Progression in low-intensity ultrasound-induced tumor radiosensitization.

BACKGROUND: Radiotherapy (RT) is a widely utilized tumor treatment approach, while a significant obstacle in this treatment modality is the radioresistance exhibited by tumor cells. To enhance the effectiveness of RT, scientists have explored radiosensitization approaches, including the use of radiosensitizers and physical stimuli. Nevertheless, several approaches have exhibited disappointing results including adverse effects and limited efficacy. A safer and more effective method of radiosensitization involves low-intensity ultrasound (LIUS), which selectively targets tumor tissue and enhances the efficacy of radiation therapy. METHODS: This review summarized the tumor radioresistance reasons and explored LIUS potential radiosensitization mechanisms. Moreover, it covered diverse LIUS application strategies in radiosensitization, including the use of LIUS alone, ultrasound-targeted intravascular microbubble destruction, ultrasound-mediated targeted radiosensitizers delivery, and sonodynamic therapy. Lastly, the review presented the limitations and prospects of employing LIUS-RT combined therapy in clinical settings, emphasizing the need to connect research findings with practical applications. RESULTS AND CONCLUSION: LIUS employs cost-effective equipment to foster tumor radiosensitization, curtail radiation exposure, and elevate the quality of life for patients. This efficacy is attributed to LIUS's ability to utilize thermal, cavitation, and mechanical effects to overcome tumor cell resistance to RT. Multiple experimental analyses have underscored the effectiveness of LIUS in inducing tumor radiosensitization using diverse strategies. While initial studies have shown promising results, conducting more comprehensive clinical trials is crucial to confirm its safety and effectiveness in real-world situations.

STING agonist-conjugated metal-organic framework induces artificial leukocytoid structures and immune hotspots for systemic antitumor responses.

Radiotherapy is widely used for cancer treatment, but its clinical utility is limited by radioresistance and its inability to target metastases. Nanoscale metal-organic frameworks (MOFs) have shown promise as high-Z nanoradiosensitizers to enhance radiotherapy and induce immunostimulatory regulation of the tumor microenvironment. We hypothesized that MOFs could deliver small-molecule therapeutics to synergize with radiotherapy for enhanced antitumor efficacy. Herein, we develop a robust nanoradiosensitizer, GA-MOF, by conjugating a STING agonist, 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), on MOFs for synergistic radiosensitization and STING activation. GA-MOF demonstrated strong anticancer efficacy by forming immune-cell-rich nodules (artificial leukocytoid structures) and transforming them into immunostimulatory hotspots with radiotherapy. Further combination with an immune checkpoint blockade suppressed distant tumors through systemic immune activation. Our work not only demonstrates the potent radiosensitization of GA-MOF, but also provides detailed mechanisms regarding MOF distribution, immune regulatory pathways and long-term immune effects.

Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Unveiling Anticancer Potential of COX-2 and 5-LOX Inhibitors: Cytotoxicity, Radiosensitization Potential and Antimigratory Activity against Colorectal and Pancreatic Carcinoma.

Apart from cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells and cell antimigratory effects); however, the relationship between the inhibition of other inflammation-related enzyme 5-LOX inhibitors and anticancer activity is still not well understood. In our study, the cytotoxicity of thirteen COX-2 and 5-LOX inhibitors previously presented by our group (1-13) was tested on three cancer cell lines (HCT 116, HT-29 and BxPC-3) and one healthy cell line (MRC-5). Compounds 3, 5, 6 and 7 showed moderate cytotoxicity, but good selectivity towards cancer cell lines. IC50 values were in the range of 22.99-51.66 µM (HCT 116 cell line), 8.63-41.20 µM (BxPC-3 cell line) and 24.78-81.60 µM (HT-29 cell line; compound 7 > 100 µM). In comparison to tested, commercially available COX-2 and 5-LOX inhibitors, both cytotoxicity and selectivity were increased. The addition of compounds 6 and 7 to irradiation treatment showed the most significant decrease in cell proliferation of the HT-29 cell line (p < 0.001). The antimigratory potential of the best dual COX-2 and 5-LOX inhibitors (compounds 1, 2, 3 and 5) was tested by a wound-healing assay using the SW620 cell line. Compounds 1 and 3 were singled out as compounds with the most potent effect (relative wound closure was 3.20% (24 h), 5,08% (48 h) for compound 1 and 3.86% (24 h), 7.68% (48 h) for compound 3). Considering all these results, compound 3 stood out as the compound with the most optimal biological activity, with the best dual COX-2 and 5-LOX inhibitory activity, good selectivity towards tested cancer cell lines, significant cell antimigratory potential and a lack of toxic effects at therapeutic doses.

