X-ray responsive therapeutic systems in tumor treatments

Abstract

Due to its high energy and deep tissue penetration, X-ray is an ideal stimulus source for diagnosis and therapy. In the field of cancer treatment, by reasonably designing and using systems with X-ray responsiveness, it is possible to improve treatment methods or combine multiple treatment modalities, thereby improving treatment effectiveness and reducing side effects. This review aims to summarize the research progress of X-ray responsiveness in the field of cancer treatment in recent years. Specifically, it introduces the promotion of X-ray responsive radiosensitizers on X-ray radiation therapy itself, as well as the combination of radiotherapy and other cancer therapies mediated by X-ray responsive therapeutic systems, which mainly includes the combination of radiotherapy and photodynamic therapy through X-ray responsive scintillators and the combination of radiotherapy and chemotherapy through X-ray responsive drug delivery systems.

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Runchen Sun

Runchen Sun obtained his BA degree from Chongqing University, China, in 2022. Currently, he is a PhD student at the College of Engineering and Applied Sciences, Nanjing University, China, working on stimulus responsive materials under the supervision of Dr Tao Zhang.

Yuan Cheng

Dr Yuan Cheng graduated from Nanjing University in 2012 and is now a research fellow of Wuxi Xishan NJU Institute of Applied Biotechnology. His current research interests are focused on biomedical nanomaterials and surface functionalization of polymers for medical devices.

Tao Zhang

Dr Tao Zhang is a professor in the fields of Materials Science and Biomedical Engineering at Nanjing University. He earned his bachelor's, master's, and doctoral degrees from Nanjing Tech University, Sichuan University, and Nanjing University, respectively. His current research interests are focused on biomaterials, functional polymeric materials, nanomaterials, minimally invasive interventional medical technologies, and medical devices.

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1. Introduction

X-rays, also known as Roentgen rays, are high-energy electromagnetic waves with high frequencies and short wavelengths discovered by William Conrad Roentgen in 1895.¹ With a frequency range of 30 PHz–300 EHz, corresponding wavelengths of 0.01–10 nm, and energies of 124 eV–1.24 MeV, X-rays range between γ-radiation and UV light.^2–4 In terms of physical properties, X-rays exhibit significant penetration ability, fluorescence excitation capacity, ionization effects, and thermal effects,^5–9 as well as interference, diffraction, reflection, and refraction as electromagnetic waves.^10–14 In terms of biological properties, when X-rays irradiate biological organisms, they can inhibit cellular growth or proliferation, and even kill cells, causing varying degrees of physiological, pathological, and biochemical changes in the body.^6,15–18 The mechanism of action of X-rays on biological systems begins with their physical energy deposition process as ionizing radiation, mainly generating high-speed secondary electrons through effects such as Compton scattering. These electrons trigger subsequent chemical stages, in which indirect effects (about two-thirds) are crucial: they generate highly active hydroxyl radicals (˙OH) and other media through water ionization, which then diffuse and attack key biomolecules. In the biological stage, the resulting DNA damage, especially the difficult to repair DNA double strand breaks, is the core biological basis for cell fate decisions such as repair, apoptosis, aging, or mutation. This chain reaction from physical energy absorption to chemical free radical attack, ultimately leading to cell death or genetic changes, constitutes the molecular and cellular roots of radiation therapy effects and radiation risks.

Stimuli responsiveness is a characteristic possessed by certain designed materials, some physical or chemical properties of which can undergo responsive changes under environmental or exogenous stimuli. Common stimulating factors include force, heat, light, electrical and magnetic fields, radiation, and various controllable environmental factors such as pH values and ion strengths. Responsive behavior includes changes in various mechanical, thermal, and optoelectronic properties, such as surface energy, shape, phase state and conductivity. The system constructed based on this type of material has self-detection, self-judgment, and self-processing functions, thus demonstrating enormous potential in fields such as biomimetic driving, flexible sensing, energy storage, microfluidics, and biomedical applications.^19–27 Due to its strong penetration ability, excitation ability, and ionization effect, X-ray is an ideal source of stimulation.^5–7,28,29 Therefore, the study of X-ray responsiveness is of great significance.

In this review, we attempt to summarize the research progress of X-ray responsive therapeutic systems in the field of tumor treatment in recent years. The research in this field mainly follows two types of research approaches. The first approach is to directly apply the X-ray responsive system to the X-ray radiotherapy process. This section mainly introduces the promoting effect of X-ray responsive radiosensitizers on X-ray radiation therapy. The second approach is to combine radiation therapy mediated by X-ray responsive systems with other cancer treatment methods, where X-rays act as a “switch” for other treatment methods while producing radiation effects. This section mainly introduces the combination of radiotherapy and photodynamic therapy using X-ray responsive scintillators, as well as the combination of radiotherapy and chemotherapy using X-ray responsive drug delivery systems (Table 1).

Table 1 Summary of research approaches for enhancing radiotherapy efficacy using X-ray responsive systems

Research approach	Core strategy	Mechanism of action	Key components/materials	Treatment modality	Primary function/objective
Approach 1: direct application	Directly apply X-ray responsive systems to radiotherapy	Enhance the direct tumoricidal effect of X-rays	X-ray responsive radiosensitizers	Radiotherapy (RT)	To amplify the radiotherapy efficacy by increasing tumor cell sensitivity to radiation
Approach 2: combinatorial therapy	Combine X-ray radiotherapy with other treatment modalities	X-rays serve a dual function: 1. Direct killing (radiation effect)	1. X-ray responsive scintillators	1. RT + photodynamic therapy (PDT)	1. To achieve synergistic therapy, overcoming limitations of single-modality treatment
		2. Control switch (activate other therapies)	2. X-ray responsive drug delivery systems	2. RT + chemotherapy	2. To utilize the deep-tissue penetration of X-rays for precise activation of therapies in deep-seated tumors

