Radiodynamic Therapy Research Articles

Treating Deep-Seated Tumors with Radiodynamic Therapy: Progress and Perspectives.

Radiodynamic therapy (RDT), as an emerging cancer treatment method, has attracted attention due to its remarkable therapeutic efficacy using low-dose, high-energy radiation (such as X-rays) and has shown significant potential in cancer treatment. The RDT system typically consists of scintillators and photosensitizers (PSs). Scintillators absorb X-rays and convert them to visible light, activating nearby PSs to generate cytotoxic reactive oxygen species (ROS). Challenges faced by the two-component strategy, including low loading capacity and inefficient energy transfer, hinder its final effectiveness. In addition, the tumor microenvironment (TME) with hypoxia and immunosuppression limits the efficacy of RDTs. Recent advances introduce one-component RDT systems based on nanomaterials with high-Z metal elements, which effectively inhibit deep-seated tumors. These novel RDT systems exhibit immune enhancement and immune memory, potentially eliminating both primary and metastatic tumors. This review comprehensively analyzes recent advances in the rational construction of RDTs, exploring their mechanisms and application in the treatment of deep-seated tumors. Aimed at providing a practical resource for oncology researchers and practitioners, the review offers new perspectives for potential future directions in RDT research.

Oxygen-Independent Radiodynamic Therapy: Radiation-Boosted Chemodynamics for Reprogramming the Tumor Immune Environment and Enhancing Antitumor Immune Response.

Radiodynamic therapy (RDT) has emerged as a promising modality for cancer treatment, offering notable advantages such as deep tissue penetration and radiocatalytic generation of oxygen free radicals. However, the oxygen-dependent nature of RDT imposes limitations on its efficacy in hypoxic conditions, particularly in modulating and eliminating radioresistant immune suppression cells. A novel approach involving the creation of a "super" tetrahedron polyoxometalate (POM) cluster, Fe12-POM, has been developed for radiation boosted chemodynamic catalysis to enable oxygen-independent RDT in hypoxic conditions. This nanoscale cluster comprises four P2W15 units functioning as energy antennas, while the Fe3 core serves as an electron receptor and catalytic center. Under X-ray radiation, a metal-to-metal charge transfer phenomenon occurs between P2W15 and the Fe3 core, resulting in the valence transition of Fe3+ to Fe2+ and a remarkable 139-fold increase in hydroxyl radical generation compared to Fe12-POM alone. The rapid generation of hydroxyl radicals, in combination with PD-1 therapy, induces a reprogramming of the immune environment within tumors. This reprogramming is characterized by upregulation of CD80/86, downregulation of CD163 and FAP, as well as the release of interferon-γ and tumor necrosis factor-α. Consequently, the occurrence of abscopal effects is facilitated, leading to significant regression of both local and distant tumors in mice. The development of oxygen-independent RDT represents a promising approach to address cancer recurrence and improve treatment outcomes.

Advances in Nanodynamic Therapy for Cancer Treatment.

Nanodynamic therapy (NDT) exerts its anti-tumor effect by activating nanosensitizers to generate large amounts of reactive oxygen species (ROS) in tumor cells. NDT enhances tumor-specific targeting and selectivity by leveraging the tumor microenvironment (TME) and mechanisms that boost anti-tumor immune responses. It also minimizes damage to surrounding healthy tissues and enhances cytotoxicity in tumor cells, showing promise in cancer treatment, with significant potential. This review covers the research progress in five major nanodynamic therapies: photodynamic therapy (PDT), electrodynamic therapy (EDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT), and chemodynamic therapy (CDT), emphasizing the significant role of advanced nanotechnology in the development of NDT for anti-tumor purposes. The mechanisms, effects, and challenges faced by these NDTs are discussed, along with their respective solutions for enhancing anti-tumor efficacy, such as pH response, oxygen delivery, and combined immunotherapy. Finally, this review briefly addresses challenges in the clinical translation of NDT.

Abstract 5762: Engineering cell membrane nanoparticlesenhance immunotherapy and radiodynamic therapy for lung adenocarcinoma by promoting cGAS-STING and ferroptosis

