Tumor Cell Membrane-Encapsulated MLA Solid Lipid Nanoparticles for Targeted Diagnosis and Radiosensitization Therapy of Cutaneous Squamous Cell Carcinoma.

Squamous cell carcinoma (SCC) is a common nonmelanoma skin cancer. Radiotherapy plays an integral role in treating SCC due to its characteristics, such as diminished intercellular adhesion, heightened cell migration and invasion capabilities, and immune evasion. These problems lead to inaccurate tumor boundary positioning and radiotherapy tolerance in SCC treatment. Thus, accurate localization and enhanced radiotherapy sensitivity are imperative for effective SCC treatment. To address the existing limitations in SCC therapy, we developed monoglyceride solid lipid nanoparticles (MG SLNs) and enveloped them with the A431 cell membrane (A431 CM) to create A431@MG. The characterization results showed that A431@MG was spherical. Furthermore, A431@MG had specific targeting for A431 cells. In A431 tumor-bearing mice, A431@MG demonstrated prolonged accumulation within tumors, ensuring precise boundary localization of SCC. We further advanced the approach by preparing MG SLNs encapsulating 5-aminolevulinic acid methyl ester (MLA) and desferrioxamine (DFO) with an A431 CM coating to yield A431@MG-MLA/DFO. Several studies have revealed that DFO effectively reduced iron content, impeding protoporphyrin IX (PpIX) biotransformation and promoting PpIX accumulation. Simultaneously, MLA was metabolized into PpIX upon cellular entry. During radiotherapy, the heightened PpIX levels enhanced reactive oxygen species (ROS) generation, inducing DNA and mitochondrial damage and leading to cell apoptosis. In A431 tumor-bearing mice, the A431@MG-MLA/DFO group exhibited notable radiotherapy sensitization, displaying superior tumor growth inhibition. Combining A431@MG-MLA/DFO with radiotherapy significantly improved anticancer efficacy, highlighting its potential to serve as an integrated diagnostic and therapeutic strategy for SCC.

Application of High-Z Nanoparticles to Enhance Current Radiotherapy Treatment.

Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.

Radiosensitizing effects of heparinized magnetic iron oxide nanoparticles in colon cancer.

The combination of radiation treatment and chemotherapy is currently the standard for management of cancer patients. However, safe doses do not often provide effective therapy, then pre-treated patients are forced to repeat treatment with often already increased tumor resistance to drugs and irradiation. One of the solutions we suggest is to improve primary course of radiation treatment via enhancing radiosensitivity of tumors by magnetic-guided iron oxide nanoparticles (magnetite). We obtained spherical heparinized iron oxide nanoparticles (hIONPs, ∼20 nm), characterized it by TEM, Infrared spectroscopy and DLS. Then hIONPs cytotoxicity was assessed for colon cancer cells (XTT assay) and cellular uptake of nanoparticles was analyzed with X-ray fluorescence. Combination of ionizing radiation (IR) and hIONPs in vitro caused an increase of G2/M arrest of cell cycle, mitotic errors and decrease in survival (compared with samples exposed to IR and hIONPs separately). The promising results were shown for magnetic-guided hIONPs in CT26-grafted BALB/C mice: the combination of intravenously administrated hIONPs and IR showed 20,8% T/C ratio (related to non-treated mice), while single radiation had no shown significant decrease in tumor growth (72,4%). Non-guided by magnets hIONPs with IR showed 57,9% of T/C. This indicates that ultra-small size and biocompatible molecule are not the key to successful nano-drug design, in each case, delivery technologies need to be improved when transferred to in vivo model.

Zinc nanoparticles coated with doxorubicin-conjugated alginate as a radiation sensitizer in triple-negative breast cancer cells.

The main treatment modalities for breast cancer include surgery, chemotherapy, and radiotherapy, and each treatment will bring different side effects. Design and synthesizing a novel nanostructure for chemo-radiotherapy has been proposed as an effective method in consideration to enhance the drug efficiency as well as improve the effect of radiotherapy. This study aimed to synthesize zinc nanoparticles (ZnNPs) coated with alginate conjugated with Doxorubicin (Dox) drug and investigate its effects along with X-irradiation on MDA-MB-231 triple-negative breast cancer cell line. ZnNPs coated with alginate were synthesized and conjugated to Dox by covalent bonding and characterized using various physicochemical tests. A hemolysis test was used to assess blood biocompatibility. The radiosensitization properties and anti-cancer effects of the synthesized nanostructures were tested by cell uptake, cell viability, apoptosis, cell cycle, and scratch assays with and without radiation exposure. The physicochemical characterization results showed that the synthesis of nanostructures was successfully carried out. The obtained results from the cell uptake assay showed the effective absorption of nanostructures by the cells. The Zn@Alg-Dox NPs significantly reduced cell growth, increased apoptosis, inhibited cell migration, and led to the arrest of different cell cycle phases in both conditions with and without X-ray exposure. Coating ZnNPs with alginate and Doxorubicin conjugation leads to an increase the radiation sensitivity in radiotherapy as well as therapeutic efficiency. Therefore, Zn@Alg-Dox NPs can be used as radiosensitizing nanomedicine for in vivo studies in the future.

