Ionizing radiation-induced drug release is a combined chemoradiation therapy, which aims to reduce the systemic toxicity of chemotherapeutics. Radiation is used for both radiotherapy and to trigger the release of a chemotherapeutic. To understand radiation-induced drug activation and to design new radiation-sensitive chemotherapeutics, it is important to become familiar with the underlying reaction mechanisms. Here, we provide an overview of the crucial process of water radiolysis induced by ionizing radiation and the mechanisms of reactive species generation. We also discuss the reactivity of these species with cellular components and chemical functional groups, to give insight into selective drug activation in complex cellular environments. Finally, we discuss recent progress on radiation-induced drug release focusing on the reaction of water radiolysis products with drug caging groups and the yield of released drugs. We aim to bridge the gap between basic chemical processes in water radiolysis and their relevance for drug release and provide suggestions on the design of radiation-sensitive prodrugs or nanocarriers.

The radionuclide 99mTc, obtained as a decay product of 99Mo from a 99Mo/99mTc generator, is extensively used as a diagnostic agent in nuclear medicine. Presently, high specific activity 99Mo is predominantly produced in nuclear reactors as a byproduct from 235U fission. However, this approach generates large amounts of nuclear waste and also faces challenges due to the decommissioning of aging research reactors. Alternative production routes using 98Mo or 100Mo as target materials have gained attention, but they inevitably result in low specific activity 99Mo. Additionally, the limited adsorption capacity of the aluminum oxide, the conventional sorbent in the 99Mo/99mTc generator, restricts its use with low specific activity 99Mo. We therefore propose to use molybdenum-based nanomaterials functioning as both target as well as generator material for the selective extraction of 99mTc. By circumventing the necessity for sorbent material, we greatly increase the amount of Mo in the generator itself such that the low specific activity is no longer an issue. The ability to selectively extract 99mTc while keeping the nanomaterial intact allows for re-irradiation, making the process recyclable. We have synthesized MoS2 nanomaterials with distinct morphologies─nanoflowers, nanotubes, calcinated nanotubes, and nanodispersed sheets─and evaluated their properties. The material morphology significantly influenced the physicochemical properties, consequently impacting the 99mTc extraction efficiencies. Among these materials, nanodispersed sheets, having the highest surface area (124 ± 35 m2/g), exhibited superior performance, achieving 12% 99mTc extraction in methylethylketone (MEK) with negligible Mo contamination. These nanodispersed sheets also demonstrated excellent structural stability over multiple irradiation–extraction cycles, paving the way for a recyclable and cost-effective 99Mo/99mTc generator.

Irradiation of aqueous solutions containing alkyl chlorides generates peroxyl radicals by reactions of alkyl chlorides, aqueous electrons, and dissolved oxygen. The peroxyl radical can oxidize thioethers to sulfoxides, a transformation that has relevance for targeted or triggered drug delivery. However, small-molecule alkyl chlorides can induce liver damage, which limits their potential for application in anticancer therapy. Here, we show that alkyl chlorides bound to a hydrophilic random copolymer chain behave similar to small-molecule alkyl chlorides. Our work shows that using polymeric alkyl chlorides can be an alternative to small-molecule alkyl chlorides provided that the alkyl chloride functionalities are easily accessible to aqueous electrons.

The interest in hybrid nanoparticles for various applications in biomedicine is growing inevitably, stimulating research towards not only more effective, but also more accessible systems. This resulted in the emergence of advanced synthetic protocols with optimized conditions for the production of nanoparticles with high yields and desired morphologies, which ultimately determine their physicochemical and biomedical properties. While these challenges were sufficient for scientists a few decades ago, the sustainability of the synthetic methods is now an important aspect. From this perspective, nanoparticle production methods based on physical principles, such as spark discharge phenomena, could provide an interesting alternative to labor-intensive and environmentally harmful chemical synthesis. The benefits of clean and sustainable physical production routes for various nanomaterials are already recognized in the fields of catalysis and electronics. Biomedicine on the other hand has been reluctant to embrace the new methodologies, as they do not inherently provide nanoparticles dispersed in aqueous media, which is essential for their safe administration and reliable physiological performance. In this work, we investigated the potential of spark discharge as an alternative method to produce hybrid palladium/iron oxide nanoparticles intended for cancer thermo-brachytherapy by leveraging the magnetothermal properties of iron and the favorable radioactive features of the palladium radioisotope. Focusing on the aqueous harvesting of the nanoparticles produced in VSParticle’s spark discharge generator, we determined the optimal settings compatible with the connected bubbling column and identified the pitfalls and possible solutions to the intrinsic challenges, such as low yields and aggregation.