Abstract Background: Immunotherapy is a promising approach for lung cancer, but its effectiveness is limited by tumor heterogeneity. Nanoparticle-based targeted drug delivery systems offer advantages such as targeted drug-loading capacity, and hypotoxicity, showing great potential in improving therapeutic efficacy. This study introduces a targeted drug delivery strategy based on immune-activating nanoparticles that achieves precise drugs delivery in tumor areas. Consequently, this approach remodels the microenvironment and induces tumor cytotoxicity. Method: In this study, we first constructed a targeted nanoparticle delivery system FP@CC. The vehicle utilized lung adenocarcinoma cell membranes as the outer shell and encapsulated iron-platinum nanoparticles and STING agonist Vadimezan. Then, TREM2 antibodies were conjugated on the outer layer. The structure of FP@CC-aT2 was characterized by HADDF-STEM and its safety was evaluated by hemolysis test. In vitro, its ability to induce death was verified by AM/PI staining, and to induce ferroptosis was detected by C11 assay. Furthermore, we evaluated its antitumor effects in subcutaneous tumor models. The composition of immune cells within the tumor microenvironment was analyzed using flow cytometry. Results: We initially performed HADDF-STEM analysis on the nanoparticle precursor FP/Vad@CC, revealing its uniform sphericity. For security, no significant hemolysis was observed at different concentrations of FP/Vad@CC. Then, the structures of FP/Vad@CC-aT2 and FP/Vad@CC are relatively stable (Fig 1).The number of dead cells significantly increased after deal with FP@CC, and the effect was significantly enhanced when combined with X-ray. Moreover, C11, utilizing to assess the changes in intracellular reactive oxygen species (ROS), found that FP@CC led to a significant increase in ROS, comparable to induction by H2O2. Both could be effectively prevented by ferroptosis inhibitor(Fig 2).In vivo, FP/Vad@CC-aT2 was applied to a subcutaneous tumor model in C57. It exhibited excellent therapeutic efficacy and biocompatibility. Flow cytometry revealed that FP/Vad@CC-aT2 had the anticipated impact on macrophages within the tumor: a significant reduction in CD11high/CD206high cells and opposite in the ratio of M1/M2-like macrophages (Fig 3). Conclusion: This study developed a targeted drug delivery strategy, FP/Vad@CC-aT2, to improve the tumor microenvironment (TME). We conducted preliminary experiments in vitro and in vivo to validate its physicochemical properties and tumor inhibitory effects, including the induction of ferroptosis. We assessed its safety in mouse and obtained initial evidence of FP/Vad@CC-aT2's ability to remodel the subtypes of macrophage.Moving forward, we will validate its therapeutic and impact on the TME after surgical procedures. Citation Format: Haiyu Zhou, Hongrui Qiu, Shiying Li, Bin Xu, Shengbo Liu, Huili Wang, Hengliang Hou. Engineering cell membrane nanoparticlesenhance immunotherapy and radiodynamic therapy for lung adenocarcinoma by promoting cGAS-STING and ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5762.

PEGylated Molybdenum-Iodine Nanocluster as a Promising Radiodynamic Agent against Prostatic Adenocarcinoma.

The combination of photodynamic therapy and radiotherapy has given rise to a modality called radiodynamic therapy (RDT), based on reactive oxygen species-producing radiosensitizers. The production of singlet oxygen, O2(1Δg), by octahedral molybdenum (Mo6) clusters upon X-ray irradiation allows for simplification of the architecture of radiosensitizing systems. In this context, we prepared a radiosensitizing system using copper-free click chemistry between a Mo6 cluster bearing azido ligands and the homo-bifunctional linker bis-dPEG11-DBCO. The resulting compound formed nanoparticles, which featured production of O2(1Δg) and efficient cellular uptake, leading to remarkable photo- and radiotoxic effects against the prostatic adenocarcinoma TRAMP-C2 cell line. Spheroids of TRAMP-C2 cells were also used for evaluation of toxicity and phototoxicity. In vivo experiments on a mouse model demonstrated that subcutaneous injection of the nanoparticles is a safe administration mode at a dose of up to 0.08 g kg-1. The reported results confirm the relevancy of Mo6-based radiosensitizing nanosystems for RDT.

ALA-RDT in GBM: protocol of the phase I/II dose escalation trial of radiodynamic therapy with 5-Aminolevulinic acid in patients with recurrent glioblastoma