Radiation therapy for triple-negative breast cancer: from molecular insights to clinical perspectives.

INTRODUCTION: Triple-negative breast cancer (TNBC) lacks three common receptors, making traditional treatments less effective. This review highlights the importance of radiotherapy and emerging therapeutic strategies to enhance treatment outcomes in TNBC. AREAS COVERED: We conducted a literature search on PubMed for publications from 2000 to 2023 to discuss the critical role of radiotherapy in managing TNBC, emphasizing its applications from locoregional control to improving survival rates. The review explores molecular mechanisms underlying TNBC's radiotherapy response, including DNA damage repair and apoptosis, with a focus on BRCA1/2 mutations and Poly (ADP-ribose) polymerase (PARP) inhibition. We summarize preclinical and clinical research on radiosensitization strategies, from gene-targeted therapies to immunotherapy combinations, and the impact of post-mastectomy radiation therapy on locoregional control. The potential of personalized treatment approaches, integrating molecular profiling, targeted radiosensitizers, and the synergistic effects of radiotherapy with immunotherapy, is also discussed. EXPERT OPINION: Future TNBC treatment strategies should focus on precision medicine, integrating immunotherapy, developing novel radiosensitizers, and targeting biological pathways to overcome radioresistance. The integration of radiomics and artificial intelligence offers promising avenues for enhancing treatment personalization and efficacy, aiming to improve patient outcomes in TNBC.

A Novel Activatable Nanoradiosensitizer for Second Near-Infrared Fluorescence Imaging-Guided Safe-Dose Synergetic Chemo-Radiotherapy of Rheumatoid Arthritis.

The precise theranostics of rheumatoid arthritis (RA) remains a formidable challenge in clinical practice. Exploring novel applications of contemporary therapeutic approaches like chemo-radiotherapy is promising as a highly effective strategy for RA. Herein, a novel activatable nanoradiosensitizer-40 (denoted as IRnR-40) is developed, based on encapsulating the clinically approved drugs cisplatin (DDP) and indocyanine green (ICG) within a gelatin shell to achieve second near-infrared fluorescence (NIR-II FL) imaging-guided safe-dose synergetic chemo-radiotherapy. The high concentration of matrix metalloproteinase-9 (MMP-9) in the RA microenvironment plays a pivotal role in triggering the responsive degradation of IRnR-40, leading to the rapid release of functional molecules DDP and ICG. The released ICG serves the dual purpose of illuminating the inflamed joints to facilitate accurate target volume delineation for guiding radiotherapy, as well as acting as a real-time reporter for quantifying the release of DDP to monitor efficacy. Meanwhile, the released DDP achieves highly effective synergistic chemotherapy and radiosensitization for RA via the dual reactive oxygen species (ROS)-mediated mitochondrial apoptotic pathway. To sum up, this activatable nanoradiosensitizer IRnR-40 is believed to be the first attempt to achieve efficient NIR-II FL imaging-guided safe-dose chemo-radiotherapy for RA, which provides a new paradigm for precise theranostics of refractory benign diseases.

The impact of Human Papilloma Virus status on the prediction of head and neck cancer chemoradiotherapy outcomes using the pre-treatment apparent diffusion coefficient.