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2. Direct promotion of X-ray radiotherapy: radiosensitizers

Radiotherapy, surgery, and chemotherapy are the three major methods of cancer treatment.^17,30 Approximately 70% of cancer patients require radiation therapy during the treatment process, and about 40% of cancers can probably be cured through radiation therapy.³¹ The radiation sources for radiotherapy mainly include α-rays, β-rays and γ-rays produced by radioactive isotopes and X-rays, electron beams, proton beams and other particle beams produced by various X-ray therapy machines or accelerators. However, X-ray is the earliest and most widely used radiation source.³²

As for radiotherapy with X-rays as the radiation source, the radiation dose needs to be strictly restrained due to the acute toxicity and potential long-term adverse reactions, making it difficult to fully exert its therapeutic effect.^33–37 Therefore, there is an urgent need to develop drugs which can enhance the radiation effect for tumor tissues, namely radiosensitizers, to improve the therapeutic effect of radiation therapy. Based on their functional mechanism, radiosensitizers can be regarded as a kind of X-ray responsive system.^28,38,39

In the process of radiotherapy, X-rays not only cause DNA strand breakage through direct action, but also indirectly damage various bases, which is attributed to the reactive oxygen species (ROS) produced by X-ray irradiation.⁴⁰ Therefore, the generation and clearance of ROS are important criteria for determining the radio sensitivity of a potential substance. Moriyama et al.⁴¹ conducted a screening study in 2019 aimed at finding substances with specific X-ray responsiveness for the development of next-generation radiosensitizers. They selected over 9600 organic compounds and found that up to nearly 300 organic compounds exhibited significant release of superoxide and/or hydroxyl radicals under X-ray irradiation at the same dose as general radiation therapy. This study has important enlightening significance for the development of a new generation of organic radiosensitizers. However, the screened substances did not exhibit obvious similarities or patterns in structure, so the mechanism by which these substances produce ROS needs further clarification. On the other hand, cellular uptake and intracellular distribution also have a significant impact on the effectiveness of radiosensitizers,^38,42–45 on which future research on organic compound radiosensitizers needs to be focused.

In addition to some organic compounds, high Z (high atomic number) metal-based materials have the potential to be utilized as excellent radiosensitizers due to their high absorption rate and effective deposition of energy for X-rays.³⁸ They can generate Auger electrons and photoelectrons through photoelectric and Compton effects under X-ray irradiation, thereby generating a large amount of ROS and achieving radio sensitization.^5,46–48 However, traditional high Z metals such as Ir, Ru, and Pt generally have poor biocompatibility,^49,50 and it is necessary to develop new biocompatible materials. As a highly attractive metal material (perhaps more attractive economically than scientifically), gold has typical high-Z characteristics and good biocompatibility. Gold based radiosensitizers are also the most reported type among many high-Z materials, with good development prospects and enormous application potential. In 2008, Hainfeld et al.⁵¹ first proposed and validated an innovative cancer treatment strategy of enhancing tumor sensitivity to radiation therapy through intravenous injection of gold nanoparticles. By utilizing the strong absorption ability of gold (Z = 79) for X-rays, the tumor site can deposit more radiation energy, significantly improving the killing effect of radiotherapy on cancer cells while relatively protecting surrounding normal tissues. The study achieved significant results in a mouse model, with a long-term cure rate of 86% achieved by combining gold nanoparticles with radiotherapy, far higher than the 20% achieved by radiotherapy alone. This study successfully demonstrated for the first time in a live animal model that gold nanoparticles can serve as highly efficient radiosensitizers, significantly improving the cure rate of radiotherapy, which opens up a promising new avenue for improving the effectiveness of cancer radiotherapy. Gold nanoparticles, as a multifunctional platform, demonstrate enormous clinical translational potential by combining their targeted enrichment ability in tumors and their physical enhancement effect on radiation. In recent years, research on gold based radiosensitizers has mainly focused on leveraging their multifunctional platform characteristics, integrating multiple functions into a single gold based nanoplatform. A typical example is a gold coated lipid polymer hybrid nanosystem (PCAu NPs) developed and validated by Appidi et al.⁵² in 2025, which innovatively integrates three functions of radiosensitization, drug delivery, and CT imaging into a single nanoplatform. This “three in one” strategy has shown excellent therapeutic effects and good safety in various cancer cell and animal models. This study successfully integrated diagnosis and treatment, using external radiation as a key “switch” to activate both radiosensitization and drug release modules, representing the cutting-edge development direction of nanomedicine in cancer treatment. The idea of precise spatiotemporal control of “radiotherapy triggered chemotherapy” is also an important theoretical basis for the discussion in Section 3.1 on radiotherapy combined with chemotherapy. Of course, besides gold, other types of high-Z metals have also been proven to have good biocompatibility and clinical application potential. Zhang et al.⁵³ reported the design of coordination frameworks for a series of lanthanide (Ln) based radiosensitizers in 2021. Using 2-(2-pyridyl)-1H-benzimidazole-6-carboxylic acid (Hpbc) as a ligand, they synthesized, characterized, and tested X-ray responsive radiosensitizers Ln (Hpbc)₂Cl (Ln = Dy 1; Gd 2; Eu 3) based on high Z metals (Fig. 1A), then demonstrated their benign biocompatibility and radiosensitizer effect. This study also provides important references for the design of high Z metal-based radiosensitizers in the future.

Fig. 1 (A) 1: Central metal ion coordination pattern diagram; 2: four Hpbc ligands link two adjacent Ln³⁺ ions through the carboxylate group; 3: three-dimensional structure of the framework. Purple: Ln; gray: C; blue: N; and red: O.⁵³ Copyright 2021, Royal Society of Chemistry. (B) Mechanism of Cu₂(OH)PO₄@PAAS NCs as a smart radiosensitizer for enhanced radiotherapeutic efficacy through X-ray-triggered Fenton-like reaction.⁶⁰ Copyright 2019, American Chemical Society. (C) X-ray responsive PEGylated AuNPs functionalized with nitroimidazole and nucleus-targeting CPP for enhanced radiotherapy.⁶⁷ Copyright 2017, Royal Society of Chemistry.