BackgroundDespite improvements in surgical as well as adjuvant therapies over the last decades, the prognosis for patients with glioblastoma remains poor. Five-Aminolevulinic acid (5-ALA) induced porphyrins are already used for fluorescence-guided resection and as photosensitizer for photodynamic therapy. New findings reveal their potential use as sensitizing agents in combination with ionizing radiation.MethodsWe initiated a phase I/II dose escalation study, treating patients with recurrence of glioblastoma with oral 5-ALA concurrent to radiotherapy (RT). This prospective single-center study based in the University Hospital Münster aims to recruit 30 patients over 18 years of age with histologically verified recurrence of supratentorial glioblastoma in good performance status (KPS ≥ 60). Following a 3 + 3 dose-escalation design, patients having undergone re-resection will receive a 36 Gy RT including radiodynamic therapy fractions (RDT). RDT constitutes of oral administration of 5-ALA before the irradiation session. Two cohorts will additionally receive two fractions of neoadjuvant treatment three and two days before surgery. To determine the maximum tolerated dose of repeated 5-ALA-administration, the number of RDT-fractions will increase, starting with one to a maximum of eight fractions, while closely monitoring for safety and toxicity. Follow-up will be performed at two and five months after treatment. Primary endpoint will be the maximum tolerated dose (MTD) of repeated ALA-administration, secondary endpoints are event-free-, progression-free-, and overall-survival. Additionally, 5-ALA metabolites and radiobiological markers will be analysed throughout the course of therapy and tissue effects after neoadjuvant treatment will be determined in resected tissue. This protocol is in accordance with the SPIRIT guidelines for clinical trial protocols.DiscussionThis is the protocol of the ALA-RDT in GBM-study, the first-in-man evaluation of repeated administration of 5-ALA as a radiosensitizer for treatment of recurrent glioblastoma.Trial registrationThis study was approved by the local ethics committee of the Medical Association of Westphalia-Lippe and the University of Münster on 12.10.2022, the German federal institute for Drugs and medical devices on 13.10.2022 and the federal office for radiation protection on 29.08.2022. This trial was registered on the public European EudraCT database (EudraCT-No.: 2021-004631-92) and is registered under www.cliniclatrials.gov (Identifier: NCT05590689).

Hafnium (Hf)-Chelating Porphyrin-Decorated Gold Nanosensitizers for Enhanced Radio-Radiodynamic Therapy of Colon Carcinoma.

X-ray-induced radiodynamic therapy (RDT) that can significantly reduce radiation dose with an improved anticancer effect has emerged as an attractive and promising therapeutic modality for tumors. However, it is highly significant to develop safe and efficient radiosensitizing agents for tumor radiation therapy. Herein, we present a smart nanotheranostic system FA-Au-CH that consists of gold nanoradiosensitizers, photosensitizer chlorin e6 (Ce6), and folic acid (FA) as a folate-receptor-targeting ligand for improved tumor specificity. FA-Au-CH nanoparticles have been demonstrated to be able to simultaneously serve as radiosensitizers and RDT agents for enhanced computed tomography (CT) imaging-guided radiotherapy (RT) of colon carcinoma, owing to the strong X-ray attenuation capability of high-Z elements Au and Hf, as well as the characteristics of Hf that can transfer radiation energy to Ce6 to generate ROS from Ce6 under X-ray irradiation. The integration of RT and RDT in this study demonstrates great efficacy and offers a promising therapeutic modality for the treatment of malignant tumors.

Designing Bimetallic Metal‐Organic Framework‐Based Heterojunction Radiosensitizer for Enhanced Radiodynamic Therapy and Immunotherapy

AbstractRadiotherapy, as one of the most common strategies for clinical cancer treatment, suffers from failure due to the hypoxia, inflammation, and radiosensitivity difference of malignant tumors, side effects, and radioresistance. Heterojunction‐based radiosensitizers attract great attention to the lower excitation energy and remarkable catalytic activity as compared to typical transition metal radiosensitizers. However, the bio‐application of heterojunction radiosensitizers is in its infancy due to the challenges in structure engineering, rational energy band alignment, and ideal photogenerated carrier migration. Herein, a bimetallic metal‐organic framework (MOF)‐based heterojunction radiosensitizer is reasonably designed to enhance the radiodynamic therapeutic efficiency of Ru complex, and to activate natural killer (NK) cell‐mediated innate immune responses for promoted tumor immunotherapy. This study not only designs a novel bimetallic MOF‐based heterojunction structure but also elucidates the underlying action mechanisms in inhibiting cancer proliferation, which sheds light on the practicable design of radiosensitizers and the tumor combination treatment.

Recent Updates on the Efficacy of Mitocans in Photo/Radio-Therapy for Targeting Metabolism in Chemo/Radio-Resistant Cancers: Nanotherapeutics.

