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EJNMMI Radiopharmacy and Chemistry May 2024A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach...
BACKGROUND
A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach for cancer treatment tackling disseminated cancer. As tumor size decreases, alpha-particles gain prominence due to their high Linear Energy Transfer (LET) and short path length. Among alpha-particle emitters, At stands out with its 7.2 hour half-life and 100% alpha emission decay. However, optimizing the pharmacokinetics of radiopharmaceuticals with short lived radionuclides such as At is pivotal, and in this regard, pretargeting is a valuable tool. This method involves priming the tumor with a modified monoclonal antibody capable of binding both the tumor antigen and the radiolabeled carrier, termed the "effector molecule. This smaller, faster-clearing molecule improves efficacy. Utilizing the Diels Alder click reaction between Tetrazine (Tz) and Trans-cyclooctene (TCO), the Tz-substituted effector molecule combines seamlessly with the TCO-modified antibody. This study aims to evaluate the in vivo biodistribution of two Poly-L-Lysine-based effector molecule sizes (10 and 21 kDa), labelled with At, and the in vitro binding of the most favorable polymer size, in order to optimize the pretargeted radioimmunotherapy with At.
RESULTS
In vivo results favor the smaller polymer's biodistribution pattern over the larger one, which accumulates in organs like the liver and spleen. This is especially evident when comparing the biodistribution of the smaller polymer to a directly labelled monoclonal antibody. The smaller variant also shows rapid and efficient binding to SKOV-3 cells preloaded with TCO-modified Trastuzumab in vitro, emphasizing its potential. Both polymer sizes showed equal or better in vivo stability of the astatine-carbon bond compared to a monoclonal antibody labelled with the same prosthetic group.
CONCLUSIONS
Overall, the small Poly-L-Lysine-based effector molecule (10 kDa) holds the most promise for future research, exhibiting significantly lower uptake in the kidneys and spleen compared to the larger effector (21 kDa) while maintaining an in vivo stability of the astatine-carbon bond comparable to or better than intact antibodies. A proof of concept in vitro cell study demonstrates rapid reaction between the small astatinated effector and a TCO-labelled antibody, indicating the potential of this novel Poly-L-Lysine-based pretargeting system for further investigation in an in vivo tumor model.
PubMed: 38775973
DOI: 10.1186/s41181-024-00273-z -
Pharmacology Research & Perspectives Jun 2024The toxicity of inhaled particulate air pollution perseveres even at lower concentrations than those of the existing air quality limit. Therefore, the identification of...
The toxicity of inhaled particulate air pollution perseveres even at lower concentrations than those of the existing air quality limit. Therefore, the identification of safe and effective measures against pollutant particles-induced vascular toxicity is warranted. Carnosol is a bioactive phenolic diterpene found in rosemary herb, with anti-inflammatory and antioxidant actions. However, its possible protective effect on the thrombotic and vascular injury induced by diesel exhaust particles (DEP) has not been studied before. We assessed here the potential alleviating effect of carnosol (20 mg/kg) administered intraperitoneally 1 h before intratracheal (i.t.) instillation of DEP (20 μg/mouse). Twenty-four hours after the administration of DEP, various parameters were assessed. Carnosol administration prevented the increase in the plasma concentrations of C-reactive protein, fibrinogen, and tissue factor induced by DEP exposure. Carnosol inhibited DEP-induced prothrombotic effects in pial microvessels in vivo and platelet aggregation in vitro. The shortening of activated partial thromboplastin time and prothrombin time induced by DEP was abated by carnosol administration. Carnosol inhibited the increase in pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor α) and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin) in aortic tissue. Moreover, it averted the effects of DEP-induced increase of thiobarbituric acid reactive substances, depletion of antioxidants and DNA damage in the aortic tissue. Likewise, carnosol prevented the decrease in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) caused by DEP. We conclude that carnosol alleviates DEP-induced thrombogenicity and vascular inflammation, oxidative damage, and DNA injury through Nrf2 and HO-1 activation.
Topics: Animals; Abietanes; Mice; Male; Vehicle Emissions; Thrombosis; Lung; Vascular System Injuries; Antioxidants; Particulate Matter; NF-E2-Related Factor 2; Air Pollutants; Oxidative Stress; Platelet Aggregation
PubMed: 38775298
DOI: 10.1002/prp2.1201 -
JU Open Plus Apr 2024Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have...
Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.
BACKGROUND
Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature.
MATERIALS AND METHODS
The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators.