Radiosensitization effect of quinoline-indole-schiff base derivative 10E on non-small cell lung cancer cells in vitro and in tumor xenografts.

Radioresistance is an inevitable obstacle in the clinical treatment of inoperable patients with non-small cell lung cancer (NSCLC). Combining treatment with radiosensitizers may improve the efficacy of radiotherapy. Previously, the quinoline derivative 10E as new exporter of Nur77 has shown superior antitumor activity in hepatocellular carcinoma. Here, we aimed to investigate the radiosensitizing activity and acting mechanisms of 10E. In vitro, A549 and H460 cells were treated with control, ionizing radiation (IR), 10E, and 10E + IR. Cell viability, apoptosis, and cycle were examined using CCK-8 and flow cytometry assays. Protein expression and localization were examined using western blotting and immunofluorescence. Tumor xenograft models were established to evaluate the radiosensitizing effect of 10E in vivo. 10E significantly inhibited cell proliferation and increased their radiosensitivity while reducing level of p-BCRA1, p-DNA-PKs, and 53BP1 involved in the DNA damage repair pathway, indicating that its radiosensitizing activity is closely associated with repressing DNA damage repair. A549 cells showed low level of Nur77 and a low response to IR but 10E-treated A549 cells showed high level of Nur77 indicating that Nur77 is a core radiosensitivity factor and 10E restores the expression of Nur77. Nur77 and Ku80 extranuclear co-localization in the 10E-treated A549 cells suggested that 10E-modulated Nur77 nuclear exportation inhibits DNA damage repair pathways and increases IR-triggered apoptosis. The combination of 10E and IR significantly inhibits tumor growth in a tumor xenograft model. Our findings suggest that 10E acts as a radiosensitizer and that combining 10E with radiotherapy may be a potential strategy for NSCLC treatment.

Effect of Raltitrexed on ECA109 Cellular Radiosensitivity and Its Mechanism in Esophageal Cancer.

BACKGROUND: To investigate the effect of raltitrexed + X-ray irradiation on esophageal cancer ECA109 cells and analyze the potential action mechanism. METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to analyze the inhibitory effect of raltitrexed on cell proliferation. The effect of raltitrexed on radiosensitivity was studied through a clone-forming experiment. The scratch assay and invasion test were performed to understand the cell migration and invasion abilities. The apoptosis rate change was measured using a flow cytometer, and Western Blotting was used to determine the expression of B cell lymphoma-2 (Bcl-2) and Bcl2-associated X protein (Bax) in each group. RESULTS: Raltitrexed significantly inhibited ECA109 proliferation in a time-dose-dependent manner; there were significant differences among different concentrations and times of action. The results of the clone-forming experiment showed a sensitization enhancement ratio of 1.65, and this demonstrated a radiosensitization effect. After the combination of raltitrexed with X-ray, the cell migration distance was shortened, and the number of cells penetrating the membrane was reduced. CONCLUSION: Raltitrexed can inhibit the growth of esophageal cancer ECA109 cells and has a radiosensitization effect.

Manipulating Radiation-Sensitive Z-DNA Conformation for Enhanced Radiotherapy.

DNA double-strand breaks (DSBs) yield highly determines radiotherapy efficacy. However, improving the inherent radiosensitivity of tumor DNA to promote radiation-induced DSBs remains a challenge. Using theoretical and experimental models, the underexplored impact of Z-DNA conformations on radiosensitivity, yielding higher DSBs than other DNA conformations, is discovered. Thereout, a radiosensitization strategy focused on inducing Z-DNA conformation, utilizing CBL@HfO2 nanocapsules loaded with a Z-DNA inducer CBL0137, is proposed. A hollow mesoporous HfO2 (HM-HfO2) acts as a delivery and an energy depositor to promote Z-DNA breakage. The nanocapsule permits the smart DSBs accelerator that triggers its radiosensitization with irradiation stimulation. Impressively, the CBL@HfO2 facilitates the B-Z DNA conformational transition, augmenting DSBs about threefold stronger than irradiation alone, generating significant tumor suppression with a 30% cure rate. The approach enables DSBs augmentation by improving the inherent radiosensitivity of DNA. As such, it opens up an era of Z-DNA conformation manipulation in radiotherapy.