Conventional therapeutic modalities against the cancers such as surgery, chemotherapy (CT) and radiotherapy (RT) have limited efficacy due to drug resistance, and adverse effects. Recent developments in nanoscience emphasized novel approaches to overcome the aforementioned limitations and subsequently improve overall clinical outcomes in cancer patients. Photodynamic therapy (PDT), photothermal therapy (PTT), and radiodynamic therapy (RDT) can be used as cancer treatments due to their high selectivity, low drug resistance, and low toxicity. Mitocans are the therapeutic molecules that can produce anti-cancer effects by modulating mitochondria functions and they have significant implications in cancer therapy. Mitochondria- targeted therapy is a promising strategy in cancer treatment as these organelles play a crucial function in the regulation of apoptosis and metabolism in tumor cells and are more vulnerable to hyperthermia and oxidative damage. The aim of this review is used to explore the targeting efficacy of mitocans in the nanotherapeutic formulation when combined with therapies like PDT, PTT, RDT. We searched several databases include Pubmed, relemed, scopus, google scholar, Embase and collected the related information to the efficacy of mitocans in nanotherapeutics when combined with photo-radiotherapy to target chemo/radio-resisant tumor cells. In this review, we vividly described research reports pertinent to the selective delivery of chemotherapy molecules into specific sub-organelles which can significantly improve the efficiency of cancer treatment by targeting tumor cell metabolism. Furthermore, the rational design, functionalization and application of various mitochondrial targeting units, including organic phosphine/sulfur salts, quaternary ammonium salts, transition metal complexes, and mitochondria-targeted cancer therapy such as PDT, PTT, RDT, and others were summarized. Mainly, the efficacy of these modalities against mtDNA and additional nanotherapeutic strategies with photosensitizers, or radiotherapy to target mitochondrial metabolism in tumor cells with chemo/radio-resistance were delineated. This review can benefit nanotechnologists, oncologists, and radiation oncologists to develop rational designs and application of novel mitochondrial targeting drugs mainly to target metabolism in chemo/radio-resistant cancer cells in cancer therapy.

Oxygen-Enriched MOF-Hemoglobin X-ray Nanosensitizer for Enhanced Cancer Radio–Radiodynamic Therapy

Oxygen-Enriched MOF-Hemoglobin X-ray Nanosensitizer for Enhanced Cancer Radio–Radiodynamic Therapy

Combined photodynamic and radiodynamic therapy with a chlorine photosensitizer under fractionated radiation exposure to transplanted tumors in an <i>in vivo</i> experiment

Introduction. The current direction of scientific research in experimental and clinical oncology is radiodynamic therapy (RDT), a treatment method based on the activation of photosensitizers (PS) by ionizing radiation. As the results of in vitro / in vivo studies show, a number of photosensitizing agents have radiomodifying properties, and the method itself is characterized by high antitumor efficacy.Aim. To study the possibility of increasing the effectiveness of photodynamic therapy (PDT) through its combined use with RDT in an in vivo experiment.Materials and methods. The work was performed on 26 white non-linear rats weighing 180 ± 50 g. Pliss lymphosarcoma was used as a tumor model, which was transplanted subcutaneously. The chlorine-based PS (Belmedpreparaty, Republic of Belarus) was administered intravenously at a dose of 2.5 mg / kg of body weight. The RDT session was performed by the contact method (CRT) after 2.5–3, 24 and 48 hours after the end of PS administration on the microSelectron-HDR V3 Digital device (Elekta, Sweden) using γ-radiation (192Ir) in a single focal dose (SFD) of 2 Gy until the total focal dose of 6 Gy is reached. A PDT session was performed once immediately after the first exposure to ionizing radiation using a PDT diode laser (Imaf Axicon, Republic of Belarus, λ = 660 ± 5 nm) at an exposure dose of 100 J / cm² with a power density of 0.2 w / cm² and a power of 0.353 w. All rats were divided into 4 groups of 6–7 animals each: intact control, PS + PDT, PS + CRT, PS + CRT + PDT. The criteria for evaluating antitumor efficacy were: the average volume of tumors (Vav), the coefficient of absolute growth of tumors (K), the coefficient of tumor growth inhibition (TGI), the frequency of complete tumor regressions (CR), the proportion of cured rats, an increase in the average duration of dead rats. Differences were considered statistically significant at p <0.05.Results. On the 18th day of the experiment, Vav in groups was 65.98 ± 0.81 cm³; 24.02 ± 4.01 cm³ (р <0.00001); 17.11 ± 4.13 cm³ (р <0.00001); 4.42 ± 1.65 cm³ (р <0.00001), respectively. Coefficients K – 5497.33 OE; 1714.71 OE; 1424.83 OE; 367.33 OE. TGI coefficients – 63.60 % (PS + PDT); 74.07 % (PS + CRT); 93.30 % (PS + CRT + PDT). An in crease in the average duration of dead rats indicator – 25.31 % (PS + PDT); 55.06 % (PS + CRT); 158.22 % (PS + CRT + PDT). On the 60th and 90th days of the experiment, the frequency of CR and the proportion of cured rats were the same and amounted to 0; 16.7; 14.3 and 42.9 %, respectively.Conclusion. The results obtained indicate that the chlorine PS has, in addition to photosensitizing properties, also radiomodifying properties, and the developed method of combined therapy is characterized by high antitumor efficacy.