OBJECTIVE: To determine the impact of Human Papilloma Virus (HPV) oropharyngeal cancer (OPC) status on the prediction of head and neck squamous cell cancer (HNSCC) chemoradiotherapy (CRT) outcomes with pre-treatment quantitative diffusion-weighted magnetic resonance imaging (DW-MRI). METHODS: Following ethical approval, 65 participants (53 male, age 59.9 ± 7.86) underwent pre-treatment DW-MRI in this prospective cohort observational study. There were 46 HPV OPC and 19 other HNSCC cases with Stage III/IV HNSCC. Regions of interest (ROIs) (volume, largest area, core) at the primary tumour (n = 57) and largest pathological node (n = 59) were placed to analyse ADCmean and ADCmin. Unpaired t-test or Mann-Whitney test evaluated the impact of HPV OPC status and clinical parameters on their prediction of post-CRT 2 year locoregional and disease-free survival (LRFS and DFS). Multivariate logistic regression compared significant variables with 2 year outcomes. RESULTS: On univariate analysis of all participants, the primary tumour area ADCmean was predictive of 2 year LRFS (p = 0.04). However, only the HPV OPC diagnosis (LFRS p = 0.03; DFS p = 0.02) predicted outcomes on multivariate analysis. None of the pre-treatment ADC values were predictive of 2 year DFS in the HPV OPC subgroup (p = 0.21-0.68). Amongst participants without 2 year disease-free survival, HPV-OPC was found to have much lower primary tumour ADCmean values than other HNSCC. CONCLUSION: Knowledge of HPV OPC status is required in order to determine the impact of the pre-treatment ADC values on post-CRT outcomes in HNSCC. ADVANCES IN KNOWLEDGE: Pre-treatment ADCmean and ADCmin values acquired using different ROI methods are not predictive of 2 year survival outcomes in HPV OPC.

Mathematical evaluation of post-radiotherapy salivary gland function using salivary gland scintigraphy.

OBJECTIVE: Xerostomia is the most common treatment-related toxicity after radiotherapy (RT) for head and neck carcinoma, reducing the quality of life of patients due to a decrease in salivary gland function. METHODS: Salivary gland scintigraphy was performed to quantitatively evaluate the salivary gland functions in patients undergoing RT. It was done chronologically for 62 salivary glands of 31 patients before RT and retested 12 months later. RESULTS: The salivary gland functions of most patients deteriorated post-RT and recovered when the radiation dose to the salivary gland was not high. The mean dose to the salivary gland was found to be the most reliable factor in deteriorating salivary gland function, and the tolerance dose was determined to be 46 Gy. The recovery rate of salivary gland function after 1 year of RT was 72% in the RT alone group (n = 10), 56% in the conformal radiotherapy group (n = 15), and 44% in the bioradiotherapy group (n = 6). CONCLUSION: Scintigraphy revealed that the salivary glands recovered from post-RT hypofunction when decreased doses were administered. The determined tolerance dose of 46 Gy may guide the approach to minimizing associated xerostomia in RT. ADVANCES IN KNOWLEDGE: In this study, the average tolerated dose to the salivary glands was 46 Gy.

Tumor-derived biomimetic nanozyme with immune evasion ability for synergistically enhanced low dose radiotherapy.

High doses of radiation can cause serious side effects and efficient radiosensitizers are urgently needed. To overcome this problem, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for enhanced low-dose radiotherapy (RT). CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH-OXD) and peroxidase (POD) activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2 Gy) can provide a substantial suppression of tumor proliferation. This is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes.

Tumor radiosensitization by photobiomodulation.

PURPOSE: To investigate the safety of photobiomodulation therapy (PBM) in tumors and its potential as a radiosensitizer when combined with radiotherapy. METHODS: We have performed in vitro experiments in A431 cells to assess proliferation and cell cycle after PBM, as well as clonogenic assay and H2AX-gamma immunolabeling to quantify double strand breaks after the combination of PBM and radiation. In vivo experiments in xenografts included Kaplan-Meier survival analysis, optical coherence tomography (OCT) and histological analysis. RESULTS: PBM did not induce proliferation in vitro, but increased the G2/M fraction by 27% 24h after illumination, resulting in an enhancement of 30% in radiation effect in the clonogenic assay. The median survival of the PBM-RT group increased by 4 days and the hazard ratio was 0.417 (CI 95%: 0.173-1.006) when compared to radiation alone. OCT analysis over time demonstrated that PBM increases tumor necrosis due to radiation, and histological analysis showed that illumination increased cell differentiation and angiogenesis, which may play a role in the synergetic effect of PBM and radiation. CONCLUSION: PBM technique may be one of the most appropriate approaches for radiosensitizing tumors while protecting normal tissue because of its low cost and low training requirements for staff.

Redox-sensitive iodinated polymersomes carrying histone deacetylase inhibitor as a dual-functional nano-radiosensitizer for enhanced radiotherapy of breast cancer.