One of the biggest challenges in the field of radiosensitizers currently is that traditional radiosensitizers cannot be selectively distributed in the body, resulting in uncontrollable activation and non-selective cell killing, and potential hazards are still posed to normal tissues.⁵⁴ In recent years, accumulating efforts have been devoted to solving this problem by utilizing endogenous substances in the tumor micro environment (TME).^55–59 Inspired by this approach, Zhang et al.⁶⁰ developed a novel intelligent radiosensitizer, copper hydroxy-phosphate nanocrystals (Cu₂(OH)PO₄NCs). This radiosensitizer decomposes overexpressed H₂O₂ in the TME to highly reactive and cytotoxic ˙OH through Fenton-like reaction (Cu²⁺/Cu¹⁺ cycle), achieving radio sensitization and effective cell killing (Fig. 1B). The key is to achieve spatiotemporal control of the aforementioned Fenton-like reaction. Previous studies have shown that Cu₂(OH)PO₄NCs can generate Cu¹⁺ sites under visible light irradiation and trigger Fenton-like reactions in a controllable manner.^61,62 However, the tissue penetration ability of visible light is poor and cannot act on deep tumors. Zhang et al. attempted to use X-rays as the stimulus source and successfully observed the Cu¹⁺ sites produced by Cu₂(OH)PO₄NCs in TME and the ˙OH produced by Fenton-like reactions under X-ray irradiation, while the relatively oxygen rich environment and the relative lack of H₂O₂ in normal tissue cells inhibited the production of Cu¹⁺ sites. This study provides an important idea for the development of targeted radiosensitizers in the future by combining exogenous and endogenous stimuli. The idea of reasonably extending the response characteristics of substances from visible light to X-rays is also worthy of investigation for future researchers.

At present, most of the reported radiosensitizers achieve cell killing through the production of ROS, but some types of tumors have hypoxic microenvironments, which may develop a certain resistance to ROS mediated radio sensitization.^17,63,64 Therefore, attempting to find novel radiosensitizers that are not entirely mediated by ROS may be an effective way. In recent years, some studies have found that reactive nitrogen species (RNS), such as nitrogen dioxide radicals (˙NO₂) and nitrogen peroxide (ONOO⁻), are potential substitutes with similar effects to ROS.^65,66 In 2017, Liu et al.⁶⁷ reported a gold nanoparticle (AuNP) based system AuNP@nIm-CPP functionalized with nitroimidazole (nIm), cell penetrating peptide (CPP), and polyethylene glycol (PEG) (Fig. 1C). Previous reports have shown that nIms can release nitrite ions under ionizing radiation irradiation,⁶⁸ and nitrite is easily converted into small molecule RNS nitric oxide (NO) in acidic or hypoxic tumor microenvironments.^69,70 In addition, nitrite and NO can react with peroxides produced by water radiolysis to form highly active RNS (such as ONOO⁻),⁷¹ thereby endowing nIms with RNS mediated radio sensitization properties. AuNPs belong to high Z metal-based materials and can absorb X-ray energy.^72,73 The results of the standard Griess assay demonstrate that combining the two can promote the release of nitrite under X-ray irradiation, with a linear relationship between the amount released and the radiation dose received. An improved radio sensitization effect was observed due to the additional generation of RNS. This study has certain inspirations for the diversification of radiation sensitizers in the future.

3. The combination of X-ray radiotherapy and other cancer treatment methods

3.1 Combination with photodynamic therapy: X-ray responsive scintillator

Photodynamic therapy (PDT) and radiation therapy (RT) are both important local tumor ablation methods, and they share common anti-tumor effects, but their core principles and clinical characteristics are quite different. The similarity between the two is rooted in their ultimate cytotoxic effects: both can induce the generation of ROS, directly or indirectly causing oxidative damage to key biomolecules (such as DNA), ultimately triggering cell apoptosis and necrosis. However, there are fundamental differences in the mechanisms of action between PDT and RT. PDT is an oxygen dependent photochemical reaction that relies on the selective retention of photosensitizers in target tissues and local irradiation of specific wavelengths of light to achieve “dual targeting”,⁷⁴ but the depth of tissue penetration is limited.⁶ In contrast, RT is a physical process that relies on the direct energy deposition of high-energy ionizing radiation and the indirect radiation decomposition of water bodies. Although it can penetrate deep tissues,^75,76 its specificity mainly depends on the physical accuracy of the irradiation field, which can cause cumulative damage to normal tissues along the path. Therefore, PDT is more suitable for superficial or intracavitary lesions, with local phototoxicity and transient photosensitivity as the main side effects; RT has a wider range of indications and is suitable for most deep solid tumors, but it may cause systemic effects such as acute and chronic toxicity and bone marrow suppression related to the irradiation field. These two treatment methods each have their own advantages and disadvantages, and how to leverage their strengths while avoiding their weaknesses is a problem they face together. Some scholars have thus proposed X-ray induced photodynamic therapy (X-PDT), attempting to use X-ray as an initiator of photodynamic therapy to improve the selectivity of radiotherapy and the therapeutic effect on deep located cancer.⁷⁷ However, the X-ray energy used in clinical radiation therapy is generally in the range of hundreds of keV to MeV,⁷⁸ which differs greatly from that of traditional initiators such as visible light and UV light, resulting in an energy level mismatch, making it difficult for X-rays to directly and effectively activate most of the PDT photosensitizers.⁷⁹ Therefore, achieving X-PDT requires the involvement of a physical transducer that can absorb the energy of X-rays and convert it into photons of appropriate wavelengths that photosensitizers can effectively absorb. This type of transducer is generally referred to as a scintillator and has typical X-ray responsiveness. Scintillators can exhibit X-ray excited optical luminescence (XEOL), making it possible for X-rays to excite photosensitizers.⁶ XEOL is a photophysical process in which materials emit light in the low-energy optical band under high-energy X-ray irradiation. Scintillators achieve energy level matching between X-rays and photosensitizers through this process.