Tumor Regression with 5-Aminolevulinic Acid (5-ALA)-Mediated Radiodynamic Therapy (RDT) Using Different Megavoltage Energies

5-aminolevulinic acid (5-ALA) accumulates in target tumor cells, where it is metabolized to a photosensitizer - protoporphyrin IX (PpIX). Cherenkov light induced by high-energy photon beams effectively activates the PpIX due to the Soret band. The activated photosensitizers lead to cellular toxicities to kill malignant tumor cells by converting surrounding tissue oxygens into singlet oxygens. Radiodynamic therapy (RDT) utilizes cellular damage caused by both radiation dose and activated photosensitizer. The emission of Cherenkov light was observed higher with higher energy irradiation in phantom and ex-vivo tissues. Therefore, using an in-vivo mouse model, this study aimed to investigate the efficacy and energy dependency of RDT combined with 5-ALA and different ranges of megavoltage photon irradiation. In order to investigate individual and synergistic effects of 5-ALA administration and radiation treatment, the tumors (n = 344) were randomized into eight groups: control (untreated), 5-ALA only, 6-, 15-, and 45-MV conventional radiation treatment (RT) only, 6-, 15-, and 45-MV RDT. 4 Gy in a single fraction was delivered to the tumors using three different energy photons for RT only and RDT groups. 5-ALA was systemically injected into 5-ALA only and RDT groups at 100 mg/kg by tail-vein 4 hours before irradiation for endogenous PpIX accumulation in the tumor. Tumor growth was measured using a 1.5 T MR scanner on the day of treatment (prior to the treatment), 3, 7, and 14 days post-treatment. Two-way repeated ANOVA with Bonferroni correction was used to compare each treatment group to determine the statistically significant difference in tumor growth. A total of 45 MV RDT resulted in the most significant decrease in tumor growth by 58.8 ± 3.4 %, 58.0 ± 3.0 %, and 55.0 ± 3.0 % compared to 5-ALA, 45 MV RT, and control group on 7 days post-treatment (P<0.001), respectively. Moreover, a synergistic effect of 45 MV RDT causes a 47.1-54.1 % additional decrease in tumor growth toward the effective treatment outcome. Compared to the different energies, 45 MV RDT resulted in a 52.2 ± 3.1 % and 19.7 ± 7.2 % decrease in tumor growth compared to 6 MV RDT and 15 MV RDT on 7 days post-treatment, respectively (P<0.001), whereas the conventional RT was not. Radiodynamic therapy using 5-ALA administration and 45MV photon beam irradiation resulted in the most significant tumor growth control. A photon energy dependency was observed in radiodynamic therapy. 45MV photon beams showed greater in activating PpIX, improving the synergistic effects of radiation dose and activated photosensitizer than the other energies. The preliminary results provide a foundation for new innovative treatment strategies that have the potential to improve cancer treatment.

Investigation of Hydrogen Peroxide for 45MV 5-Aminolevulinic Acid-Mediated Radiodynamic Therapy

Cytotoxicity caused by the reactive oxygen species (ROS), such as singlet oxygen species (1O2), superoxide radical (O2-), and hydroxyl radical (HO), is a mechanism for treating cancer cells in radiation therapy. 5-aminolevulinic acid (5-ALA)-mediated radiodynamic therapy (RDT) is more effective in killing tumor cells than conventional radiation therapy. ROS is produced not only by ionizing radiation but also by Cherenkov light-activated protoporphyrin IX (PpIX), which is metabolized endogenously from 5-ALA. Moreover, PpIX also catalyzes hydrogen peroxide to generate 1O2, and an enhanced catalytic yield of 1O2 was observed in X-ray irradiation in vitro. Therefore, using an in-vivo mouse model, this study aimed to investigate the effect of hydrogen peroxide as a coenzyme catalyst on a novel 45MV 5-ALA-mediated RDT. A subcutaneous C57BL/6 mouse model of KP1 cell line was used. The tumors (n = 240) were randomized into six groups, consisting of untreated, conventional radiation treatment (RT), and RDT with or without hydrogen peroxide: 1. control (untreated), 2. hydrogen peroxide, 3. 45MV RT, 4. 45MV RT + hydrogen peroxide, 5. 45MV RDT, 6. 45MV RDT + hydrogen peroxide. For 45MV photon irradiation, a single fraction of 4 Gy was delivered to the tumors. 5-ALA was systemically injected at 100 mg/kg by tail-vein 4 hours before the treatment for endogenous PpIX accumulation in the tumor. Carbamide peroxide was used to deliver hydrogen peroxide to tissue and was administered at 60 mg/kg intratumorally into tumors ∼3-5 min before the treatment. The treatment effect of a single fraction of treatment was measured by calculating tumor growth, measured using a 1.5 T MR scanner on the day of treatment (prior to the treatment), 3 and 7 days post-treatment. Two-way repeated ANOVA with Bonferroni correction was used to compare each treatment group to determine the statistically significant difference in tumor growth. A total of 45MV RDT with hydrogen peroxide was shown to significantly delay the tumor growth for the mouse model and cell line investigated in this work. 45MV RDT with hydrogen peroxide group resulted in a decrease in tumor growth by 51.3 ± 4.1 % and 56.1 ± 5.1 % compared to the control group on 3 and 7 days post-treatment, respectively (P<0.001), and 43.4 ± 0.8 % and 50.9 ± 0.8 % compared to 45MV RT alone on 3 and 7 days post-treatment, respectively. Moreover, the enhancement effect of hydrogen peroxide on 45MV RDT was 2.2-4.7 times greater on 45MV RT alone (P<0.05). Hydrogen peroxide did not contribute to tumor growth when administered alone. A total of 45MV 5-ALA-mediated RDT with hydrogen peroxide resulted in the most significant tumor growth delay compared to the other groups. The catalytic effect of PpIX and hydrogen peroxide was observed in-vivo. These preliminary results demonstrate an effective cancer treatment modality.