Inhibition of ribonucleotide reductase subunit M2 enhances the radiosensitivity of metastatic pancreatic neuroendocrine tumor.

Ribonucleotide Reductase (RNR) is a rate-limiting enzyme in the production of deoxyribonucleoside triphosphates (dNTPs), which are essential substrates for DNA repair after radiation damage. We explored the radiosensitization property of RNR and investigated a selective RRM2 inhibitor, 3-AP, as a radiosensitizer in the treatment of metastatic pNETs. We investigated the role of RNR subunit, RRM2, in pancreatic neuroendocrine (pNET) cells and responses to radiation in vitro. We also evaluated the selective RRM2 subunit inhibitor, 3-AP, as a radiosensitizer to treat pNET metastases in vivo. Knockdown of RNR subunits demonstrated that RRM1 and RRM2 subunits, but not p53R3, play significant roles in cell proliferation. RRM2 inhibition activated DDR pathways through phosphorylation of ATM and DNA-PK protein kinases but not ATR. RRM2 inhibition also induced Chk1 and Chk2 phosphorylation, resulting in G1/S phase cell cycle arrest. RRM2 inhibition sensitized pNET cells to radiotherapy and induced apoptosis in vitro. In vivo, we utilized pNET subcutaneous and lung metastasis models to examine the rationale for RNR-targeted therapy and 3-AP as a radiosensitizer in treating pNETs. Combination treatment significantly increased apoptosis of BON (human pNET) xenografts and significantly reduced the burden of lung metastases. Together, our results demonstrate that selective RRM2 inhibition induced radiosensitivity of metastatic pNETs both in vitro and in vivo. Therefore, treatment with the selective RRM2 inhibitor, 3-AP, is a promising radiosensitizer in the therapeutic armamentarium for metastatic pNETs.

Nonpersistent Nanoarchitectures Enhance Concurrent Chemoradiotherapy in an Immunocompetent Orthotopic Model of HPV+ Head/Neck Carcinoma.

Cisplatin chemoradiotherapy (CRT) is the established standard of care for managing locally advanced human papillomavirus-positive head/neck carcinoma. The typically young patients may suffer serious and long-time side effects caused by the treatment, such as dysphagia, and hearing loss. Thus, ensuring a satisfactory post-treatment quality of life is paramount. One potential replacing approach to the classical CRT involves the combination of standard-dose radiotherapy and radiosensitizers such as noble metal nanoparticles (NPs). However, several concerns about size, shape, and biocompatibility limit the translation of metal nanomaterials to the clinical practice. Here, it is demonstrated that a new model of nonpersistent gold nanoarchitectures containing cisplatin (NAs-Cluster-CisPt) generates, in combination with radiotherapy, a significant in vivo tumor-reducing effect compared to the standard CRT, achieving a complete tumor clearance in 25% of the immunocompetent models that persist for 60 days. These findings, together with the negligible amount of metals recognized in the excretory organs, highlight that the concurrent administration of NAs-Cluster-CisPt and radiotherapy has the potential to overcome some clinical limitations associated to NP-based approaches while enhancing the treatment outcome with respect to standard CRT. Overall, despite further mechanistic investigations being essential, these data support the exploiting of nonpersistent metal-nanomaterial-mediated approaches for oral cancer management.

Rare Earth Nanoprobes for Targeted Delineation of Triple Negative Breast Cancer and Enhancement of Radioimmunotherapy.