In addition to serving as an excitation light source for PDT, previous studies have shown that direct killing of cancer cells by X-rays plays an undeniable role during the X-PDT process.^80–83 Therefore, X-PDT essentially achieves the synergy of RT and PDT. Compared to standalone PDT or RT, X-PDT has several advantages in addition to expanding the effective therapeutic range of PDT. X-PDT can kill some tumor cells that are only resistant to radiation therapy (such as glioblastoma cells, prostate cancer cells, and colon cancer cells), and its required X-ray dose (generally within the range of 2–5 Gy) is lower than that of RT applied alone, which thereby reduces its side effects on normal tissues.⁶ Therefore, X-PDT has important research value and broad development prospects.

In 2006, the concept of X-PDT mediated by scintillator nanoparticles was first proposed.⁸⁴ Early research mainly focused on the establishment of X-PDT theoretical models and the feasibility verification of scintillator mediated X-PDT strategies for producing ROS in aqueous systems. These studies laid an important foundation for the subsequent development of this field. In 2009, Morgan et al.⁸⁵ proposed the first X-PDT theoretical model based on the assumption that X-ray photons colliding with nanoparticles would transfer all their energy to the nanoparticles, providing the relationship between the necessary emission yield of nanoscintillators and the incident X-ray energy. As the first attempt, this model has important guiding significance, although it has high uncertainty and only provides simulation results for one type of nanoscintillator (LaF₃). On the basis of Morgan's work, Bulin et al.⁸⁶ realized the fact that the range of secondary electrons generated by nanoscintillators is much larger than their own size, causing most of the X-ray energy transferred to the medium outside the scintillator, thus introducing a loss parameter η to quantify the actual energy transferred to the scintillator and partially improving the theoretical model of X-PDT. Klein et al.⁸⁷ then found that the electron absorption cross-section is a better predictor of the efficacy of X-PDT than the X-ray cross-section and further improved the theoretical model with the new benchmark. This model can predict the upper limit of the number of scintillation photons emitted by the scintillator. However, there are still some factors that have not been taken into account in the current proposed X-PDT models, such as uneven radiation dose deposition caused by density changes in the nanoparticle aggregation area. Therefore, there is seldom a comprehensive theoretical model that can fully explain the X-PDT phenomenon observed in preclinical testing. In most experimental studies, the luminescence intensity of scintillators excited by X-rays is weaker than that required by traditional PDT. However, the therapeutic effect of X-PDT can be observed, and some studies have even found that X-rays can directly activate certain types of photosensitizers without the involvement of scintillators.^88,89 Therefore, the actual X-PDT process may involve some non-optical forms of energy transfer, and there may also be a synergistic effect between RT and PDT. In the field of theoretical modeling, plenty of research works are still needed to truly elucidate the mechanism behind the phenomenon of X-ray stimulating PDT photosensitizers through scintillators.

The early experimental research on X-PDT mainly focused on verifying the ability of certain scintillators in solution systems to excite photosensitizers to produce ROS under X-ray irradiation. The research objects mainly include some fluoride and oxide scintillators. For example, members of the Yang group^90,91 synthesized mesoporous LaF₃:Tb nanoscintillators based on fluoride LaF₃ (Fig. 2A), which can emit green XEOL that can be absorbed by the photosensitizer Bengal rose red (RB) under X-ray irradiation, and detected the generation of ROS. Based on the oxide Tb₂O₃, Bulin et al.⁹² synthesized Dujardin group conjugated silica coating Tb₂O₃(Tb₂O₃@SiO₂) (Fig. 2B), the XEOL of which matches well with the absorption of the photosensitizer porphyrin and can also produce detectable ROS. In addition, similar studies have also been conducted on some scintillators based on lanthanide elements. For example, Kascákova et al.⁹³ reported the hydrophilic micelles of X-PDT composed of lanthanide chelates GdEuC₁₂ and hypericin (Hyp) (Fig. 2C), which can exhibit Eu³⁺ characteristic luminescence in the visible spectrum region that matches the absorption of Hyp under X-ray irradiation. The ability of this system to generate ROS has also been experimentally confirmed. These early experimental research results provide an important basis for future researchers to conduct in vitro cell experiments and in vivo therapeutic experiments.

Fig. 2 (A) Construction of an X-ray stimulated deep PDT system with silica-modified LaF₃:Tb–RB nanocomposites.⁹¹ Copyright 2015, Royal Society of Chemistry. (B) Synthesis of porphyrin-Tb₂O₃@SiO₂.⁹² Copyright 2013, American Chemical Society. (C) Schematic representation of the Hyp-GdEuC₁₂ micelles and the respective structures of the amphiphilic GdLnC₁₂ complex and the Hyp.⁹³ Copyright 2015, Springer Nature. (D) A nano-scintillator core made of SAO is coated with two layers of silica, an inner solid layer and an outer mesoporous layer. Into the mesoporous silica layer, a photosensitizer, MC540, is loaded. Under X-ray irradiation, SAO converts X-rays to visible light photons (XEOL). The visible light photons, in turn, activate near-by MC540 molecules to produce cytotoxic ¹O₂ that destroys nearby cancer cells. ³O₂ is the ground-state oxygen.⁹⁸ Copyright 2015, American Chemical Society.