Molecular radio afterglow probes for cancer radiodynamic theranostics.

X-ray-induced afterglow and radiodynamic therapy tackle the tissue penetration issue of optical imaging and phototherapy. However, inorganic nanophosphors used in this therapy have their radio afterglow dynamic function as always on, limiting the detection specificity and treatment efficacy. Here we report organic luminophores (IDPAs) with near-infrared afterglow and 1O2 production after X-ray irradiation for cancer theranostics. The in vivo radio afterglow of IDPAs is >25.0 times brighter than reported inorganic nanophosphors, whereas the radiodynamic production of 1O2 is >5.7 times higher than commercially available radio sensitizers. The modular structure of IDPAs permits the development of a smart molecular probe that only triggers its radio afterglow dynamic function in the presence of a cancer biomarker. Thus, the probe enables the ultrasensitive detection of a diminutive tumour (0.64 mm) with superb contrast (tumour-to-background ratio of 234) and tumour-specific radiotherapy for brain tumour with molecular precision at low dosage. Our work reveals the molecular guidelines towards organic radio afterglow agents and highlights new opportunities for cancer radio theranostics.

Experimental in vivo studies of the antitumor efficacy of photodynamic and radiodynamic therapy and their combinations

The authors studied the antitumor efficacy of photodynamic therapy (PDT) in combination with radiodynamic therapy (RDT) in an in vivo experiment. The study was approved by the Ethics Committee of the N.N. Alexandrov National Cancer Center of Belarus (protocol dated February 25, 2022, № 180). The work was performed on 26 white non-linear rats weighing 200 ± 50 g. Pliss lymphosarcoma (PLS) was used as a tumor model, which was transplanted subcutaneously. Photosensitizer (PS) «Photolon» (RUE «Belmedpreparaty», Belarus) was administered intravenously at a dose of 2.5 mg/kg of body weight. The RDT session was performed by the contact method (CRT) once 2.5–3 times after the end of the infusion of the PS on the «microSelectron-HDR V3 Digital apparatus» (Elekta, Sweden) using γ-radiation (192Ir) in a single focal dose 6 Gy. A PDT session was performed once immediately after exposure to ionizing radiation using a «PDT diode laser» (LTD Imaf Axicon, Belarus, λ=660±5 nm) at an exposure dose of 100 J/cm2 with a power density of 0.2 W/cm2 and a power of 0.353 watts. All rats were divided into 4 groups of 6–7 animals each: intact control (IC), PS + PDT, PS + CRT, PS + CRT + PDT. The criteria for evaluating antitumor efficacy were: the average volume of tumors (Vav, cm3 ), the coefficient of absolute growth of tumors (K, in RU), the coefficient of tumor growth inhibition (TGI, %), the frequency of complete tumor regressions (CR, %), the proportion of cured rats (%), an increase in the average duration of dead rats (%). Differences were considered statistically significant at p&lt;0.05. On the 18th day of the experiment, Vav. in groups was 63.25±2.76 cm³; 29.03±6.06 cm³ (p=0.0002); 22.18±5.94 cm³ (р&lt;0.0001); 11.76±3.29 cm³ (p=0.0000), respectively. Coefficients K – 4516.86 RU; 2638.09 RU; 2024.45 RU; 979.00 RU. TGI coefficients – 54.10% (PS + PDT); 64.93% (PS + CRT); 81.41% (PS + CRT + PDT). An increase in the average duration of dead rats indicator – 48.57% (PS + PDT); 60.00% (PS + CRT); 97.71% (PS + CRT + PDT). On the 60th and 90th days of the experiment, the frequency of PR and the proportion of cured rats were the same and amounted to 0%; 16.7%; 14.3%, and 28.6%, respectively. The results obtained indicate the prospects and relevance of further research in this scientific direction.