RESULTS
This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non- mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies.
CONCLUSIONS
The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.
PubMed: 38774467
DOI: 10.1097/ju9.0000000000000138 -
JU Open Plus Apr 2024Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded...
PURPOSE
Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC.
MATERIALS AND METHODS
The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy.
RESULTS
The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC.
CONCLUSIONS
CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.
PubMed: 38774466
DOI: 10.1097/ju9.0000000000000137 -
Theranostics 2024Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (Ac), a potent alpha-emitting... (Review)
Review
Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (Ac), a potent alpha-emitting radionuclide, may be incorporated into targeting vectors, causing robust and in some cases sustained antitumor responses. The development of radiolabeling techniques involving EDTA, DOTA, DOTPA, and Macropa chelators has laid the groundwork for advancements in this field. At the forefront of clinical trials with Ac in PCa are PSMA-targeted TAT agents, notably [Ac]Ac-PSMA-617, [Ac]Ac-PSMA-I&T and [Ac]Ac-J591. Ongoing investigations spotlight [Ac]Ac-hu11B6, [Ac]Ac-YS5, and [Ac]Ac-SibuDAB, targeting hK2, CD46, and PSMA, respectively. Despite these efforts, hurdles in Ac production, daughter redistribution, and a lack of suitable imaging techniques hinder the development of TAT. To address these challenges and additional advantages, researchers are exploring alpha-emitting isotopes including Th, Ra, At, Bi, Pb or Tb, providing viable alternatives for TAT.
Topics: Humans; Male; Actinium; Prostatic Neoplasms; Alpha Particles; Radiopharmaceuticals; Animals
PubMed: 38773983
DOI: 10.7150/thno.96403 -
Ultrasonics Sonochemistry Jul 2024Ultrasound envelope statistics imaging, including ultrasound Nakagami imaging, homodyned-K imaging, and information entropy imaging, is an important group of...
Multimodality quantitative ultrasound envelope statistics imaging based support vector machines for characterizing tissue scatterer distribution patterns: Methods and application in detecting microwave-induced thermal lesions.
Ultrasound envelope statistics imaging, including ultrasound Nakagami imaging, homodyned-K imaging, and information entropy imaging, is an important group of quantitative ultrasound techniques for characterizing tissue scatterer distribution patterns, such as scatterer concentrations and arrangements. In this study, we proposed a machine learning approach to integrate the strength of multimodality quantitative ultrasound envelope statistics imaging techniques and applied it to detecting microwave ablation induced thermal lesions in porcine liver ex vivo. The quantitative ultrasound parameters included were homodyned-K α which is a scatterer clustering parameter related to the effective scatterer number per resolution cell, Nakagami m which is a shape parameter of the envelope probability density function, and Shannon entropy which is a measure of signal uncertainty or complexity. Specifically, the homodyned-K log(α), Nakagami-m, and horizontally normalized Shannon entropy parameters were combined as input features to train a support vector machine (SVM) model to classify thermal lesions with higher scatterer concentrations from normal tissues with lower scatterer concentrations. Through heterogeneous phantom simulations based on Field II, the proposed SVM model showed a classification accuracy above 0.90; the area accuracy and Dice score of higher-scatterer-concentration zone identification exceeded 83% and 0.86, respectively, with the Hausdorff distance <26. Microwave ablation experiments of porcine liver ex vivo at 60-80 W, 1-3 min showed that the SVM model achieved a classification accuracy of 0.85; compared with single log(α),m, or hNSE parametric imaging, the SVM model achieved the highest area accuracy (89.1%) and Dice score (0.77) as well as the smallest Hausdorff distance (46.38) of coagulation zone identification. We concluded that the proposed multimodality quantitative ultrasound envelope statistics imaging based SVM approach can enhance the capability to characterize tissue scatterer distribution patterns and has the potential to detect the thermal lesions induced by microwave ablation.
Topics: Microwaves; Support Vector Machine; Animals; Swine; Ultrasonography; Liver; Phantoms, Imaging; Image Processing, Computer-Assisted
PubMed: 38772312
DOI: 10.1016/j.ultsonch.2024.106910 -
Communications Biology May 2024Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be...
Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7; Nras; p53 (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS.
Topics: Animals; Glutamine; Mice; Glutaminase; Sarcoma; Glucose; Disease Models, Animal; Radiation Tolerance
PubMed: 38769385
DOI: 10.1038/s42003-024-06262-x -
Scientific Reports May 2024Astronauts travelling in space will be exposed to mixed beams of particle radiation and photons. Exposure limits that correspond to defined cancer risk are calculated by...
