Biological effects in normal human fibroblasts following chronic and acute irradiation with both low- and high-LET radiation.

Introduction: Radiobiological studies at low dose rates allow us to improve our knowledge of the mechanisms by which radiation exerts its effects on biological systems following chronic exposures. Moreover, these studies can complement available epidemiological data on the biological effects of low doses and dose rates of ionizing radiation. Very few studies have simultaneously compared the biological effects of low- and high-LET radiations at the same dose rate for chronic irradiation. Methods: We compared, for the first time in the same experiment, the effects of chronic (dose rates as low as ~18 and 5 mGy/h) and acute irradiations on clonogenicity and micronucleus formation in AG1522 normal human skin fibroblasts in the confluent state exposed to doses of low- and high-LET radiation (gamma rays and alpha particles) to investigate any differences due to the different radiation quality and different dose rate (in the dose range 0.006-0.9 Gy for alpha particles and 0.4-2.3 Gy for gamma rays). Results: As expected, alpha particles were more effective than gamma rays at inducing cytogenetic damage and reduced clonogenic cell survival. For gamma rays, the cytogenetic damage and the reduction of clonogenic cell survival were greater when the dose was delivered acutely instead of chronically. Instead, for the alpha particles, at the same dose, we found equal cytogenetic damage and reduction of clonogenic cell survival for both chronic and acute exposure (except for the highest doses of 0.4 and 0.9 Gy, where cytogenetic damage is greater at a low dose rate). Conclusion: The results of this study may have an impact on space and terrestrial radioprotection of humans at low doses and low dose rates, on biodosimetry, and on the use of ionizing radiation in medicine. These results also provide insights into understanding damage induction and cell reaction mechanisms following chronic exposure (at dose rates as low as 18 and 5 mGy/h) to low- and high-LET radiation.

Fabrication of a cell irradiation technique by alpha-particles using allyl diglycol carbonate (ADC) detector and micro-capillary tubes.

Objective: To study the impact of micro-alpha irradiation collimator with a specific design to irradiate specific normal or up-normal cells using capillary tubes and nuclear track detector type CR-39. METHODS: The in vitro experimental study was conducted at radiobiology Lab, of the Physics department, Salahaddin University, Erbil, Iraq from February to April 2022. Several alpha irradiation collimators were calibrated using allyl diglycol carbonate to fabricate a suitable blood cell irradiation technique. Time of irradiation and alpha particle energy were calibrated. Healthy blood samples of Albino rats and cancer blood samples were used to assess the applicability of the fabricated cell irradiation technique. The Rats were divided into intervention and control groups. Data was analysed using SPSS software version 28. RESULTS: Of the 15 healthy, male Albino rats having a mean weight of 230±12g each, there were 12(80%) in the intervention group and 3(20%) in the control group. Microcapillary tubes with suitable diameters had high stability for deposition of a sufficient density of alpha particles on the surface of allyl diglycol carbonate and blood samples. The optimum time of irradiation that had a significant (p<0.05) effect was 20 sec corresponding to alpha energy 4.5MeV. CONCLUSIONS: Low irradiation time had significant impact of alpha particles on the average percentage of lymphocyte and neutrophil cells.

Fluorine-18 incorporation and radiometal coordination in macropa ligands for PET imaging and targeted alpha therapy.

The development of theranostic agents for radiopharmaceuticals based on therapeutic alpha emitters marks an important clinical need. We describe a strategy for the development of theranostic agents of this type via the functionalization of the ligand with the diagnostic radionuclide fluorine-18. An analogue of macropa, an 18-membered macrocyclic chelator with high affinity for alpha therapeutic radiometals, was synthesized and its complexation properties with metal ions were determined. The new macropa-F ligand was used for quantitative radiometal complexation with lead-203 and bismuth-207, as surrogates for their alpha-emitting radioisotopes. As a diagnostic partner, a radiofluorinated macropa ligand was used for quantitative bismuth(III) and lead(II) complexation. All fluorine-18 and radiometal complexes are highly stable in human serum over several days. This study presents a new proof-of-principle approach for developing theranostic agents based on alpha-emitting radionuclides and fluorine-18.

Role of damaged mitochondrial transfer in alpha-particle generator 212Pb radiation-induced bystander effect.

