-
Cancer Research Feb 2020Preclinical studies, , and studies, in combination with mathematical modeling can help optimize and guide the design of clinical trials. The design and optimization of...
Preclinical studies, , and studies, in combination with mathematical modeling can help optimize and guide the design of clinical trials. The design and optimization of alpha-particle emitter radiopharmaceutical therapy (αRPT) is especially important as αRPT has the potential for high efficacy but also high toxicity. We have developed a mathematical model that may be used to identify trial design parameters that will have the greatest impact on outcome. The model combines Gompertzian tumor growth with antibody-mediated pharmacokinetics and radiation-induced cell killing. It was validated using preclinical experimental data of antibody-mediated Bi and Ac delivery in a metastatic transgenic breast cancer model. In modeling simulations, tumor cell doubling time, administered antibody, antibody specific-activity, and antigen-site density most impacted median survival. The model was also used to investigate treatment fractionation. Depending upon the time-interval between injections, increasing the number of injections increased survival time. For example, two administrations of 200 nCi, Ac-labeled antibody, separated by 30 days, resulted in a simulated 31% increase in median survival over a single 400 nCi administration. If the time interval was 7 days or less, however, there was no improvement in survival; a one-day interval between injections led to a 10% reduction in median survival. Further model development and validation including the incorporation of normal tissue toxicity is necessary to properly balance efficacy with toxicity. The current model is, however, useful in helping understand preclinical results and in guiding preclinical and clinical trial design towards approaches that have the greatest likelihood of success. SIGNIFICANCE: Modeling is used to optimize αRPT.
Topics: Actinium; Alpha Particles; Animals; Antibodies, Monoclonal; Bismuth; Breast Neoplasms; Cell Line, Tumor; Diffusion Magnetic Resonance Imaging; Disease Management; Dose Fractionation, Radiation; Drug Administration Schedule; Female; Humans; Image Processing, Computer-Assisted; Mice; Mice, Transgenic; Models, Biological; Positron-Emission Tomography; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals; Receptor, ErbB-2; Single Photon Emission Computed Tomography Computed Tomography
PubMed: 31772036
DOI: 10.1158/0008-5472.CAN-19-2553 -
Cancers Dec 2021The Geant4-DNA low energy extension of the Geant4 Monte Carlo (MC) toolkit is a continuously evolving MC simulation code permitting mechanistic studies of cellular... (Review)
Review
The Geant4-DNA low energy extension of the Geant4 Monte Carlo (MC) toolkit is a continuously evolving MC simulation code permitting mechanistic studies of cellular radiobiological effects. Geant4-DNA considers the physical, chemical, and biological stages of the action of ionizing radiation (in the form of x- and γ-ray photons, electrons and β-rays, hadrons, α-particles, and a set of heavier ions) in living cells towards a variety of applications ranging from predicting radiotherapy outcomes to radiation protection both on earth and in space. In this work, we provide a brief, yet concise, overview of the progress that has been achieved so far concerning the different physical, physicochemical, chemical, and biological models implemented into Geant4-DNA, highlighting the latest developments. Specifically, the "dnadamage1" and "molecularDNA" applications which enable, for the first time within an open-source platform, quantitative predictions of early DNA damage in terms of single-strand-breaks (SSBs), double-strand-breaks (DSBs), and more complex clustered lesions for different DNA structures ranging from the nucleotide level to the entire genome. These developments are critically presented and discussed along with key benchmarking results. The Geant4-DNA toolkit, through its different set of models and functionalities, offers unique capabilities for elucidating the problem of radiation quality or the relative biological effectiveness (RBE) of different ionizing radiations which underlines nearly the whole spectrum of radiotherapeutic modalities, from external high-energy hadron beams to internal low-energy gamma and beta emitters that are used in brachytherapy sources and radiopharmaceuticals, respectively.
PubMed: 35008196
DOI: 10.3390/cancers14010035 -
European Journal of Nuclear Medicine... Sep 2022Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate...