Electroactive membrane fusion-liposome for increased electron transfer to enhance radiodynamic therapy.

Dynamic therapies have potential in cancer treatments but have limitations in efficiency and penetration depth. Here a membrane-integrated liposome (MIL) is created to coat titanium dioxide (TiO2) nanoparticles to enhance electron transfer and increase radical production under low-dose X-ray irradiation. The exoelectrogenic Shewanella oneidensis MR-1 microorganism presents an innate capability for extracellular electron transfer (EET). An EET-mimicking photocatalytic system is created by coating the TiO2 nanoparticles with the MIL, which significantly enhances superoxide anions generation under low-dose (1 Gy) X-ray activation. The c-type cytochromes-constructed electron channel in the membrane mimics electron transfer to surrounding oxygen. Moreover, the hole transport in the valence band is also observed for water oxidation to produce hydroxyl radicals. The TiO2@MIL system is demonstrated against orthotopic liver tumours in vivo.

5‑aminiolevulinic acid induces a radiodynamic effect with enhanced delayed reactive oxygen species production under hypoxic conditions in lymphoma cells: An invitro study.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of intracranial tumor. However, PCNSL is radiosensitive; thus, whole-brain radiotherapy (WBRT) is often selected as an alternative consolidation therapy. WBRT-related delayed neurotoxicity can affect the quality of life of the elderly. 5-aminolevulinic acid (ALA) is a natural precursor of heme and has been widely used as a live molecular fluorescence marker in brain tumor surgery. Experimental studies have demonstrated that combination therapy with 5-ALA and ionizing irradiation (IR), denoted radiodynamic therapy (RDT), resulted in tumor suppression in cancer, including glioma, melanoma, colorectal cancer, prostate cancer, breast cancer and lung cancer; however, to the best of our knowledge, this method has not been investigated in lymphoma. The present study aimed to investigate the radiodynamic effect of 5-ALA on lymphoma cells in vitro. The synthesis of 5-ALA-induced protoporphyrin IX (PpIX) was assessed under normal and hypoxic conditions in lymphoma cells (Raji, HKBML and TK). Subsequently, the radiodynamic effect of 5-ALA was evaluated using a colony formation assay and reactive oxygen species (ROS) production after RDT was examined using flow cytometry. Finally, the mitochondrial density in the lymphoma cells was evaluated. Lymphoma cells exhibited a high accumulation of 5-ALA-induced PpIX in the flow cytometric analysis, and a decrease in the surviving fraction under IR in cells with 5-ALA treatment compared with cells not treated with 5-ALA in the colony formation assay under normal and hypoxic conditions. Although ROS production 12 h after IR was increased compared with that immediately after IR (0 h), pretreatment with 5-ALA enhanced the delayed ROS production in each lymphoma cell line under normoxic conditions. Raji and TK cells exhibited an increase in ROS production 12 h after IR compared with that at 0 h in the 5-ALA-untreated cells under hypoxic conditions. Raji, HKBML and TK cells exhibited an increase in ROS production 12 h after IR compared with that at 0 h in the 5-ALA-treated cells, while TK cells exhibited enhancement of ROS production 12 h after IR in 5-ALA-treated cells compared with 5-ALA-untreated cells under hypoxic conditions. Other studies have demonstrated that impaired mitochondria damaged by IR produce ROS via the metabolic process, then damage the rest of the surrounding normal mitochondria, consequently propagating oxidative stress within tumor cells and leading to cell death. Thus, we hypothesized that the propagating oxidative stress after IR was associated with mitochondrial density in tumor cells. Namely, high accumulation of 5-ALA-indcued PpIX may promote ROS production in mitochondria of tumor cells after IR, and suppress the cell surviving fraction via the propagation of oxidative stress. In the colony formation assay, Raji cell colony formation was suppressed by RDT with 5-ALA. Simultaneously, the mitochondrial density in the Raji cells was higher than that in other cell lines. Pretreatment with 5-ALA enhanced delayed ROS production after IR in lymphoma cells under normoxic conditions. Under hypoxic conditions, only TK cells exhibited enhancement of ROS production 12 h after IR in the 5-ALA-treated group compared with the 5-ALA-untreated group. Although further studies evaluating the effect of hypoxic conditions in lymphoma cells are needed, the results suggested that RDT with 5-ALA could suppress colony formation under normal and hypoxic conditions in lymphoma cells. Therefore, RDT with 5-ALA is a potential treatment option for PCNSL.

Mitochondria-Targeted Nanosystem Enhances Radio-Radiodynamic-Chemodynamic Therapy on Triple Negative Breast Cancer.