Rationale: 212Pb, a promising in vivo alpha-particle generator of 212Bi, has aroused much interest as a therapeutic radionuclide. For the development of targeted alpha therapy (TAT), it is important to determine the contribution of targeted effects in irradiated cells, and also of non-targeted effects in non-irradiated bystander cells. Currently, the critical roles of mitochondrial transfer in cellular crosstalk have garnered significant attention. However, the specific involvement of damaged mitochondrial transfer in orchestrating this alpha-particle radiation-induced bystander effect (RIBE) needs to be further explored. Methods: A novel alpha-emitting radiopharmaceutical, 212Pb-hydrogel nanoparticles (HNPs), was synthesized and subsequently evaluated its theranostics effects. The impact of irradiated cell-conditioned media (ICCM), collected at different times post-212Bi irradiation, on bystander cancer cells regarding cell viability was also investigated. Additionally, damaged mitochondria were isolated and cultured with non-irradiated bystander cells to assess their role. Results: 212Pb-HNPs exhibited efficient therapeutic antitumor effects in vitro, including increased GSH depletion, ROS accumulation, and mitochondrial damage in irradiated tumor cells. In vivo studies demonstrated its imaging potential through SPECT/CT, and RNA sequencing results indicated activation of oxidative stress-related pathways in irradiated tumors. Additionally, ICCM influenced the viability of non-irradiated bystander cells, suggesting a radiation-induced bystander effect by the alpha-particle 212Bi. Interestingly, damaged mitochondria isolated from ICCM were observed to enter co-cultured non-irradiated bystander cells. Further experiments confirmed that the transfer of damaged mitochondria results in the death of non-irradiated bystander cells. Conclusion: The present study highlights the theranostic potential of the alpha-particle generator 212Pb and, more importantly, elucidates the role of damaged mitochondrial transfer in alpha-particle RIBE. These findings provide a novel theoretical mechanism for the antitumor effects of alpha-particles and expand the clinical application prospects of TAT.

Nicotine interacts with DNA lesions induced by alpha radiation which may contribute to erroneous repair in human lung epithelial cells.

PURPOSE: Epidemiological studies show that radon and cigarette smoke interact in inducing lung cancer, but the contribution of nicotine in response to alpha radiation emitted by radon is not well understood. MATERIALS AND METHODS: Bronchial epithelial BEAS-2B cells were either pre-treated with 2 µM nicotine during 16 h, exposed to radiation, or the combination. DNA damage, cellular and chromosomal alterations, oxidative stress as well as inflammatory responses were assessed to investigate the role of nicotine in modulating responses. RESULTS: Less γH2AX foci were detected at 1 h after alpha radiation exposure (1-2 Gy) in the combination group versus alpha radiation alone, whereas nicotine alone had no effect. Comet assay showed less DNA breaks already just after combined exposure, supported by reduced p-ATM, p-DNA-PK, p-p53 and RAD51 at 1 h, compared to alpha radiation alone. Yet the frequency of translocations was higher in the combination group at 27 h after irradiation. Although nicotine did not alter G2 arrest at 24 h, it assisted in cell cycle progression at 48 h post radiation. A slightly faster recovery was indicated in the combination group based on cell viability kinetics and viable cell counts, and significantly using colony formation assay. Pan-histone acetyl transferase inhibition using PU139 blocked the reduction in p-p53 and γH2AX activation, suggesting a role for nicotine-induced histone acetylation in enabling rapid DNA repair. Nicotine had a modest effect on reactive oxygen species induction, but tended to increase alpha particle-induced pro-inflammatory IL-6 and IL-1ß (4 Gy). Interestingly, nicotine did not alter gamma radiation-induced γH2AX foci. CONCLUSIONS: This study provides evidence that nicotine modulates alpha-radiation response by causing a faster but more error-prone repair, as well as rapid recovery, which may allow expansion of cells with genomic instabilities. These results hold implications for estimating radiation risk among nicotine users.

Dosimetry at cellular level for the alpha-emitting radionuclides actinium-225, astatine-211 and radium-223 for bone metastasis cells from castration resistant prostate cancer.