Chromium-51 (51Cr) is an attractive radionuclide for diagnosis, which is usually applied for red cells and platelet radiolabeling. However, commercially available 51Cr produced in nuclear reactors via neutron activation requires long irradiation times and complex separation methods. In this work, five metal–organic frameworks (MIL-100 (Cr), MIL-100 (Fe), MIL-100 (Al), MIL-101 (Cr) and aluminium fumarate MOF (FuAl)) were synthesized and the effect of gamma ray irradiation with a high dose rate and a maximum dose of 6 MGy was investigated. The two chromium-based MOFs, MIL-100 (Cr) and MIL-101 (Cr), were selected as radiation targets to produce high specific activity 51Cr by the Szilard-Chalmers effect. A solid–liquid extraction was applied to extract the produced 51Cr under different conditions, including different extractants, extraction times and pH. The most promising results were achieved when using irradiated MIL-101 (Cr) and EDTA as extracting agent, reaching an enrichment factor of 1132 ± 50.

Photosensitizers have significant potential as radiosensitizers in cancer treatment, yet the mechanism of ionizing-radiation-induced singlet oxygen (¹O₂) generation remains unclear. Here, we systematically investigated ¹O₂ production by the photosensitizer Chlorin e6 (Ce6) using the Singlet Oxygen Sensor Green probe and imidazole/ p -nitroso- N , N -dimethylaniline detection methods, evaluating the effects of photon energy (X-rays up to 310 kV and ⁶⁰Co gamma rays at 1.17 and 1.33 MeV), dose, and dose rate. Ce6 produced more ¹O₂ with increasing photon energy. At 5 Gy, the lowest dose rate (0.005 Gy/min) yielded significantly more ¹O₂ than higher dose rates (7–0.05 Gy/min). Scavenging experiments identified superoxide anions (·O₂⁻) as a key intermediate. We propose that, unlike classical triplet-state photosensitization, ionizing radiation induces Ce6 radical cations (Ce6^⋅+), which react with radiation-induced ·O₂⁻ to generate ¹O₂. These findings suggest potential for photosensitizer-radiation combinations in low-dose-rate therapies, although further biological validation and consideration of tumor redox status are required.

A combination of spontaneous Raman, stimulated Raman, and photothermal expansion (AFM-IR) spectromicroscopy is reported for probing the impact of different radiation doses (2–10 Gy) on U87 glioma cells ex vivo. Most significant are alterations in spectral profiles caused by radiation-induced changes, while keeping the cell fixation delay constant at 24 h. The changes in delay of the fixation ranging up to 5 d at a dose of 2 Gy were also investigated for probing cellular recovery processes of exposed cells. Both, the Raman-based and AFM-IR spectral analyses identified statistically significant spectral changes and radiation-induced alterations in cellular proteins, nucleic acids, and lipids. Specifically, these label-free approaches revealed a 3-fold and 2-fold decrease in nucleic acid and lipid content, respectively, for cells treated with 10 Gy compared to untreated control samples. This study unravels the potential of a combination of Raman-based approaches and AFM-IR that is of use for therapeutics and offers a novel way to monitor and localize radiotherapy-induced changes in tumor cells.

Boronic acid and ester-caged prodrugs have been widely investigated in cellular-generated hydrogen peroxide triggered release. Although it is well-known that ionizing radiation generates hydrogen peroxide in aqueous solution, using this approach to activate boronic acid or ester-based prodrugs suffers from low H₂ O₂ yields and thus low uncaging efficiency. However, the organochloride peroxyl radical formed from irradiating an aqueous solution of an organochloride may increase the uncaging efficiency. In this study, we used a boronic acid-caged coumarin derivative to quantify the yield of oxidation induced by clinical doses of radiation (less than 8 Gy), and boronic acid-caged gemcitabine to assess the activation of a prodrug upon irradiation. Irradiation of the coumarin derivative in phosphate buffered saline shows a low yield of 0.048 µM per Gy, and the prodrug after irradiation has only limited toxicity to the U87 cell line, indicating limited uncaging. The oxidation of boronic acid can be greatly enhanced by the peroxyl radical generated from irradiation of dilute PBS-organochloride solutions, with the yield increasing to 0.13 µM per Gy. Moreover, the oxidation by peroxyl radical can be catalyzed by N,N-dimethylaniline derivatives, increasing the yield to 0.19 µM per Gy. Clinical dose irradiation of the caged gemcitabine derivative in a solution of PBS with trichloroethanol and 2-(dimethylamino)benzoic acid shows efficient tumor cell killing and a comparable toxicity with that of the parent drug, indicating efficient uncaging.