After early experimental studies confirmed the feasibility of the X-PDT strategy in generating ROS, its application in cancer cells became a new research focus. Shortly after the concept of X-PDT was proposed, Takahashi et al.⁹⁴ first analyzed a batch of particle-form X-PDT scintillators in HeLa cells, mainly including TiO₂, ZnS: Ag, CeF₃, and quantum dots (CdTe and CdSe). They found a linear relationship between the production of ROS and the concentration of scintillator particles, and that its efficacy was not as expected, which may be attributed to poor uptake of scintillators by cancer cells. Abliz et al.⁹⁵ investigated the efficacy of terbium doped gadolinium oxysulfide scintillators (Gd₂O₂S: Tb) in activating the photosensitizer Photofrin II by an X-PDT strategy in human glioblastoma cell lines. They successfully observed significant inhibition of cancer cell growth, but due to the larger particle size of the scintillator (20 µm) and resulting poor internal circulation, it is still difficult to apply in vivo experiments. Ma et al.⁹⁶ attempted to investigate the in vitro cellular efficacy of ZnS: Cu, Co afterglow nanoparticles by utilizing the properties of persistent luminescent phosphors. The green XEOL of this scintillator can effectively activate the photosensitizer TBrRh123, and its XEOL can continue for more than 10 minutes after stopping X-ray irradiation. In the end, good therapeutic effects were observed, demonstrating the potential of afterglow nanoparticles to become excellent X-PDT scintillators. These studies have demonstrated the feasibility of X-PDT at the cellular level, but there are still drawbacks such as poor cellular uptake and poor in vivo circulation, thus giving X-PDT great potential for improvement. In addition to these studies on the performance of scintillators, there are also some in vitro studies pointing out other possibilities for achieving X-PDT. Traditionally, photodynamic therapy based on X-ray excitation typically relies on scintillators as energy transduction mediators, whose function is to convert high-energy X-ray photons into visible light and activate matching photosensitizers. However, in 2018, Clement et al.⁹⁷ proposed an important paradigm shift: in some cases, direct activation of photosensitizers by X-rays can be achieved without scintillators. Their in vitro experiment demonstrates that the nanosystem constructed using clinically approved polymer nanocarrier PLGA encapsulated photosensitizer Verteporfin can effectively generate singlet oxygen and induce significant cancer cell killing effects under 6 MeV therapeutic grade X-ray irradiation. Researchers attribute this phenomenon to two key physical mechanisms unrelated to scintillators: direct excitation by Cherenkov radiation and the action of high-energy secondary electrons. This study provides a possibility to achieve X-PDT without using scintillators. If this conclusion can be extended to a more general situation, it is possible to greatly simplify the design of X-PDT nanoplatforms and provide more attractive prospects for the rapid translation of this therapy into clinical applications. This is also a research direction worth exploring.

In the decade or so after the concept of X-PDT was proposed, there were almost no reports on in vivo experiments of X-PDT due to the relative lack of preliminary work such as solution system experiments and cell experiments. However, in recent years, with the improvement of the previous research mentioned above, more and more scholars have begun to focus on the in vivo efficacy of X-PDT, which has led this field to a new stage. Chen et al.⁹⁸ synthesized M-SAO@SiO₂ nanoparticles using scintillator nanoparticles SrAl₂O₄: Eu (SAO) as the core and loaded with Merocyanin 540 (MC540) silica coating (Fig. 2D). The bright green XEOL of SAO nanoparticles can effectively activate the photosensitizer MC540. It was successfully observed that M-SAO@SiO₂ nanoparticles effectively damaged RT resistant cancer cells under low-dose X-ray (0.5 Gy, single dose) irradiation, and no side effects on normal tissues were observed. The good hydrolysis ability of SAO also to some extent, avoided the possibility of long-term side effects of the nanoparticles. Compared to RT alone, in addition to making effective killing of cancer cells resistant to RT possible, another important goal of X-PDT is to minimize the required X-ray dose for treatment. Song et al.⁹⁹ synthesized (ZGO: Cr/W) nanocrystals by doping W (VI) in the scintillator ZnGa₂O₄:Cr (Fig. 3A) based on the characteristic that high Z metal elements can effectively deposit X-ray energy.^100,101 The XEOL intensity of the nanocrystals increased sharply compared to before doping, and they also had afterglow, enabling the long-time activation of the PDT process. The activation and significant therapeutic effect of the X-PDT process under low-dose X-ray irradiation (0.18 Gy) were successfully observed, proving that scintillators with appropriate designing can activate continuous X-PDT process under intermittent X-ray irradiation, effectively reducing the total X-ray dose required for treatment. Based on high Z metal elements alike, Sun et al.¹⁰² synthesized aggregates (AIE Au), which are composed of glutathione protected gold clusters (GCs) and Bengal rose red (RB) (Fig. 3B). Their XEOL is 5.2 times stronger than that of GC alone. When X-PDT takes effect, the large number of radiosensitive high Z gold atoms present in AIE-Au nanoparticles can also achieve radio sensitization simultaneously. The synergistic effect of the two enables the nanoparticles to efficiently inhibit tumor growth under low-dose X-ray irradiation. The above-mentioned in vivo experimental studies were conducted in a subcutaneous tumor model, which to some extent demonstrated the advantages of X-PDT compared to RT alone. The effective therapeutic depth advantage of X-PDT compared to PDT alone cannot be solely demonstrated by the experimental results of subcutaneous tumor tissue. In response to this issue, Wang et al.⁸¹ attempted to simulate a deep tumor environment by placing a piece of pork with a thickness of approximately 1–2 cm between the X-ray source and subcutaneous tumor tissue. The results showed that the depth of tumor tissue had barely effect on the efficacy of X-PDT. This simulation method, although simple, is effective. Overall, the in vivo experimental research of X-PDT is still in its early stages and requires more research work and experimental support.