Objectives.The aim of this work is to evaluate energy deposition in the nucleus and cytoplasm in targeted alpha therapy of metastatic castration-resistant prostate cancer by modeling two cell lines, PC3 (osteolytic) and LNCaP C4-2 (osteoblastic), for actinium-225, astatine-211, and radium-223 and their progeny, using Monte Carlo simulations with the GATE/Geant4 code.Approach.We developed single cell and cell clusters models to Monte Carlo simulations, performed on the GATE platform version 9.3, with the GEANT4-DNA physics list emstandard_opt3_mixed_dna for At-211, Ac-225 and Ra-223 progenies. We considered three radionuclide distributions as a sources: the nucleus, the cytoplasm and the whole cell.Main results.When the nucleus was considered as a target, theS-values (N←N) calculated for At-211, Ac-225 and Ra-223 progenies were significantly higher, within 60%-90%, thanS-values (N←Cy), demonstrating less influence of cytoplasm only internalization. When the cytoplasm was considering as a target, theS-values (Cy←Cy) calculated for At-211, Ac-225 and Ra-223 progeny were significantly higher, within 30%-90%, than theS-values (Cy←N). When no progeny migration occurs and for target nucleus , the cumulativeS-values (N←N) calculated for At-211, Ac-225 and Ra-223 were significantly higher, within 50%-70%, than theS-values (N←N) computed for At-211, Ac-225, and Ra-223. Comparing the cumulativeS-values, Ac-225 and Ra-223 therapies is more effective, in terms of deposited energy in a target, than that with At-211.Significance.The data presented in this research indicates that Ac-225 therapy may be the optimum choice due to the energy deposited in the nucleus, as long as the recoil effects and redistribution of progeny are understood. In contrast, At-211 is an alternative to avoid progeny migration. However, to completely analyze the efficacy of radionuclide therapy, other parameters must be considered, such as biological half-life, stability of the transport molecule, progeny migration, excretion pathways, and uptake in different organs.

Energy resolution improvement in simplified alpha spectroscopy for radionuclidic purity tests on 225Ac production floors.

This study investigated the feasibility of a simplified method of alpha spectroscopy for radionuclidic purity tests at 225Ac production sites that eliminates the need for a vacuum chamber. The impact of enhancing the energy resolution using a collimator was evaluated through radiation transport simulations. The results showed that a full width at tenth maximum (FWTM) of <300 keV was achieved for alpha particles from 241Am, for which the main energy peak was 5.5 MeV. Experimental validation using an electrodeposition source containing 237Np, 241Am, and 244Cm confirmed an FWTM of 272 keV for both 241Am and 244Cm. These two peaks, with a difference of ~300 keV, were effectively separated. In response to the growing demand for targeted radioisotope therapy, this simplified alpha spectroscopy method offers the potential to detect 226Ra mixed with 225Ac generated by accelerators, given the alpha energy difference of ~700 keV.

Interlaboratory comparison of gross alpha/beta activity of drinking water over a decade.

Interlaboratory comparison exercises for determining the gross alpha and beta activity concentrations in drinking water, organized by the National Institute for Radiological Protection (NIRP), China CDC, have been carried out since 2012. The purpose of this study is to assess the accuracy and precision of gross alpha and beta analyses of low-level radioactivity concentrations. Natural water samples were used for the comparison, and the performance of the participating laboratories was evaluated with respect to the reference values using the Z-score performance indicator. The comparison data from 2012 to 2022 were analyzed, where the percentage of laboratories with acceptable results was 80-92%, and the dispersion of the measurement results across laboratories became smaller over time. The results demonstrate that these exercises can help laboratories to resolve issues in gross α/ß analysis and improve the consistency of the measurement results.

Immune effects of α and ß radionuclides in metastatic prostate cancer.

External beam radiotherapy is used for radical treatment of organ-confined prostate cancer and to treat lesions in metastatic disease whereas molecular radiotherapy with labelled prostate-specific membrane antigen ligands and radium-223 (223Ra) is indicated for metastatic prostate cancer and has demonstrated substantial improvements in symptom control and overall survival compared with standard-of-care treatment. Prostate cancer is considered an immunologically cold tumour, so limited studies investigating the treatment-induced effects on the immune response have been completed. However, emerging data support the idea that radiotherapy induces an immune response in prostate cancer, but whether the response is an antitumour or pro-tumour response is dependent on the radiotherapy regime and is also cell-line dependent. In vitro data demonstrate that single-dose radiotherapy regimes induce a greater immune-suppressive profile than fractionated regimes; less is known about the immune response induced by molecular radiotherapy agents, but evidence suggests that these agents might induce an immune-suppressive systemic immune response, indicated by increased expression of inhibitory checkpoint molecules such as programmed cell death 1 ligand 1 and 2, and that these changes could be associated with clinical response. Different radiotherapy modalities can induce distinct immune profiles, which can either activate or suppress immune-mediated tumour killing and the current preclinical models used for prostate cancer research are not yet optimal for studying the complexity of the radiotherapy-induced immune response.

