) that can interact with various cellular components. These ROS, such as superoxide radicals (O₂^-), hydrogen peroxide and hydroxyl radicals (•OH), have the potential to cause direct damage to biological molecules or induce oxidative stress, leading to cell death through apoptosis or necrosis [138–141]. Although tumors, including melanomas, have high levels of antioxidants and their associated enzymes to counteract oxidative stress, nanoparticles can disrupt these antioxidant systems. For instance, studies have shown that certain nanoparticles can significantly increase ROS levels, thereby inducing apoptosis and necrosis by targeting key antioxidant mechanisms. Iron oxide nanoparticles, for example, have been reported to increase ROS, induce endothelial leakiness and promote tumor necrosis and cell death through enhanced oxidative stress [142]. Similarly, gold nanoparticles coated with glucose and gold ions encapsulated in nanoliposomes have been observed to induce ROS, increase the expression of apoptosis-related genes (such as p53, Bax, caspase 3 and caspase 7) and increase caspase activity while decreasing anti-apoptotic Bcl-2 protein levels [56].

The sensitivity of cells to radiation is largely determined by the stage of the cell cycle they are in. Cells in late G2 or mitosis tend to be more sensitive to radiation, whereas cells in the late S phase tend to be more resistant [143]. Additionally, high-Z metal nanoparticles can make cells more sensitive to radiation by causing them to pause in the G2/M phase of the cell cycle [143,144]. When exposed to ionizing radiation, DNA damage can occur, including single-strand breaks (SSBs), double-strand breaks (DSBs) and modifications to the DNA bases [145]. Chithrani and colleagues reported that the presence of nanoparticles led to increased residual damage, which suggests a delay in DNA repair. This delay in DNA repair has been suggested as a significant mechanism for radiosensitization [146]. The bystander effect is a phenomenon whereby the impact of radiotherapy can be amplified through intercellular communication. This means that neighboring cells not directly exposed to radiation could still experience damage due to receiving signals from nearby irradiated cells [147,148]. According to reports, high-Z metal NPs can cause changes in the production of proteins and cytokines, which may increase the bystander effect when used in conjunction with radiotherapy.

Li et al. conducted a comprehensive study to investigate radiation's physical and chemical phase events in melanoma cells. The physical phase events included DNA damage, characterized by double-strand breaks and other types of damage in melanoma cells due to ionizing radiation (x-rays). In the chemical phase, platinum ions in the nanobraker played a crucial role in facilitating the production of ROS during x-ray irradiation. This process led to radiosensitization, enhancing the damaging effects on tumor cells. Additionally, the chemical phase revealed intriguing anti-angiogenic effects, as the downregulation of the HIF-1α/VEGF signaling pathway in tumors indicated reduced tumor angiogenesis. The study suggested that this reduction in angiogenesis was likely caused by ROS-induced inhibition of HIF-1α, ultimately leading to the suppression of tumor blood vessel formation.

Moreover, the mTOR inhibitor TAK228 present in the nanobraker played a crucial role in the biological phase, contributing to the arrest of proliferative B16F10 cells in the G1 phase. The G1 phase arrest is a critical step preceding DNA replication during cell division. Furthermore, the combination of mTOR inhibition, aPD-L1 blockade and x-ray irradiation led to significant tumor cell apoptosis, inhibiting tumor growth. These findings highlight the profound impact of the biological phase events on melanoma cells and offer valuable insights into potential therapeutic strategies for melanoma treatment [43]. The study conducted by Kim and colleagues examines the effects of AuNPs on melanoma cells' response to x-ray radiation. Firstly, AuNPs contribute to the physical effect by promoting the formation of DSBs, as evidenced by an increased percentage of gamma-H2AX-positive cells, indicating DNA damage. sly, the chemical effect is observed as AuNPs influence cell survival after irradiation. Clonogenicity analysis reveals melanoma cells treated with AuNPs display altered survival and colony-forming capabilities following radiation exposure. Thirdly, the biological effect is explored through changes in cell cycle distribution. AuNP treatment leads to alterations in the cell cycle, particularly affecting the G2/M phase, indicating a biological impact on cell behavior [149].