The original publication of this article contained an incorrect author name. The incorrect and correct information is listed in this correction article. The original article has been updated.

Objective: To investigate the potential of hybrid Pd/Fe-oxide magnetic nanoparticles designed for thermo-brachytherapy of breast cancer, considering their specific loss power (SLP) and clinical constraints in the applied magnetic field. Methods: Hybrid nanoparticles consisting of palladium-core and iron oxide shell of increasing thickness, were suspended in water and their SLPs were measured at varying magnetic fields (12–26 mT peak) and frequencies (50–730 kHz) with a commercial alternating magnetic field generator (magneTherm™ Digital, nanoTherics Ltd.). Results: Validation of the heating device used in this study with commercial HyperMag-C nanoparticles showed a small deviation (±4%) over a period of 1 year, confirming the reliability of the method. The integration of dual thermometers, one in the center and one at the bottom of the sample vial, allowed monitoring of homogeneity of the sample suspensions. SLPs measurements on a series of nanoparticles of increasing sizes showed the highest heating for the diameter of 21 nm (SLP = 225 W/g) at the applied frequencies of 346 and 730 kHz. No heating was observed for the nanoparticles with the size <14 nm, confirming the importance of the size-parameter. The heating ability of the best performing Pd/Fe-oxide-21 was calculated to be sufficient to ablate tumors with a radius ±4 and 12 mm using 10 and 1 mg/mL nanoparticle concentration, respectively. Conclusions: Nanoparticles consisting of non-magnetic palladium-core and magnetic iron oxide shell are suitable for magnetic hyperthermia/thermal ablation under clinically safe conditions of 346 kHz and 19.1 mT, with minimal eddy current effects in combination with maximum SLP.

The controlled release of drugs using local ionizing radiation presents a promising approach for targeted cancer treatment, particularly when applied in concurrent radio-chemotherapy. In these approaches, radiation-generated reactive species often play an important role. However, the reactive species that can be used to trigger release have low yield and lack selectivity. Here, we demonstrate the generation of highly oxidative species when aqueous solutions containing low concentrations of organochlorides (such as chloroform) are irradiated with ionizing radiation at therapeutically relevant doses. These reactive species were identified as peroxyl radicals, which formed in a reaction cascade between organochlorides and aqueous electrons. We employed stilbene-based probes to investigate the oxidation process, showing double bond oxidation and cleavage. To translate this reactivity into a radiation-sensitive material, we synthesized a micelle-forming amphiphilic block copolymer that has stilbene as the linker between two blocks. Upon exposure to ionizing radiation, the oxidation of stilbene led to the cleavage of the polymer, which induces the dissociation of the block-copolymer micelles and the release of loaded drugs.

Radionuclide therapy employing alpha emitters holds great potential for personalized cancer treatment. However, certain challenges remain when designing alpha radiopharmaceuticals, including the lack of stability of used radioconjugates due to nuclear decay events. In this work, ultrasmall silver telluride nanoparticles with a core diameter of 2.1 nm were prepared and radiolabeled with lead-212 using a chelator-free method with a radiolabeling efficiency of 75%. The results from the in vitro radiochemical stability assay indicated a very high retention of bismuth-212 despite the internal conversion effects originating from the decay of 212Pb. To further evaluate the potential of the nanoparticles, they were radiolabeled with indium-111, and their cell uptake and subcellular distribution were determined in 2D U87 cells, showing accumulation in the nucleus. Although not intentional, it was observed that the indium-111-radiolabeled nanoparticles induced efficient tumor cell killing, which was attributed to the Auger electrons emitted by indium-111. Combining the results obtained in this work with other favorable properties such as fast renal clearance and the possibility to attach targeting vectors on the surface of the nanoparticles, all well-known from the literature, these ultra-small silver telluride nanoparticles provide exciting opportunities for the design of theragnostic radiopharmaceuticals.