Radiotherapy demonstrates a synergistic effect with immunotherapy by inducing a transformation of "immune cold" tumors into "immune hot" tumors in triple negative breast cancer (TNBC). Nevertheless, the effectiveness of immunotherapy is constrained by low expression of tumor-exposed antigens, inadequate inflammation, and insufficient tumor infiltrating lymphocyte (TILs). To address this predicament, novel lutecium-based rare earth nanoparticles (RENPs) are synthesized with the aim of amplifying radiation effect and tumor immune response. The nanoprobe is characterized by neodymium-based down-conversion fluorescence, demonstrating robust photostability, biocompatibility, and targetability. The conjugation of RENPs with a CXCR4 targeted drug enables precise delineation of breast tumors using a near-infrared imaging system and improves radiation efficacy via lutetium-based radio-sensitizer in vivo. Furthermore, the study shows a notable enhancement of immune response through the induction of immunogenic cell death and recruitment of TILs, resulting in the inhibition of tumor progression both in vitro and in vivo models following the administration of nanoparticles. Hence, the novel multifunctional nanoprobes incorporating various lanthanide elements offer the potential for imaging-guided tumor delineation, radio-sensitization, and immune activation post-radiation, thus presenting an efficient radio-immunotherapeutic approach for TNBC.

A Dual-Channel Ca2+ Nanomodulator Induces Intracellular Ca2+ Disorders via Endogenous Ca2+ Redistribution for Tumor Radiosensitization.

Tumor cells harness Ca2+ to maintain cellular homeostasis and withstand external stresses from various treatments. Here, a dual-channel Ca2+ nanomodulator (CAP-P-NO) is constructed that can induce irreversible intracellular Ca2+ disorders via the redistribution of tumor-inherent Ca2+ for disrupting cellular homeostasis and thus improving tumor radiosensitivity. Stimulated by tumor-overexpressed acid and glutathione, capsaicin and nitric oxide are successively escaped from CAP-P-NO to activate the transient receptor potential cation channel subfamily V member 1 and the ryanodine receptor for the influx of extracellular Ca2+ and the release of Ca2+ in the endoplasmic reticulum, respectively. The overwhelming level of Ca2+ in tumor cells not only impairs the function of organelles but also induces widespread changes in the gene transcriptome, including the downregulation of a set of radioresistance-associated genes. Combining CAP-P-NO treatment with radiotherapy achieves a significant suppression against both pancreatic and patient-derived hepatic tumors with negligible side effects. Together, the study provides a feasible approach for inducing tumor-specific intracellular Ca2+ overload via endogenous Ca2+ redistribution and demonstrates the great potential of Ca2+ disorder therapy in enhancing the sensitivity for tumor radiotherapy.

Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape.

BACKGROUND: Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or ß-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups. MAIN BODY: Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with 111In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [111In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with ß-particle emitting 177Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [90Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [177Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (111In, 99mTc, 125I, 103Pd, 193mPt, 195mPt), ß-particles (177Lu, 186Re, 188Re, 90Y, 198Au, 131I) or α-particles (225Ac, 213Bi, 212Pb, 211At, 223Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity. CONCLUSIONS: Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.

Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy.

Tumor cells establish a robust self-defense system characterized by hypoxia, antioxidant overexpression, DNA damage repair, and so forth to resist radiotherapy. Targeting one of these features is insufficient to overcome radioresistance due to the feedback mechanisms initiated by tumor cells under radiotherapy. Therefore, we herein developed an engineering biomimetic nanosystem (M@HHPt) masked with tumor cell membranes and loaded with a hybridized protein-based nanoparticle carrying oxygens (O2) and cisplatin prodrugs (Pt(IV)) to target multiple tumor radioresistance hallmarks for enhanced radiotherapy. After administration, M@HHPt actively targeted and smoothly accumulated in tumor cells by virtue of its innate homing abilities to realize efficient co-delivery of O2 and Pt(IV). O2 introduction induced hypoxia alleviation cooperated with Pt(IV) reduction caused glutathione consumption greatly amplified radiotherapy-ignited cellular oxidative stress. Moreover, the released cisplatin effectively hindered DNA damage repair by crosslinking with radiotherapy-produced DNA fragments. Consequently, M@HHPt-sensitized radiotherapy significantly suppressed the proliferation of lung cancer H1975 cells with an extremely high sensitizer enhancement ratio of 1.91 and the progression of H1975 tumor models with an excellent tumor inhibition rate of 94.7%. Overall, this work provided a feasible strategy for tumor radiosensitization by overcoming multiple radioresistance mechanisms.