The study investigated by Kotb et al. explored the radiosensitization effects of AGuIX^® nanoparticles in melanoma brain metastases. The study revealed three key phases: physical, chemical and biological. Physically, AGuIX^® nanoparticles efficiently internalized into melanoma cells, increasing DNA double-strand breaks (DSBs) as demonstrated by γ-H2AX assays. The dose enhancement fraction (DEF) of 1.3 indicated enhanced radiation-induced cell death. Chemically, the combination of AGuIX^® and radiation-induced sustained production of reactive oxygen species (ROS) at 24 h post-irradiation contributes to persistent DNA damage. This sustained ROS production hindered the cell's ability to repair DNA damage efficiently, leading to prolonged DNA lesions and promoting a more effective radiosensitization. In vivo studies using a mouse model demonstrated AGuIX^® accumulation in tumor areas, leading to a significantly higher lifespan (sensitivity enhancement ratio - SER) when combined with radiation compared with radiation alone. This enhanced radiosensitization observed in the biological phase was attributed to the efficient internalization of AGuIX^® nanoparticles in tumor cells, resulting in increased radiation-induced cell death and improved therapeutic outcomes [70].

6. Conclusion

The use of high-Z metal nanoparticles as radiation sensitizers in cancer therapy, specifically for melanoma, has shown great potential in enhancing the effectiveness of radiotherapy. These nanoparticles possess unique properties, such as efficient x-ray absorption, targeted delivery and the ability to induce oxidative stress, making them attractive candidates for improving treatment outcomes. Research on high-Z metal nanoparticles has provided valuable insights into their potential applications and mechanisms of action enhancing radiosensitivity [132]. The studies discussed in this review demonstrate significant advancements in nanomedicine and radiation therapy. High-Z metal nanoparticles, including gold, magnetic iron oxide, gadolinium, copper-cysteamine and platinum nanoparticles, have exhibited promising results in sensitizing melanoma cells to radiation. Combining radiotherapy with hyperthermia using magnetic iron oxide nanoparticles or utilizing gadolinium-loaded nanoparticles for enhanced imaging and treatment planning could revolutionize cancer therapy [60,70]. However, despite the promising results, several challenges and considerations must address before translating these findings into clinical applications. One crucial aspect is ensuring the safety and biocompatibility of high-Z metal nanoparticles. Although some studies have reported minimal toxicity, further investigations are necessary to comprehensively evaluate their long-term effects on healthy tissues and potential side effects [100]. Moreover, the precise mechanisms by which high-Z metal nanoparticles enhance radiosensitivity require further exploration. Understanding these mechanisms will enable researchers to optimize nanoparticle designs and develop more targeted and effective therapies. Additionally, establishing optimal administration and dosing strategies for nanoparticles is essential to achieve desired therapeutic effects while minimizing potential adverse effects. Standardizing synthesis methods and nanoparticle coatings is crucial to ensure reproducibility and scalability for clinical applications [150].

7. Future perspective

One promising future prospect involves the targeted delivery of higher radiation doses to melanoma cells using nanoparticles. Given the lower alpha/beta ratio of melanoma, which makes it resistant to conventional radiotherapy, nanoparticles could allow for these higher doses to be delivered directly to the tumor cells, increasing treatment efficacy while minimizing damage to healthy tissues. This targeted approach can innovate and enhance the overall treatment protocol for melanoma, thereby offering new hope for improving patient outcomes. Furthermore, optimizing the combination of passive and active targeting strategies is necessary to improve nanoparticle delivery to tumor tissues and achieve the best results [151]. Despite these challenges, the potential of high-Z metal nanoparticles as radiation sensitizers for melanoma treatment offers new hope for patients with this aggressive form of skin cancer. As nanomedicine continues to evolve, it promises to revolutionize cancer treatment by providing more effective and personalized therapies with reduced side effects. Future research directions in this field include conducting preclinical studies to further validate the efficacy and safety of high-Z metal nanoparticles in combination with radiation therapy. Advancing toward clinical trials will be crucial to determine their feasibility and potential benefits for melanoma patients. In conclusion, integrating high-Z metal nanoparticles into RT can potentially transform cancer treatment and improve outcomes for melanoma patients. With continued research and innovation, nanomedicine offers exciting opportunities for targeted, efficient and safe cancer therapies that may significantly impact the future of oncology.

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/17435889.2024.2403325

Author contributions

A Bemidinezhad: conceptualization; supervision: writing – original draft; writing – review & editing. S Radmehr: conceptualization; writing – original draft. N Moosaei: conceptualization; writing – original draft. Z Efati: conceptualization; writing – review & editing. P Kesharwani: conceptualization; writing – review & editing. A Sahebkar: conceptualization; supervision: writing – original draft; writing – review & editing.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.