PURPOSE
Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate cancer (PCa). The efficacy of this therapy might be further improved by replacing the β-emitting lutetium-177 with the α-emitting actinium-225. Actinium-225 is thought to have a higher therapeutic efficacy due to the high linear energy transfer (LET) of the emitted α-particles, which can increase the amount and complexity of the therapy induced DNA double strand breaks (DSBs). Here we evaluated the relative biological effectiveness of [Ac]Ac-PSMA-I&T and [Lu]Lu-PSMA-I&T by assessing in vitro binding characteristics, dosimetry, and therapeutic efficacy.
METHODS AND RESULTS
The PSMA-expressing PCa cell line PC3-PIP was used for all in vitro assays. First, binding and displacement assays were performed, which revealed similar binding characteristics between [Ac]Ac-PSMA-I&T and [Lu]Lu-PSMA-I&T. Next, the assessment of the number of 53BP1 foci, a marker for the number of DNA double strand breaks (DSBs), showed that cells treated with [Ac]Ac-PSMA-I&T had slower DSB repair kinetics compared to cells treated with [Lu]Lu-PSMA-I&T. Additionally, clonogenic survival assays showed that specific targeting with [Ac]Ac-PSMA-I&T and [Lu]Lu-PSMA-I&T caused a dose-dependent decrease in survival. Lastly, after dosimetric assessment, the relative biological effectiveness (RBE) of [Ac]Ac-PSMA-I&T was found to be 4.2 times higher compared to [Lu]Lu-PSMA-I&T.
CONCLUSION
We found that labeling of PSMA-I&T with lutetium-177 or actinium-225 resulted in similar in vitro binding characteristics, indicating that the distinct biological effects observed in this study are not caused by a difference in uptake of the two tracers. The slower repair kinetics of [Ac]Ac-PSMA-I&T compared to [Lu]Lu-PSMA-I&T correlates to the assumption that irradiation with actinium-225 causes more complex, more difficult to repair DSBs compared to lutetium-177 irradiation. Furthermore, the higher RBE of [Ac]Ac-PSMA-I&T compared to [Lu]Lu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa.
Topics: Actinium; Cell Line, Tumor; DNA; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radioisotopes
PubMed: 35556158
DOI: 10.1007/s00259-022-05821-w -
Nuclear Medicine and Biology 2021The promising characteristics of the 7.2-h radiohalogen At have long been recognized; including having chemical properties suitable for labeling targeting vectors... (Review)
Review
The promising characteristics of the 7.2-h radiohalogen At have long been recognized; including having chemical properties suitable for labeling targeting vectors ranging from small organic molecules to proteins, and the emission of only one α-particle per decay, providing greater control over off-target effects. Unfortunately, the impact of At within the targeted α-particle therapy domain has been constrained by its limited availability. Paradoxically, the most commonly used production method - via the Bi(α,2n)At reaction - utilizes a widely available natural material (bismuth) as the target and straightforward cyclotron irradiation methodology. On the other hand, the most significant impediment to widespread At availability is the need for an accelerator capable of generating ≥28 MeV α-particles with sufficient beam intensities to make clinically relevant levels of At. In this review, current methodologies for the production and purification of At - both by the direct production route noted above and via a Rn generator system - will be discussed. The capabilities of cyclotrons that currently produce At will be summarized and the characteristics of other accelerators that could be utilized for this purpose will be described. Finally, the logistics of networks, both academic and commercial, for facilitating At distribution to locations remote from production sites will be addressed.
Topics: Cyclotrons
PubMed: 34144505
DOI: 10.1016/j.nucmedbio.2021.05.007 -
Journal of Experimental & Clinical... Mar 2023We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell...
We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated Pb, an in vivo generator of alpha-emitting Bi and Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, Pb-TCMC-YS5. We characterized Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.