Bimetallic nanoparticles as cascade sensitizing amplifiers for low-dose and robust cancer radio-immunotherapy.

Radiotherapy (RT) is one of the most feasible and routinely used therapeutic modalities for treating malignant tumors. In particular, immune responses triggered by RT, known as radio-immunotherapy, can partially inhibit the growth of distantly spreading tumors and recurrent tumors. However, the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immunogenicity of tumor. Herein, we report oxaliplatin (IV)-iron bimetallic nanoparticles (OXA/Fe NPs) as cascade sensitizing amplifiers for low-dose and robust radio-immunotherapy. The OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA (II) and Fe2+ in response to the reductive and acidic microenvironment within tumor cells. The cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage, increasing ROS and O2 levels, and amplifying the immunogenic cell death (ICD) effect after RT to facilitate potent immune activation. As a result, OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal effect. Moreover, a long-term immunological memory effect to protect mice from tumor rechallenging is observed. Overall, the bimetallic NPs-based cascade sensitizing amplifier system offers an efficient radio-immunotherapy regimen that addresses the key challenges.

Spatiotemporal Concurrent PARP Inhibitor Sensitization Based on Radiation-Responsive Nanovesicles for Lung Cancer Chemoradiotherapy.

The implementation of chemoradiation combinations has gained great momentum in clinical practices. However, the full utility of this paradigm is often restricted by the discordant tempos of action of chemotherapy and radiotherapy. Here, a gold nanoparticle-based radiation-responsive nanovesicle system loaded with cisplatin and veliparib, denoted as CV-Au NVs, is developed to augment the concurrent chemoradiation effect in a spatiotemporally controllable manner of drug release. Upon irradiation, the in situ generation of •OH induces the oxidation of polyphenylene sulfide from being hydrophobic to hydrophilic, resulting in the disintegration of the nanovesicles and the rapid release of the entrapped cisplatin and veliparib (the poly ADP-ribose polymerase (PARP) inhibitor). Cisplatin-induced DNA damage and the impairment of the DNA repair mechanism mediated by veliparib synergistically elicit potent pro-apoptotic effects. In vivo studies suggest that one-dose injection of the CV-Au NVs and one-time X-ray irradiation paradigm effectively inhibit tumor growth in the A549 lung cancer model. This study provides new insight into designing nanomedicine platforms in chemoradiation therapy from a vantage point of synergizing both chemotherapy and radiation therapy in a spatiotemporally concurrent manner.

Reactive Oxygen Species Amplifier for Apoptosis-Ferroptosis Mediated High-Efficiency Radiosensitization of Tumors.

Insufficient reactive oxygen species (ROS) production and radioresistance have consistently contributed to the failure of radiotherapy (RT). The development of a biomaterial capable of activating ROS-induced apoptosis and ferroptosis is a potential strategy to enhance RT sensitivity. To achieve precision and high-efficiency RT, the theranostic nanoplatform Au/Cu nanodots (Au/CuNDs) were designed for dual-mode imaging, amplifying ROS generation, and inducing apoptosis-ferroptosis to sensitize RT. A large amount of ROS is derived from three aspects: (1) When exposed to ionizing radiation, Au/CuNDs effectively absorb photons and emit various electrons, which can interact with water to produce ROS. (2) Au/CuNDs act as a catalase-like to produce abundant ROS through Fenton reaction with hydrogen peroxide overexpressed of tumor cells. (3) Au/CuNDs deplete overexpressed glutathione, which causes the accumulation of ROS. Large amounts of ROS and ionizing radiation further lead to apoptosis by increasing DNA damage, and ferroptosis by enhancing lipid peroxidation, significantly improving the therapeutic efficiency of RT. Furthermore, Au/CuNDs serve as an excellent nanoprobe for high-resolution near-infrared fluorescence imaging and computed tomography of tumors. The promising dual-mode imaging performance shows their potential application in clinical cancer detection and imaging-guided precision RT, minimizing damage to adjacent normal tissues during RT. In summary, our developed theranostic nanoplatform integrates dual-mode imaging and sensitizes RT via ROS-activated apoptosis-ferroptosis, offering a promising prospect for clinical cancer diagnosis and treatment.