A finite volume approach to dosimetric calculations in diffusing alpha-emitters radiation therapy.

Objective.In diffusing alpha-emitters radiation therapy ('Alpha DaRT'), the diffusion-leakage (DL) model is used to determine the spatial distributions of the emitters and the corresponding alpha dose, critical for a successful treatment. This work first introduces a finite volume (FV) approach to develop numerical schemes to simulate the DL model in one, two and three dimensions then presents how variations over realistic ranges of the DL model parameters related to desorption, diffusion and leakage processes affect the alpha dose distribution and the position of the clinically significant alpha particle10Gy isodose. This work also presents the effects of three modeling approximations: two source geometry approximations (solid cylinder instead of hollow, pixelized cross section instead of circular), and one dosimetric approximation (single-source dose superposition instead of multiple-sources direct dose calculation).Approach.The introduced FV approach was used to obtain spatial distributions of the emitters, from which the corresponding alpha dose distributions were calculated under the assumption of a local deposition of the alpha particles' energies. Variation ranges of the DL model parameters were based on previously published data. For each modeling approximation studied, the error and relative error on the alpha dose distribution were calculated and the displacement of the10Gy isodose was evaluated.Main results.Over realistic ranges, the desorption probabilities, diffusion lengths, and leakage probabilities affect the position of the alpha particle10Gy isodose by∼0.1mm,∼1.5mm and∼0.5mm, respectively. The three modeling approximations studied have a negligible effect on the alpha particle10Gy isodose position, with displacements⩽0.01mm.Significance.This work quantitatively evaluates the relative importance of different parameters and approximations in Alpha-DaRT alpha dose calculations based on their impact not only on the dose variation at a given distance from the source but also on the displacement of clinically significant isodoses.

An electrochemical generator for the continual supply of 213Bi from 225Ac for use in targeted alpha therapy applications.

Bismuth-213 is a radionuclide of interest for targeted alpha therapy and is supplied via a radiochemical generator system through the decay of 225Ac. Radionuclide generators employ longer lived "parent" radionuclides to routinely supply shorter-lived "daughter" radionuclides. The traditional 225Ac/213Bi radiochemical generator relies on an organic cation exchange resin where 225Ac binds to the resin and 213Bi is routinely eluted. These resins degrade when they absorb large doses of ionizing radiation (>1 × 106 Gy/mg), which has been observed when the loading activity of 225Ac exceeds 2.59*109 Bq (70 mCi). Herein we report the development of an electrochemical generator for the supply of 213Bi that has the potential to overcome this limitation. Bismuth-213 spontaneously electrodeposits onto nickel foils in 0.1 M hydrochloric acid at 70 °C. Using this method, we were able to plate an average of 73 ± 4 % of the 213Bi in solution and obtain a final 213Bi recovery of 65 ± 8 % in 0.1 M citrate pH 4.5 via reverse electrolysis using titanium as the cathode. The recovered 213Bi had an average radiochemical purity of >99.8 % and was successfully used to radiolabel DOTATATE with an average radiochemical yield of 85.1 % (not optimized).

Comparative study of 155Tb production via 155Dy precursor with p, d and α beams on natural targets for medical applications.

Three different reactions with the use of natural targets are investigated to produce 155Tb for medical applications from the decay of its precursor 155Dy. The TALYS code has been exploited to optimize the cross section description and to improve the agreement with the full set of available data. The study is completed by a theoretical model for the two radio-chemical separations: optimal solutions are presented for the production of high quality 155Tb samples, guaranteed by the absence of the main contaminant, 156Tb.

Development of a 213Bi-Labeled Pyridyl Benzofuran for Targeted α-Therapy of Amyloid-ß Aggregates.