Fig. 3 (A) Schematic illustration for the design of X-ray activated PLNP-mediated PDT nanoplatform.⁹⁹ Copyright 2018, John Wiley and Sons. (B) Schematics showing the preparation of AIE-GCs and R-AIE-Au nano-sensitizers.¹⁰² Copyright 2019, John Wiley and Sons.

3.2 Combination with chemotherapy: X-ray responsive drug delivery system

Chemotherapy, as one of the three major tumor treatment methods alongside radiation therapy and surgical treatment, is also widely used.^103–105 As a systemic treatment method, in the traditional chemotherapy process, regardless of the route of administration (oral, intravenous, intracavitary, etc.), chemotherapy drugs (usually cytotoxic drugs) will spread throughout almost all the organs and tissues through blood circulation.^106–108 Although the characteristic of chemotherapy endows it with outstanding therapeutic effects on some tumors that have a tendency to spread throughout the body and have already metastasized in the middle and advanced stages, in more common cases, the systemic distribution of cytotoxic drugs can cause damage to normal tissue cells apart from solid tumor tissue, leading to serious side effects such as digestive system adverse reactions, bone marrow suppression, hair loss, and liver and kidney dysfunction and damage, which can pose a serious adverse impact on the quality of life of patients.^109–113 Therefore, since the last century, how to minimize the side effects of chemotherapy has always been an important goal in the field of cancer treatment research, whose essence is to avoid the killing of normal tissue cells by chemotherapy drugs while maintaining their killing power against tumor tissue cells.¹⁰⁹ Developing new-type drug delivery systems (DDSs) and overcoming the limitations of conventional DDSs may be an effective solution: load chemotherapy drugs that do not have targeting properties into DDSs and control the release of chemotherapy drugs only at the tumor tissue site through specific design of DDS, thereby avoiding the systemic toxicity of traditional chemotherapy.¹¹⁴

In recent years, there has been increasing research on various DDSs, among which, radiation responsive ones have received special attention. This type of DDS can be controlled through external radiation, which means that it may become a bridge between radiotherapy and chemotherapy.^115–117 If these two treatment methods can be combined, on the one hand, the controllable advantages of radiotherapy in time and space can be utilized. The radiation used in radiotherapy (usually X-rays) can activate the DDS at specific locations, thereby controlling the release of chemotherapy drugs at specific times and locations, and reducing the side effects caused by chemotherapy. On the other hand, both the drugs used in chemotherapy and the radiation used in radiotherapy have a killing effect on cancer cells, whose combination can improve treatment efficiency, shorten treatment cycles, thus reducing the side effects caused by radiation therapy to a certain extent, and provide better economic benefits.¹¹⁵ This kind of DDS has the potential to achieve a combination of radiotherapy and chemotherapy, to some extent avoiding the shortcomings of both therapies while leveraging their advantages, thus becoming an excellent solution to solve the problem of chemotherapy side effects.

In 1999, Lehn first proposed the concept of dynamic covalent bonding (DCB).¹¹⁸ DCB is a special covalent bond that can undergo reversible exchange under certain stimuli (such as light, heat, and humidity changes). In the past few years, the potential applications of DCB in self-healing materials, shape memory materials, supramolecular chemistry, surface modification, and stimulus responsive materials have gradually been explored.^119–122 At present, various chemical bonds have been demonstrated to have dynamic covalent bonding properties, mainly including imine bonds, acylhydrazone bonds, disulfide bonds, diselenide bonds, and thioketal bonds,^123–126 some of which, mainly diselenide bonds, have also been clearly confirmed to have X-ray response characteristics.^127–130 If these X-ray responsive DCBs are applied in the design of DDSs, remote control of drug delivery through X-rays can be achieved, making the idea of combining radiotherapy and chemotherapy through DDSs a reality.

Disulfide bonds naturally exist in various protein structures and are closely related to the biological structure and activity of proteins, making them one of the earliest studied dynamic covalent bonds.^131–133 However, their bond energy (240 kJ mol⁻¹) is relatively large in various DCBs, resulting in poor ability to respond to radiation.¹³⁴ Selenium is one of the essential trace elements for the human body, which is an oxygen group element along with sulfur. Their chemical properties are similar, while selenium has a larger radius and lower electronegativity than sulfur.¹³⁵ Therefore, it can be expected that the diselenide bond has better reactivity than the disulfide bond. The bond energy data (diselenide bond energy: 172 kJ mol⁻¹)¹³⁴ and single molecule force spectroscopy (SMFS) confirm this speculation,¹³⁶ indicating that the diselenide bond is a more sensitive dynamic covalent bond than the disulfide bond. As mentioned above, diselenide bonds have demonstrated responsiveness to X-rays and are relatively feasible to synthesize. Therefore, they have received special attention among various types of DCBs, and selenium containing polymers have been widely studied as a new type of biomaterial.¹³⁷