Targeting the organelle for radiosensitization in cancer radiotherapy.

Radiotherapy is a well-established cytotoxic therapy for local solid cancers, utilizing high-energy ionizing radiation to destroy cancer cells. However, this method has several limitations, including low radiation energy deposition, severe damage to surrounding normal cells, and high tumor resistance to radiation. Among various radiotherapy methods, boron neutron capture therapy (BNCT) has emerged as a principal approach to improve the therapeutic ratio of malignancies and reduce lethality to surrounding normal tissue, but it remains deficient in terms of insufficient boron accumulation as well as short retention time, which limits the curative effect. Recently, a series of radiosensitizers that can selectively accumulate in specific organelles of cancer cells have been developed to precisely target radiotherapy, thereby reducing side effects of normal tissue damage, overcoming radioresistance, and improving radiosensitivity. In this review, we mainly focus on the field of nanomedicine-based cancer radiotherapy and discuss the organelle-targeted radiosensitizers, specifically including nucleus, mitochondria, endoplasmic reticulum and lysosomes. Furthermore, the organelle-targeted boron carriers used in BNCT are particularly presented. Through demonstrating recent developments in organelle-targeted radiosensitization, we hope to provide insight into the design of organelle-targeted radiosensitizers for clinical cancer treatment.

Microwave hyperthermia enhances radiosensitization by decreasing DNA repair efficiency and inducing oxidative stress in PC3 prostatic adenocarcinoma cells.

PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.

Application of nano-radiosensitizers in non-small cell lung cancer.

Radiotherapy stands as a cornerstone in the treatment of numerous malignant tumors, including non-small cell lung cancer. However, the critical challenge of amplifying the tumoricidal effectiveness of radiotherapy while minimizing collateral damage to healthy tissues remains an area of significant research interest. Radiosensitizers, by methods such as amplifying DNA damage and fostering the creation of free radicals, play a pivotal role in enhancing the destructive impact of radiotherapy on tumors. Over recent decades, nano-dimensional radiosensitizers have emerged as a notable advancement. Their mechanisms include cell cycle arrest in the G2/M phase, combating tumor hypoxia, and others, thereby enhancing the efficacy of radiotherapy. This review delves into the evolving landscape of nanomaterials used for radiosensitization in non-small cell lung cancer. It provides insights into the current research progress and critically examines the challenges and future prospects within this burgeoning field.

Single-Cell Profiling Reveals Immune-Based Mechanisms Underlying Tumor Radiosensitization by a Novel Mn Porphyrin Clinical Candidate, MnTnBuOE-2-PyP5+ (BMX-001).

Manganese porphyrins reportedly exhibit synergic effects when combined with irradiation. However, an in-depth understanding of intratumoral heterogeneity and immune pathways, as affected by Mn porphyrins, remains limited. Here, we explored the mechanisms underlying immunomodulation of a clinical candidate, MnTnBuOE-2-PyP5+ (BMX-001, MnBuOE), using single-cell analysis in a murine carcinoma model. Mice bearing 4T1 tumors were divided into four groups: control, MnBuOE, radiotherapy (RT), and combined MnBuOE and radiotherapy (MnBuOE/RT). In epithelial cells, the epithelial-mesenchymal transition, TNF-α signaling via NF-кB, angiogenesis, and hypoxia-related genes were significantly downregulated in the MnBuOE/RT group compared with the RT group. All subtypes of cancer-associated fibroblasts (CAFs) were clearly reduced in MnBuOE and MnBuOE/RT. Inhibitory receptor-ligand interactions, in which epithelial cells and CAFs interacted with CD8+ T cells, were significantly lower in the MnBuOE/RT group than in the RT group. Trajectory analysis showed that dendritic cells maturation-associated markers were increased in MnBuOE/RT. M1 macrophages were significantly increased in the MnBuOE/RT group compared with the RT group, whereas myeloid-derived suppressor cells were decreased. CellChat analysis showed that the number of cell-cell communications was the lowest in the MnBuOE/RT group. Our study is the first to provide evidence for the combined radiotherapy with a novel Mn porphyrin clinical candidate, BMX-001, from the perspective of each cell type within the tumor microenvironment.