Alzheimer disease is a neurodegenerative disorder with limited treatment options. It is characterized by the presence of several biomarkers, including amyloid-ß aggregates, which lead to oxidative stress and neuronal decay. Targeted α-therapy (TAT) has been shown to be efficacious against metastatic cancer. TAT takes advantage of tumor-localized α-particle emission to break disease-associated covalent bonds while minimizing radiation dose to healthy tissues due to the short, micrometer-level, distances traveled. We hypothesized that TAT could be used to break covalent bonds within amyloid-ß aggregates and facilitate natural plaque clearance mechanisms. Methods: We synthesized a 213Bi-chelate-linked benzofuran pyridyl derivative (BiBPy) and generated [213Bi]BiBPy, with a specific activity of 120.6 GBq/µg, dissociation constant of 11 ± 1.5 nM, and logP of 0.14 ± 0.03. Results: As the first step toward the validation of [213Bi]BiBPy as a TAT agent for the reduction of Alzheimer disease-associated amyloid-ß, we showed that brain homogenates from APP/PS1 double-transgenic male mice (6-9 mo old) incubated with [213Bi]BiBPy exhibited a marked reduction in amyloid-ß plaque concentration as measured using both enzyme-linked immunosorbent and Western blotting assays, with a half-maximal effective concentration of 3.72 kBq/pg. Conclusion: This [213Bi]BiBPy-concentration-dependent activity shows that TAT can reduce amyloid plaque concentration in vitro and supports the development of targeting systems for in vivo validations.

Determination of uranium isotopes in ground water by alpha spectrometry and associated age-dependent ingestion dose.

Determination of uranium isotopes in ground water plays a key role in assessment of geochemical condition of ground water and for estimating ingestion dose received by the general public because of uranium intake through drinking water. An attempt has been made in the present study to estimate isotopic composition and activity ratios (AR) of uranium isotopes by analysing the ground water samples using alpha spectrometry. Associated age-dependent ingestion dose was also calculated for the public of different age groups. 238U, 235U and 234U activity concentration was found to vary in the ranges of 5.85 ± 1.19 to 76.67 ± 4.16, < 0.90 to 3.15 ± 0.84 and 6.52 ± 1.25 to 107.02 ± 4.92 mBq/L, respectively. 235U/238U AR varies from 0.038 to 0.068 with an average of 0.047 which is close to 0.046 implies that uranium in the ground water is from natural origin. Uranium concentration was found to vary in the range of 0.47 ± 0.10 µg/L to 6.20 ± 0.34 µg/L with a mean value of 3.01 ± 0.23 µg/L, which is much lower than national as well as international recommendation value. Annual ingestion dose to the public of all age groups for uranium intake through drinking water ranges from 0.60 ± 0.11 to 19.50 ± 1.03 µSv/y.

Actinium-225 as an example for monitoring of internal exposure of occupational intakes of radionuclides in face of new nuclear-medical applications for short-lived alpha emitting particles.

Monitoring of internal exposure to short-lived alpha-emitting radionuclides such as actinium-225 (225Ac), which are becoming increasingly important in nuclear medicine, plays an important role in the radiation protection of occupationally exposed persons. After having tested gamma spectrometry, liquid scintillation counting and alpha spectrometry for monitoring of internal exposure, the focus of the present study was on solid phase extraction of 225Ac from urine in combination with alpha spectrometry. The development of the method was based on recent findings from the literature on this topic. The method was used in a pilot phase to monitor internal exposure of four workers who were directly or indirectly involved in the manufacture and/or use of 225Ac. The monitoring protocol allowed a relatively short 24-hour urine sample analysis with excellent recovery of the internal standard, but it did not allow for a detection limit of less than 1 mBq nor a sufficient yield of 225Ac. Based on these results it is concluded that an in vitro excretion analysis alone is not appropriate for monitoring internal exposure to 225Ac. Instead, different radiation monitoring techniques have to be combined to ensure the radiation protection of employees.

Incidence risk of hepatobiliary malignant neoplasms in the cohort of workers chronically exposed to ionizing radiation.

The increased risk of liver malignancies was found in workers of the first Russian nuclear production facility, Mayak Production Association, who had been chronically exposed to gamma rays externally and to alpha particles internally due to plutonium inhalation. In the present study, we updated the radiogenic risk estimates of the hepatobiliary malignancies using the extended follow-up period (1948-2018) of the Mayak worker cohort and the improved «Mayak worker dosimetry system-2013¼. The cohort comprised 22,377 workers hired at the Mayak PA between 1948 and 1982. The analysis considered 62 liver malignancies (32 hepatocellular carcinomas, 13 intrahepatic cholangiocarcinomas, 16 angiosarcomas, and 1 anaplastic cancer) and 33 gallbladder adenocarcinomas. The analysis proved the positive significant association of the liver malignancy risk (the total of histological types, hepatocellular carcinoma) with the liver absorbed alpha dose from internal exposure. The excess relative risk per Gy (95% confidence interval) of alpha dose (the linear model) was 7.56 (3.44; 17.63) for the total of histological types and 3.85 (0.95; 13.30) for hepatocellular carcinoma. Indications of non-linearity were observed in the dose-response for internal exposure to alpha radiation. No impact of external gamma-ray exposure on the liver malignancy incidence was found. In the study cohort, the number of angiosarcomas among various types of liver malignancies was very high (25.8%), and most of these tumors (73.3%) were registered in individuals internally exposed to alpha radiation at doses ranging between 6.0 and 21.0 Gy. No association with chronic occupational radiation exposure was observed for the incidence of gallbladder malignancies.