Radiodynamic therapy (RDT), which produces 1O2 and other reactive oxygen species (ROS) in response to X-rays, can be used in conjunction with radiation therapy (RT) to drastically lower X-ray dosage and reduce radio resistance associated with conventional radiation treatment. However, radiation-radiodynamic therapy (RT-RDT) is still impotent in a hypoxic environment in solid tumors due to its oxygen-dependent nature. Chemodynamic therapy (CDT) can generate reactive oxygen species and O2 by decomposing H2O2 in hypoxic cells and thus potentiate RT-RDT to achieve synergy. Herein, we developed a multifunctional nanosystem, AuCu-Ce6-TPP (ACCT), for RT-RDT-CDT. Ce6 photosensitizers were conjugated to AuCu nanoparticles via Au-S bonds to realize radiodynamic sensitization. Cu can be oxidized by H2O2 and catalyze the degradation of H2O2 to generate •OH through the Fenton-like reaction to realize CDT. Meanwhile, the degradation byproduct oxygen can alleviate hypoxia while Au can consume glutathione to increase the oxidative stress. We then attached mercaptoethyl-triphenylphosphonium (TPP-SH) to the nanosystem, targeting ACCT to mitochondria (colocalization Pearson coefficient 0.98) to directly disrupt mitochondrial membranes and more efficiently induce apoptosis. We confirmed that ACCT efficiently generates 1O2 and •OH upon X-ray irradiation, resulting in strong anticancer efficacy in both normoxic and hypoxic 4T1 cells. The down-regulation of hypoxia-inducible factor 1α expression and reduction of intracellular H2O2 concentrations suggested that ACCT could significantly alleviate hypoxia in 4T1 cells. ACCT-enhanced RT-RDT-CDT can successfully shrink or remove tumors in radioresistant 4T1 tumor-bearing mice upon 4 Gy of X-ray irradiation. Our work thus presents a new strategy to treat radioresistant hypoxic tumors.

Reactive Oxygen Species as Mediators of Disease Progression and Therapeutic Response in Colorectal Cancer.

Significance: Reactive oxygen species (ROS) are critical to normal cellular function with redox homeostasis achieved by balancing ROS production with removal through detoxification mechanisms. Many of the conventional chemotherapies used to treat colorectal cancer (CRC) derive a proportion of their cytotoxicity from ROS generation, and resistance to chemotherapy is associated with elevated detoxification mechanisms. Furthermore, cancer stem cells demonstrate elevated detoxification mechanisms making definitive treatment with existing chemotherapy challenging. In this article, we review the roles of ROS in normal and malignant colonic cell biology and how existing and emerging therapies might harness ROS for therapeutic benefit. Recent Advances: Recent publications have elucidated the contribution of ROS to the cytotoxicity of conventional chemotherapy alongside the emerging approaches of photodynamic therapy (PDT), sonodynamic therapy (SDT), and radiodynamic therapy (RDT), in which ROS are generated in response to excitatory light, sound, or X-ray stimuli to promote cancer cell apoptosis. Critical Issues: The majority of patients with metastatic CRC have a very poor prognosis with a 5-year survival of ∼13% making the need for new or more effective treatments an imperative. Future Directions: Modulation of ROS through a combination of new and emerging therapies may improve the efficacy of current chemotherapy providing novel approaches to treat the otherwise resistant disease. Antioxid. Redox Signal. 39, 186-205.

Coordination-Driven Self-Assembly Strategy-Activated Cu Single-Atom Nanozymes for Catalytic Tumor-Specific Therapy.

How to optimize the enzyme-like catalytic activity of nanozymes to improve their applicability has become a great challenge. Herein, we present an l-cysteine (l-Cys) coordination-driven self-assembly strategy to activate polyvinylpyrrolidone (PVP)-modified Cu single-atom nanozymes MoOx-Cu-Cys (denoted as MCCP SAzymes) aiming at catalytic tumor-specific therapy. The Cu single atom content of MCCP can be rationally modulated to 10.10 wt %, which activates the catalase (CAT)-like activity of MoOx nanoparticles to catalyze the decomposition of H2O2 in acidic microenvironments to increase O2 production. Excitingly, the maximized CAT-like catalytic efficiency of MCCP is 138-fold higher than that of typical MnO2 nanozymes and exhibits 14.3-fold higher affinity than natural catalase, as demonstrated by steady-state kinetics. We verify that the well-defined l-Cys-Cu···O active sites optimize CAT-like activity to match the active sites of natural catalase through an l-Cys bridge-accelerated electron transfer from Cys-Cu to MoOx disclosed by density functional theory calculations. Simultaneously, the high loading Cu single atoms in MCCP also enable generation of •OH via a Fenton-like reaction. Moreover, under X-ray irradiation, MCCP converts O2 to 1O2 for cascading radiodynamic therapy, thereby facilitating the multiple reactive oxygen species (ROS) for radiosensitization to achieve substantial antitumor.