Radiotherapy (RT) is a frequently used means in clinical tumor treatment. The outcome of RT varies, however, to a great extent, due to RT resistance or intolerable dose, which might be resolved by the development of radio-sensitizing strategies. Here, we report redox-sensitive iodinated polymersomes (RIP) carrying histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA, vorinostat), as a new dual-functional nano-radiosensitizer for breast cancer radiotherapy. SAHA-loaded RIP (RIP-SAHA) with a size of about 101 nm exhibited good colloidal stability while the reduction-activated release of SAHA, giving rise to better antitumor effect to 4T1 breast carcinoma cells than free SAHA. Accordingly, RIP-SAHA combined with a 4 Gy dose of X-ray radiation led to significantly enhanced suppression of 4T1 cells compared with SAHA combined 4 Gy of X-ray radiation, as a result of enhanced DNA damage and impeded DNA damage repair. The pharmacokinetics and biodistribution studies by single-photon emission computed tomography (SPECT) with 125I-labeled SAHA (125I-SAHA) showed a 17.3-fold longer circulation and 237.7-fold better tumor accumulation of RIP-SAHA over SAHA. The systemic administration of RIP-SAHA greatly sensitized radiotherapy of subcutaneous 4T1 breast tumors and brought about significant inhibition of tumor growth, without causing damages to major organs, compared with radiotherapy alone. RIP not only enhanced SAHA delivery but also acted as a radiosensitizer. RIP-SAHA emerges as a smart dual-functional nano-radiosensitizer to effectively enhance tumor radiotherapy.

Curcumin Administered in Combination with Glu-GNPs Induces Radiosensitivity in Transplanted Tumor MDA-MB-231-luc Cells in Nude Mice.

Curcumin is a type of plant polyphenol extracted from Curcuma longa L. rhizome, which demonstrates antitumor activity in breast cancer cells in vitro. To investigate the combined effect and possible mechanism of curcumin and glucose-gold nanoparticles (Glu-GNPs), the radiosensitivity of breast carcinoma xenografts was assessed in nude mice. MDA-MB-231 cells labeled with firefly luciferase were inoculated into the mammary fatty pads of nude mice to establish a transplantation tumor model of human breast cancer. The tumor-bearing mice were treated with different drugs (curcumin, Glu-GNPs, and cisplatin) for 3 weeks prior to radiotherapy. The body weights and tumor volumes of the mice were measured in regular intervals. Tumor bioluminescence intensity was determined in real-time using an in vivo bioluminescence imaging system to monitor tumor growth. Transplanted tumor tissue samples were taken for hematoxylin and eosin (HE) staining, and the expression of VEGF, HSP90, HIF-1α, and MMP9 was evaluated via reverse transcription-quantitative PCR or immunohistochemistry. The results revealed that the breast tumor-bearing nude mouse model was successfully established, as evidenced by a stable expression of luciferase. Curcumin inhibited the growth of tumors without causing significant weight loss in mice. Furthermore, additive inhibition was demonstrated when curcumin was administered in combination with Glu-GNPs and irradiation. Tumor bioluminescence intensity was decreased in the model group following curcumin, Glu-GNPs, and irradiation treatment. HE staining demonstrated that transplanted tumors were malignant, with necrotic tissue exhibited centrally. It was concluded that curcumin administered in combination with Glu-GNPs and X-ray irradiation could reduce the protein expression of VEGF, HSP90, HIF-1α, and MMP9 in tumor tissue when compared with the model group. Curcumin and Glu-GNPs administered with X-ray irradiation significantly inhibited tumor growth and induced radiosensitivity, which may be associated with the inhibition of angiogenesis in tumor tissue.

PKI-587 enhances radiosensitization of hepatocellular carcinoma by inhibiting the PI3K/AKT/mTOR pathways and DNA damage repair.

Radiation is an important therapeutic strategy for hepatocellular (HCC). In this study, we evaluated the role of the dual PI3K/mTOR inhibitor, PKI-587, on radiosensitization of HCC and its possible mechanism. MTT, colony formation, flow cytometry, and immunofluorescence were used to analyze the proliferation, cell cycle, formation of residual γ-H2AX foci, and apoptosis of HCC cells. A SK-Hep1 xenograft HCC model was used to assess the effects of PKI-587 in combination with ionizing radiation in vivo. The activation levels of PI3K/AKT/mTOR and DNA damage repair pathways and their downstream effector molecules were detected with Western blot. It was found that PKI-587 sensitized HCC cells to radiation by increasing DNA damage, enhancing G0/G1 cell-cycle arrest, and inducing apoptosis. In vivo, the combination of radiation with PKI-587 significantly inhibited tumor growth. These findings suggest the usefulness of PKI-587 on radiosensitization of HCC cells by inhibiting the PI3K/AKT/mTOR and DNA damage repair pathways. The combination of ionizing radiation and PKI-587 may be a strategy to improve the efficacy of treating HCC.

Apalutamide radio-sensitisation of prostate cancer.