Astronauts travelling in space will be exposed to mixed beams of particle radiation and photons. Exposure limits that correspond to defined cancer risk are calculated by multiplying absorbed doses by a radiation-type specific quality factor that reflects the biological effectiveness of the particle without considering possible interaction with photons. We have shown previously that alpha radiation and X-rays may interact resulting in synergistic DNA damage responses in human peripheral blood lymphocytes but the level of intra-individual variability was high. In order to assess the variability and validate the synergism, blood from two male donors was drawn at 9 time points during 3 seasons of the year and exposed to 0-2 Gy of X-rays, alpha particles or 1:1 mixture of both (half the dose each). DNA damage response was quantified by chromosomal aberrations and by mRNA levels of 3 radiation-responsive genes FDXR, CDKN1A and MDM2 measured 24 h post exposure. The quality of response in terms of differential expression of alternative transcripts was assessed by using two primer pairs per gene. A consistently higher than expected effect of mixed beams was found in both donors for chromosomal aberrations and gene expression with some seasonal variability for the latter. No synergy was detected for alternative transcription.
Topics: Humans; Lymphocytes; Male; Chromosome Aberrations; Radiation, Ionizing; X-Rays; DNA Damage; Space Flight; Alpha Particles; Transcription, Genetic; Adult; Gene Expression Regulation; Dose-Response Relationship, Radiation
PubMed: 38769353
DOI: 10.1038/s41598-024-62313-7 -
Scientific Reports May 2024Diffusing alpha-emitters radiation therapy (Alpha-DaRT) is a unique method, in which interstitial sources carrying Ra release a chain of short-lived daughter atoms from...
Diffusing alpha-emitters radiation therapy (Alpha-DaRT) is a unique method, in which interstitial sources carrying Ra release a chain of short-lived daughter atoms from their surface. Although DNA damage response (DDR) is crucial to inducing cell death after irradiation, how the DDR occurs during Alpha-DaRT treatment has not yet been explored. In this study, we temporo-spatially characterized DDR such as kinetics of DNA double-strand breaks (DSBs) and cell cycle, in two-dimensional (2D) culture conditions qualitatively mimicking Alpha-DaRT treatments, by employing HeLa cells expressing the Fucci cell cycle-visualizing system. The distribution of the alpha-particle pits detected by a plastic nuclear track detector, CR-39, strongly correlated with γH2AX staining, a marker of DSBs, around the Ra source, but the area of G2 arrested cells was more widely spread 24 h from the start of the exposure. Thereafter, close time-lapse observation revealed varying cell cycle kinetics, depending on the distance from the source. A medium containing daughter nuclides prepared from Ra sources allowed us to estimate the radiation dose after 24 h of exposure, and determine surviving fractions. The present experimental model revealed for the first time temporo-spatial information of DDR occurring around the source in its early stages.
Topics: Humans; Alpha Particles; HeLa Cells; DNA Breaks, Double-Stranded; DNA Damage; Cell Cycle; Histones; Cell Culture Techniques
PubMed: 38769339
DOI: 10.1038/s41598-024-62071-6 -
Carbohydrate Polymers Aug 2024Glycogen, a complex branched glucose polymer, is found in animals and bacteria, where it serves as an energy storage molecule. It has linear (1 → 4)-α glycosidic... (Review)
Review
Glycogen, a complex branched glucose polymer, is found in animals and bacteria, where it serves as an energy storage molecule. It has linear (1 → 4)-α glycosidic bonds between anhydroglucose monomer units, with branch points connected by (1 → 6)-α bonds. Individual glycogen molecules are referred to as β particles. In organs like the liver and heart, these β particles can bind into larger aggregate α particles, which exhibit a rosette-like morphology. The mechanisms and bonding underlying the aggregation process are not fully understood. For example, mammalian liver glycogen has been observed to be molecularly fragile under certain conditions, such as glycogen from diabetic livers fragmenting when exposed to dimethyl sulfoxide (DMSO), while glycogen from healthy livers is much less fragile; this indicates some difference, as yet unknown, in the bonding between β particles in healthy and diabetic glycogen. This fragility may have implications for blood sugar regulation, especially in pathological conditions such as diabetes.
Topics: Glycogen; Animals; Humans; Diabetes Mellitus; Liver
PubMed: 38763710
DOI: 10.1016/j.carbpol.2024.122195