In recent years, most research on X-ray responsive DDSs has been related to diselenide bonds. Wang et al.¹³⁸ designed a drug delivery system of X-ray responsive peptide nanogel (PNG) based on the cross linking of diselenide bonds. The nanogel was obtained by introducing diselenide bonds into the mPEG-b-P (LG-co-CELG) micelle (PM) structure through cross linking with sodium selenide (Na₂Se₂), and then encapsulated the chemotherapy drug doxorubicin (DOX) in it through diffusion and dialysis (Fig. 4A). The in vitro experiment confirmed that DOX loaded polypeptide nanogel (PNG/DOX) showed controlled rapid drug release under X-ray irradiation, and almost no encapsulated DOX could diffuse from PNG/DOX in a certain time without X-ray irradiation. The in vivo experimental results have shown that the combination of PNG/DOX and X-ray irradiation can exhibit good synergistic anti-tumor effects and relatively fewer side effects in nude mice bearing A549 lung cancer, indicating that the DDS meets the design expectations. This study demonstrates a typical structural design and performance verification process for an X-ray responsive DDS based on diselenide bonds, which is highly representative in similar studies. The DDS designed by Shao et al.¹³⁹ was based on mesoporous organosilicon nanoparticles (MONs), using the sol-gel method to bridge MON monomers with diselenide bonds. They also studied the mechanism of diselenide bond breaking (oxidized to selenite) under X-ray irradiation. Then, they loaded DOX into nanoparticles, separated 4T1 breast cancer cell membrane (CM) for wrapping, and finally obtained the drug loaded nanoparticles with CM coating (CM@MON@DOX), aiming at promoting tumor targeting and immune system escape of the nanoparticles and enabling them to be used in combination with PD-L1 immune checkpoint inhibitors (Fig. 4B). This attempt to combine radiation therapy, chemotherapy, and immunotherapy has achieved more significant therapeutic effects, but has also detected a certain degree of adverse immune reactions, which is a meaningful attempt to combine more types of therapies together. Zhang et al.¹⁴⁰ focused on the minimum X-ray dose required to trigger an X-ray responsive DDS based on diselenide bonds for drug release. Their selenium containing nanoparticles (Se NPs) were self-assembled in aqueous solution from a triblock amphiphilic copolymer containing diselenide and loaded with DOX as well. Subsequently, a series of control experiments were conducted to demonstrate that when ROS is present in the system, only 2 Gy of X-rays is needed to trigger the cleavage of diselenide bonds and effective drug release in Se NPs. They also conducted a more detailed study on the potential molecular mechanism of X-ray triggered diselenide bond cleavage through density functional theory (DFT) calculations (Fig. 4C). This study clarifies the effectiveness of DDSs based on diselenide bonds under low-dose X-rays, which to some extent proves their practical value.

Fig. 4 (A) Synthesis of mPEG-b-P(LG-co-CELG).¹³⁸ Copyright 2021, Elsevier. (B) Schematic of synthesis of diselenide-bond-bridged MONs for low-dose X-ray radiation-controllable drug release.¹³⁹ Copyright 2020, John Wiley and Sons. (C) Direct dissociation of CH₃SeSeCH₃ under irradiation (Path 0) together with oxidation steps of CH₃SeSeCH₃ (Path I) and CH₃Se˙ by H₂O₂ (Path II). Energy barriers (E_a) and reaction energies (ΔE) are noted in blue text. White, H; gray, C; red, O; and orange, Se.¹⁴⁰ Copyright 2020, American Chemical Society.

Besides serving as a DDS, certain diselenide bond structures themselves may also exhibit anti-cancer activity under X-ray irradiation. Yu et al.¹⁴¹ prepared X-ray responsive selenium containing nanoparticles (PEG–SeNPs) using polyethylene glycol as a surface modifier and template, and found that the particles had a significant radio sensitization effect on X-rays (Fig. 5A). The principle is similar to that of most other radiosensitizers, which mainly induces the generation of intracellular ROS and causes cell apoptosis. In order to investigate the reason for the radio sensitization effect of PEG–SeNP, they synthesized two other selenium-containing nanoparticles, PEGW–SeNP and PVP–SeNP. The experiment observed that the last two types of nanoparticles have a crystalline nucleus structure, and neither showed any radio sensitization effect. Therefore, the radio sensitization effect of PEG–SeNP may be attributed to its amorphous structure, which may be caused by the conjugation of selenium atoms and hydroxyl in PEG.

Fig. 5 (A) Illustration of the changes of PEG–SeNPs inside the cells.¹⁴¹ Copyright 2016, Elsevier. (B) The schematic illustration of T-(NPVP)-N-TK. Once exposed to external X-ray radiation, it can produce ROS, which not only directly kill GBM cells, but also induce substantial breakage of the TK linker, thus dissociating the nanocarriers and releasing PTX to initiate cascaded and locoregional chemotherapy.¹⁴² Copyright 2022, Royal Society of Chemistry.

In addition to diselenide bonds, certain other types of DCBs can also be applied to the design of X-ray responsive DDSs. For example, the X-ray responsiveness of a multifunctional nanocarrier (T-(NPVP)-N-TK) designed by Zhang et al.¹⁴² for glioblastoma (GBM) is derived from another DCB, the thioketal bond (TK) (Fig. 5B). In addition to reducing side effects through radiotherapy combined with chemotherapy, in order to solve the problem of poor chemotherapy efficacy of GBM due to the difficulty of conventional chemotherapy drugs penetrating the blood–brain barrier (BBB),^143,144 this nanocarrier was also functionalized through angiopeptide-2 (Ang, a protein targeting LRP-1 that is overexpressed in both the BBB and GBM cells). This nanocarrier is not only used as a DDS, in addition to loading the chemotherapy drug paclitaxel (PTX), it also carries the photosensitizer Vitipofen (VP) to enable X-PDT intervention. It was successfully observed that the nanocarrier effectively crosses the BBB, achieves controllable release of PTX, together with the ROS generated by the X-PDT process, proving the effectiveness of the above design. The simultaneous effects of RT, chemotherapy, and X-PDT significantly inhibited the in situ growth of GBM, resulting in a significantly prolonged survival time of U87-MG tumor bearing mice. This study expands the scope of DCB that can be used for DDS design, and its idea of combining more types of therapies together and special attention to X-PDT also provides new insights for future research.

On the other hand, introducing dynamic covalent bonds is not the only way to achieve the combination of radiotherapy and chemotherapy. Any system that can be activated by X-rays to produce physical or chemical changes has the potential to become an analogous drug delivery system. For example, Deng et al.¹⁴⁵ developed an innovative intelligent liposome delivery system in 2018 which co encapsulates gold nanoparticles and photosensitizer vitriprofen in a lipid bilayer and enhances its targeting of tumor cells by linking folate. When exposed to high-energy X-rays commonly used in clinical radiotherapy, the system can effectively generate singlet oxygen, disrupt the lipid membrane structure, and release the gene drugs or chemotherapy drugs loaded in its chamber as needed. This strategy successfully achieved gene silencing in vitro and significantly enhanced chemotherapy efficacy in vivo, providing a new paradigm for combination therapy of deep tumors. Therefore, future research in this field does not necessarily have to be limited to various dynamic covalent bonds, and there are more interesting unknown systems waiting to be explored.