The relatively high linear energy transfer of Auger electrons, which can cause clustered DNA damage and hence efficient cell death, makes Auger emitters excellent candidates for attacking metastasized tumors. Moreover, gammas or positrons are usually emitted along with the Auger electrons, providing the possibility of theragnostic applications. Despite the promising properties of Auger electrons, only a few radiopharmaceuticals employing Auger emitters have been developed so far. This is most likely explained by the short ranges of these electrons, requiring the delivery of the Auger emitters to crucial cell parts such as the cell nucleus. In this work, we combined the Auger emitter ¹²⁵I and ultrasmall gold nanoparticles to prepare a novel radiopharmaceutical. The ¹²⁵I labeled gold nanoparticles were shown to accumulate at the cell nucleus, leading to a high tumor-killing efficiency in both 2D and 3D tumor cell models. The results from this work indicate that ultrasmall nanoparticles, which passively accumulate at the cell nucleus, have the potential to be applied in targeted radionuclide therapy. Even better tumor-killing efficiency can be expected if tumor-targeting moieties are conjugated to the nanoparticles.

Multifunctional, biocompatible magnetic materials, such as iron oxide nanoparticles (IONPs), hold great potential for biomedical applications including diagnostics (e.g., MRI) and cancer therapy. In particular, they can play a crucial role in advancing cancer thermotherapy by generating heat when administered intratumorally and when exposed to an alternating magnetic field. This heat application is often combined with radio- (chemo)therapy and/or imaging. Consequently, the design of materials for such a multimodal approach requires hybrid nanoparticles that retain their magnetic properties while integrating additional functionalities. This work introduces synthesis and investigation of magnetically enhanced nanoparticles with a palladium core (envisioned for future radiolabeling with therapeutic 103Pd) and a magnetic iron oxide shell containing paramagnetic manganese (Pd/Fe|(nMn)-oxide, n = 0.25 and 0.5). Doping the iron oxide lattice with Mn significantly increases magnetic saturation, boosting specific loss power up to 1.7 times compared to that of undoped analogs. Interestingly, higher Mn-content in Pd/Fe|(0.5Mn)-oxide leads to a pronounced Mn outer rim, enhancing the heating efficiency at 346 kHz and 23 mT and contributing to the water exchange on the surface of the paramagnetically doped nanoparticles, resulting in additional T1 MRI contrast. The enhanced magnetic properties of the hybrid Pd/Fe|Mn-oxide nanoparticles enable effective therapeutic outcomes with injection of only small quantities of the material, offering great potential for effective cancer treatment strategies that combine hyperthermia/thermal ablation with radiotherapy while allowing for real-time monitoring via MRI.

While hyperthermia has been shown to induce a variety of cytotoxic and sensitizing effects on cancer tissues, the thermal dose–effect relationship is still not well quantified, and it is still unclear how it can be optimally combined with other treatment modalities. Additionally, it is speculated that different methods of applying hyperthermia, such as water bath heating or electromagnetic energy, may have an effect on the resulting biological mechanisms involved in cell death or in sensitizing tumor cells to other oncological treatments. In order to further quantify and characterize hyperthermia treatments on a cellular level, in vitro experiments shifted towards the use of 3D cell spheroids. These are in fact considered a more representative model of the cell environment when compared to 2D cell cultures. In order to perform radiofrequency (RF)-induced heating in vitro, we have recently developed a dedicated electromagnetic field applicator. In this study, using this applicator, we designed and validated an experimental setup which can heat 3D cell spheroids in a conical polypropylene vial, thus providing a reliable instrument for investigating hyperthermia effects at the cellular scale.

Combination of therapies is a common strategy in cancer treatment. Such combined therapies only have merit provided that there is superior therapeutic outcome with fewer side effects, compared to single therapies. Here, this work explores the possibility to combine chemotherapy with radionuclide therapy using polymeric micelles as a delivery vehicle. For this purpose, this work prepares poly(ε-caprolactone-b-ethylene oxide) (PCL-PEO) micelles and load them simultaneously with paclitaxel (PTX) and ¹⁷⁷Lu(III). This work chooses a 3D tumor spheroid composed of glioblastoma cells (U87) to evaluate the combined treatment. The diffusion of the micelles in the spheroid is investigated by confocal laser scanning microscopy (CLSM) and light-sheet fluorescence microscopy (LSFM). The results show that the micelles are able to penetrate deep into the spheroid within 24 h of incubation and mainly accumulated around or in the lysosomes once in the cell. Subsequently, this work evaluates the cell killing efficiency of the single treatments (PTX or ¹⁷⁷Lu(III)) versus combined treatment (PTX + ¹⁷⁷Lu(III)) by measuring the growth of the spheroids as well as by performing a cell-viability assay. The results indicate that the combined therapy achieves a superior therapeutic outcome with better cell growth inhibition and cell killing efficiency compared to the single treatments.