Topics: Male; Animals; Humans; Radioimmunotherapy; Lead; Alpha Particles; Prostatic Neoplasms, Castration-Resistant; Lead Radioisotopes; Membrane Cofactor Protein
PubMed: 36906664
DOI: 10.1186/s13046-023-02636-x -
Frontiers in Molecular Biosciences 2021Glycogen is a highly-branched polysaccharide that is widely distributed across the three life domains. It has versatile functions in physiological activities such as... (Review)
Review
Glycogen is a highly-branched polysaccharide that is widely distributed across the three life domains. It has versatile functions in physiological activities such as energy reserve, osmotic regulation, blood glucose homeostasis, and pH maintenance. Recent research also confirms that glycogen plays important roles in longevity and cognition. Intrinsically, glycogen function is determined by its structure that has been intensively studied for many years. The recent association of glycogen α-particle fragility with diabetic conditions further strengthens the importance of glycogen structure in its function. By using improved glycogen extraction procedures and a series of advanced analytical techniques, the fine molecular structure of glycogen particles in human beings and several model organisms such as , , , and have been characterized. However, there are still many unknowns about the assembly mechanisms of glycogen particles, the dynamic changes of glycogen structures, and the composition of glycogen associated proteins (glycogen proteome). In this review, we explored the recent progresses in glycogen studies with a focus on the structure of glycogen particles, which may not only provide insights into glycogen functions, but also facilitate the discovery of novel drug targets for the treatment of diabetes mellitus.
PubMed: 33996916
DOI: 10.3389/fmolb.2021.673315 -
Micromachines May 2020Among the different semiconductors, GaN provides advantages over Si, SiC and GaAs in radiation hardness, resulting in researchers exploring the development of GaN-based... (Review)
Review
Among the different semiconductors, GaN provides advantages over Si, SiC and GaAs in radiation hardness, resulting in researchers exploring the development of GaN-based radiation sensors to be used in particle physics, astronomic and nuclear science applications. Several reports have demonstrated the usefulness of GaN as an α-particle detector. Work in developing GaN-based radiation sensors are still evolving and GaN sensors have successfully detected α-particles, neutrons, ultraviolet rays, x-rays, electrons and γ-rays. This review elaborates on the design of a good radiation detector along with the state-of-the-art α-particle detectors using GaN. Successful improvement in the growth of GaN drift layers (DL) with 2 order of magnitude lower in charge carrier density (CCD) (7.6 × 10/cm) on low threading dislocation density (3.1 × 10/cm) hydride vapor phase epitaxy (HVPE) grown free-standing GaN substrate, which helped ~3 orders of magnitude lower reverse leakage current () with 3-times increase of reverse breakdown voltages. The highest reverse breakdown voltage of -2400 V was also realized from Schottky barrier diodes (SBDs) on a free-standing GaN substrate with 30 μm DL. The formation of thick depletion width (DW) with low CCD resulted in improving high-energy (5.48 MeV) α-particle detection with the charge collection efficiency (CCE) of 62% even at lower bias voltages (-20 V). The detectors also detected 5.48 MeV α-particle with CCE of 100% from SBDs with 30-μm DL at -750 V.
PubMed: 32443764
DOI: 10.3390/mi11050519 -
PloS One 2022Hepatocellular carcinoma is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide. Most patients with advanced disease are...