INTRODUCTION: The combination of radiotherapy with bicalutamide is the standard treatment of prostate cancer patients with high-risk or locally advanced disease. Whether new-generation anti-androgens, like apalutamide, can improve the radio-curability of these patients is an emerging challenge. MATERIALS AND METHODS: We comparatively examined the radio-sensitising activity of apalutamide and bicalutamide in hormone-sensitive (22Rv1) and hormone-resistant (PC3, DU145) prostate cancer cell lines. Experiments with xenografts were performed for the 22Rv1 cell line. RESULTS: Radiation dose-response viability and clonogenic assays showed that apalutamide had a stronger radio-sensitising activity for all three cell lines. Confocal imaging for γΗ2Αx showed similar DNA double-strand break repair kinetics for apalutamide and bicalutamide. No difference was noted in the apoptotic pathway. A striking cell death pattern involving nuclear karyorrhexis and cell pyknosis in the G1/S phase was exclusively noted when radiation was combined with apalutamide. In vivo experiments in SCID and R2G2 mice showed significantly higher efficacy of radiotherapy (2 and 4 Gy) when combined with apalutamide, resulting in extensive xenograft necrosis. CONCLUSIONS: In vitro and in vivo experiments support the superiority of apalutamide over bicalutamide in combination with radiotherapy in prostate cancer. Clinical studies are encouraged to show whether replacement of bicalutamide with apalutamide may improve the curability rates.

PARP inhibitor niraparib as a radiosensitizer promotes antitumor immunity of radiotherapy in EGFR-mutated non-small cell lung cancer

Background Poly-(ADP-Ribose)-Polymerase inhibitors (PARPi) were reported as radiosensitizers in non-small cell lung cancer (NSCLC) with wide-type epidermal growth factor receptor (EGFR), but the effects of radiation combined with PARPi were not investigated in EGFR-mutated NSCLC. Moreover, the underlying mechanisms were not well examined. This study aimed to study the efficacy of radiation combined with niraparib in EGFR-mutated NSCLC and explore their influence on the immune system. Methods Clone formation and apoptosis assay were conducted to explore the effects of niraparib and radiation. Immunofluorescence was conducted to detect the double-strand DNA breaks. Real-time PCR and immunoblotting were employed to evaluate the activation of STING/TBK1/TRF3 pathway and the expression levels of interferon β, CCL5 and CXCL10. Immunocompetent mice model bearing with subcutaneous Lewis lung cancer was established to confirm the results in vivo. Results Niraparib and radiation were synergistic to inhibit tumor both in vitro and in vivo. Radiation plus niraparib could activate anti-tumor immunity, which appeared as increased CD8+ T lymphocytes and activated STING/TBK1/IRF3 pathway. Conclusion PARPi not only as a radiosensitizer inhibited EGFR-mutated NSCLC tumor growth, but also cooperated with radiation to promote anti-tumor immune responses (AU)

Formulation Comprising Arsenic Trioxide and Dimercaprol Enhances Radiosensitivity of Pancreatic Cancer Xenografts.

OBJECTIVE: To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer xenografts. METHODS: Female BALB/c nude mice bearing SW1990 human pancreatic cancer xenografts were divided into four treatment arms, including control, radiotherapy (RT), BAL-ATO, and RT + BAL-ATO groups. Survival and tumor volume were analyzed. We also assessed apoptosis in tumor samples by live imaging and detected hypoxia by confocal laser microscope observation. We further investigated the mechanisms of BAL-ATO action in RT by detecting affected proteins by western blot and immunohistochemistry assays. RESULTS: Median survival was significantly longer in the RT + BAL-ATO group (64.5 days) compared with the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups (P < 0.001). RT + BAL-ATO inhibited the growth of tumors in mice by 73% compared with the control group, which was significantly higher than the rate of inhibition following RT alone (59%) (P < 0.01). Further analysis showed an improved microenvironment in terms of hypoxia in tumors treated with BAL-ATO alone or RT + BAL-ATO. Expression of signaling molecules associated with pancreatic cancer stem cells, including CD24, CD44, ALDH1A1, Gli-1, and Nestin, was detected in tumors treated with BAL-ATO alone or in combination with RT. CONCLUSION: These data suggest that BAL-ATO function as a radiosensitizer in mice with pancreatic cancer xenografts, via mechanisms involving hypoxia reduction and inhibition of signaling pathways associated with pancreatic cancer stem cells. BAL-ATO may thus be a promising radiosensitizing agent in patients with pancreatic cancer.

Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment. METHODS: This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing. FINDINGS: Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths. INTERPRETATION: Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting. FUNDING: QED Therapeutics and Novartis.

Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells.

PURPOSE: The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model. METHODS: SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs. RESULTS: The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 h exposure to 23.5 µg/ml SPIONs. There was also a 30.1% increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with SERs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (P < 0.05). CONCLUSIONS: SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.