4. Conclusion and prospects

This review introduces the research progress of X-ray responsiveness in the field of tumor treatment in recent years. Specifically, it introduces the promotion of X-ray responsive radiosensitizers on X-ray RT itself, as well as the combination of RT and other cancer therapies mediated by X-ray responsive therapeutic systems, which mainly includes the combination of RT and PDT through X-ray responsive scintillators and the combination of RT and chemotherapy through X-ray responsive DDSs.

The use of radiosensitizers is an important way to improve the efficacy of tumor RT and reduce side effects. In recent years, research in this field has developed rapidly, with the main trend being to make them more efficient, safe, intelligent, and diverse. At present, this field still faces many challenges, such as poor biocompatibility, poor targeting, low efficiency, etc. Several research works introduced in this review have partially solved these problems through various strategies, but there are still challenges to develop truly large-scale clinical use of radiation sensitizers. How to thoroughly solve these problems will still be the key to developing new radiosensitizers in the future. When designing radiosensitizers, there are several aspects that need to be carefully considered, including: (1) better targeting, not only to tumor tissue, but also to cells as much as possible to achieve a high T/N ratio; (2) the ability to quickly enrich and clear in tumor tissue; and (3) the verification of the changes, metabolic pathways, and safety after X-ray irradiation.

X-ray responsive scintillator mediated X-PDT, as an emerging cancer treatment method, is essentially a combination therapy of RT and PDT. Compared with single RT or PDT, it has significant advantages, especially in breaking through the effective treatment depth limitations of traditional PDT. Since its concept was first proposed, X-PDT has made significant progress. However, the in vivo experimental research of X-PDT is still in its early stages, and there are still significant areas for improvement in both theoretical model construction and in vitro experiments. In terms of constructing theoretical models, there is currently no comprehensive theoretical model that can fully explain the X-PDT phenomenon observed in preclinical testing, and research on the mechanism of X-PDT is still in the exploratory stage, which may also limit the development of experimental research to a certain extent. In terms of experimental research, for in vitro experiments, there are currently few types of scintillators studied, and the cellular uptake of scintillators is generally poor. Therefore, it may be necessary to explore more types of scintillators, such as organic scintillators or light element-based scintillators, or find suitable modification methods to improve the cellular uptake of scintillators. On the other hand, the possibility of realizing X-PDT without the involvement of scintillators is also worth exploring. For in vivo experiments, the number of reported research works related is still relatively limited, thus more research work and experimental data support are needed. In addition, almost all existing in vivo experimental studies have directly injected nanoparticles into tumor tissue, and few studies have included the targeting and migration of nanoparticles in the research scope. Therefore, the non-invasive treatment ability of X-PDT on deep tumor tissue has not been clearly demonstrated through experiments, and more detailed design of nanoparticles is still needed, such as binding with certain targeted groups. The utilization of XEOL during the X-PDT process is also enlightening. In the future, it may be attempted to apply it to other fields besides PDT, such as photothermal therapy (PTT).

The X-ray responsive DDS can achieve the combination of chemotherapy and RT, reducing chemotherapy side effects while improving the efficiency of RT, and has unique advantages. Compared with research in the X-PDT field, research in this field is relatively more mature, but there is still much room for improvement. On the one hand, the types of DCBs that can be used for DDS design still need further expansion. In recent years, most related studies have used diselenide bonds as the source of X-ray responsiveness. Although in the current reported research, diselenide bonds almost never cause off target release of chemotherapy drugs without stimulation, some scholars still have doubts about their stability in certain tumor cell environments due to the low bond energy. At present, the adaptability of these DDSs based on diselenide bonds to different drugs and their response to low-dose X-rays also require more in-depth animal and clinical trial validation. Enriching the available types of DCBs can provide a theoretical basis for the design of DDSs tailored to different scenarios and needs. On the other hand, the design of DDSs still needs to be more refined. The future DDS will not only be able to achieve controlled drug release, but also require more targeted designs, such as designs targeting the immune system or the BBB mentioned above, or even programmable designs. In addition, besides systems based on dynamic covalent bonds, other systems that can respond to X-rays and undergo physical and chemical changes also have the potential to become similar drug delivery systems. Therefore, the future of this field has infinite possibilities.

Overall, these research fields are different but closely related, essentially all aimed at achieving more efficient and targeted tumor cell killing. There is also a possibility of combining them, such as improving the in vivo distribution of radiosensitizers/photosensitizers through delivery systems. In recent years, the latest research works also have regular patterns to follow; most studies that combine more than two therapies have achieved unexpected results. Therefore, the synergistic effect between different therapies may be the key to further improving efficacy. The future overall development trend of X-ray responsive therapeutic systems in cancer treatment may be to integrate as many different therapies as possible on a single nanoparticle to achieve the maximum synergistic effect. Obviously, research on X-ray responsive therapeutic systems will continue to deepen in the future. We believe that with the joint efforts of scholars around the world, this unique type of system will make greater contributions to the management and healthcare for tumor treatments.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

The authors would like to acknowledge the financial support provided by the National Key R&D Program of China (2022YFA1203002) and Jiangsu Provincial Science and Technology Plan Special Fund (BM2023008). Additionally, the research endeavors have received partial funding from the Fundamental Research Funds for the Central Universities, from the MOE Key Laboratory of High-Performance Polymer Materials & Technology at Nanjing University (Grand No. 020514380274), as well as from the joint support from the Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine (funded by the Nanjing Municipal Health Commission) and its Jiangsu counterpart.

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