Hepatocellular carcinoma is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide. Most patients with advanced disease are offered non-surgical palliative treatment options. This work explores the first alpha-particle emitting radioembolization for the treatment and monitoring of hepatic tumors. Furthermore, this works demonstrates the first in vivo simultaneous multiple-radionuclide SPECT-images of the complex decay chain of an [225Ac]Ac-labeled agent using a clinical SPECT system to monitor the temporal distribution. A DOTA chelator was modified with a lipophilic moiety and radiolabeled with the α-particle emitter Actinium-225. The resulting agent, [225Ac]Ac-DOTA-TDA, was emulsified in ethiodized oil and evaluated in vivo in mouse model and the VX2 rabbit technical model of liver cancer. SPECT imaging was performed to monitor distribution of the TAT agent and the free daughters. The [225Ac]Ac-DOTA-TDA emulsion was shown to retain within the HEP2G tumors and VX2 tumor, with minimal uptake within normal tissue. In the mouse model, significant improvements in overall survival were observed. SPECT-imaging was able to distinguish between the Actinium-225 agent (Francium-221) and the loss of the longer lived daughter, Bismuth-213. An α-particle emitting TARE agent is capable of targeting liver tumors with minimal accumulation in normal tissue, providing a potential therapeutic agent for the treatment of hepatocellular carcinoma as well as a variety of hepatic tumors. In addition, SPECT-imaging presented here supports the further development of imaging methodology and protocols that can be incorporated into the clinic to monitor Actinium-225-labeled agents.
Topics: Alpha Particles; Animals; Bismuth; Carcinoma, Hepatocellular; Embolization, Therapeutic; Hep G2 Cells; Humans; Liver Neoplasms, Experimental; Male; Mice; Rabbits; Radioisotopes; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Xenograft Model Antitumor Assays
PubMed: 35061763
DOI: 10.1371/journal.pone.0261982 -
PloS One 2023DNA double strand breaks (DSBs) are a deleterious form of DNA damage. Densely ionising alpha radiation predominantly induces complex DSBs and sparsely ionising gamma...
DNA double strand breaks (DSBs) are a deleterious form of DNA damage. Densely ionising alpha radiation predominantly induces complex DSBs and sparsely ionising gamma radiation-simple DSBs. We have shown that alphas and gammas, when applied simultaneously, interact in producing a higher DNA damage response (DDR) than predicted by additivity. The mechanisms of the interaction remain obscure. The present study aimed at testing whether the sequence of exposure to alphas and gammas has an impact on the DDR, visualised by live NBS1-GFP (green fluorescent protein) focus dynamics in U2OS cells. Focus formation, decay, intensity and mobility were analysed up to 5 h post exposure. Focus frequencies directly after sequential alpha → gamma and gamma → alpha exposure were similar to gamma alone, but gamma → alpha foci quickly declined below the expected values. Focus intensities and areas following alpha alone and alpha → gamma were larger than after gamma alone and gamma → alpha. Focus movement was most strongly attenuated by alpha → gamma. Overall, sequential alpha → gamma exposure induced the strongest change in characteristics and dynamics of NBS1-GFP foci. Possible explanation is that activation of the DDR is stronger when alpha-induced DNA damage precedes gamma-induced DNA damage.
Topics: Alpha Particles; Gamma Rays; Records; DNA Breaks, Double-Stranded; DNA Damage; Green Fluorescent Proteins
PubMed: 37307266
DOI: 10.1371/journal.pone.0286902 -
Clinical Cancer Research : An Official... Apr 2021Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus,...
PURPOSE
Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA ().
EXPERIMENTAL DESIGN
LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and _Hi- transgenic mice were imaged with Zr- or treated with Y- or Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [Ac]hu5A10 and [Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [Zr]hu5A10 in nonhuman primates (NHP) were determined using PET.
RESULTS
Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [Y]/[Ac]hu5A10 effectively reduced tumor burden and prolonged survival ( ≤ 0.0054). Effects of [Y]hu5A10 were more immediate than [Ac]hu5A10 (TTN, < 0.0001) but less sustained (TTP, < 0.0001). Complete responses were observed in 7 of 18 [Ac]hu5A10 and 1 of 9 mice [Y]hu5A10. Pharmacokinetics of [Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.
CONCLUSIONS
We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.
Topics: Alpha Particles; Animals; Beta Particles; Disease Models, Animal; Electrons; Linear Energy Transfer; Macaca fascicularis; Male; Mice; Mice, Inbred BALB C; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Radioimmunotherapy; Receptors, Androgen; Tissue Distribution
PubMed: 33441295
DOI: 10.1158/1078-0432.CCR-20-3614