[Proposal and Analysis of "Ternary" Model of Sensitization for Proton Therapy].

In order to improve the biological effect of proton therapy, the authors first propose a new method of boron-based proton-enhanced radiotherapy in a " ternary " radiotherapy mode, based on the existing sensitizing effect of proton radiotherapy: i.e, Boron-based mediators (11B and 10B) induce the proton-hydrogen-boron fusion reaction of the low-energy protons arriving at the Bragg peak region of the tumor target area (p+11B→3α) and thermal neutron capture (10B+n→7Li3+(0.84 MeV)+4He2+(1.47 MeV)+γ(0.477 MeV)), which release low-energy α-particles with high LETs to enhance the biological effect of proton dose in the target area, thus improve the clinical effect of proton therapy. Then, the advantages and disadvantages of the "ternary" model were analyzed from the theoretical basis and current research status, and finally, the "ternary" model is summarized and prospected.

Development of a Neopentyl 211At-Labeled Activated Ester Providing In Vivo Stable 211At-Labeled Antibodies for Targeted Alpha Therapy.

In this study we developed a neopentyl 211At-labeled activated ester that incorporates a triazole spacer and applied it to the synthesis of an 211At-labeled cetuximab. The activated ester was synthesized via the nucleophilic 211At-astatination of a neopentyl sulfonate carrying two long alkyl chains that serve as a lipid tag, which was followed by the hydrolysis of an acetal. Additionally, we developed a novel Resin-Assisted Purification and Deprotection (RAPD) protocol involving a solid-phase extraction of the protected 211At-labeled compound from the mixture of the labeling reaction, hydrolysis of the acetal on the resin, and finally an elution of the 211At-labeled activator from the resin. This method allows the synthesis of an 211At-labeled activated ester with high purity through a simplified procedure that circumvents the need for HPLC purification. Using this 211At-labeled activated ester, we efficiently synthesized 211At-labeled cetuximab in 27±1 % radiochemical yield with 95 % radiochemical purity. This 211At-activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 min. In comparative biodistribution studies between 211At-labeled cetuximab and the corresponding 125I-labeled cetuximab in normal mice, both the thyroid and stomach showed radioactivity levels that were less than 1.0 % of the injected dose.

APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy.

Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (224Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using 224Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.

Development of 225Ac-doped biocompatible nanoparticles for targeted alpha therapy.

Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes. Encapsulating α-emitting radionuclides within nanoparticles can help overcome many of these challenges. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are a biodegradable and biocompatible delivery platform that has been used for drug delivery. In this study, PLGA nanoparticles are utilized for encapsulation and retention of actinium-225 ([225Ac]Ac3+). Encapsulation of [225Ac]Ac3+ within PLGA nanoparticles (Zave = 155.3 nm) was achieved by adapting a double-emulsion solvent evaporation method. The encapsulation efficiency was affected by both the solvent conditions and the chelation of [225Ac]Ac3+. Chelation of [225Ac]Ac3+ to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([225Ac]AcBLPhen) significantly decreased its release (< 2%) and that of its decay daughters (< 50%) from PLGA nanoparticles. PLGA nanoparticles encapsulating [225Ac]AcBLPhen significantly increased the delivery of [225Ac]Ac3+ to murine (E0771) and human (MCF-7 and MDA-MB-231) breast cancer cells with a concomitant increase in cell death over free [225Ac]Ac3+ in solution. These results demonstrate that PLGA nanoparticles have potential as radionuclide delivery platforms for TAT to advance precision radiotherapy for cancer. In addition, this technology offers an alternative use for ligands with poor aqueous solubility, low stability, or low affinity, allowing them to be repurposed for TAT by encapsulation within PLGA nanoparticles.