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Questions and Answers
What quality control measure is used to assess the radiochemical purity of the [225Ac]Ac-DOTA-peptide?
What is the specified gamma counting RCP value validated for the [225Ac]Ac-DOTA-peptide using accelerator produced material?
Which technique is NOT utilized to report the radioisotopic composition of the [225Ac]Ac-DOTA-peptide?
What is the half-life of 227Ac, which is significant in the context of the 227/225Ac-labeled agents?
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How long post-separation is 227Th at equilibrium with 227Ac according to the Bateman equations?
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What is one of the reasons that the quality control of alpha-emitting isotopes is considered challenging?
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What is the half-life of Actinium-225?
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Which of the following isotopes does not decay into a stable isotope but instead continues to produce alpha-emitting progenies?
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What is an important consideration regarding the amount of activity required for alpha-emitting isotopes in vivo detection compared to therapy efficacy?
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When does secular equilibrium occur during the decay of Actinium-225?
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Study Notes
Quality Control of Long-Lived Alpha-Emitting Radiopharmaceuticals
- Focus on Actinium-225/227, Thorium-227, and Radium-223 for quality control (QC).
- QC challenges for alpha-emitting isotopes due to complex detection methods and contaminants/progenies.
- Targeted Alpha Particle Therapy (TAPT) is effective due to high Linear Energy Transfer (LET) and short tissue path-length.
- Alpha particle emission leads to severe DNA damage: single and double-strand breaks.
Actinium-225 Overview
- Actinium-225 has a half-life of 9.92 days and is used in targeted constructs for radio-labeled therapies.
- Key decay products include 213Bi (45 min T½) and 221Fr (5 min T½) with significant gamma emissions.
- Secular equilibrium affects QC procedures, reaching after approximately 55 min and 6.5 hours for certain isotopes.
Actinium-225 Supply and Demand
- Current production capacity is low compared to growing research and industrial interest.
- Active production sites: Oak Ridge National Laboratories (USA), Rosatom (Russia), Institute for Transuranium Elements (Germany).
- Innovative methods are being developed to boost supply.
Quality Control Procedures
- QC processes for [225Ac]Ac-DOTA-peptide include ensuring radiochemical purity, chemical identity, and radioisotopic purity.
- Techniques employed: Thin Layer Chromatography (TLC), High-Performance Liquid Chromatography (HPLC), and gamma counting.
- Specific quality control metrics involve achieving radiochemical purity (RCP) greater than 99.9%.
Alternative Production Routes for Actinium-225
- Alternative methods involve using accelerator-produced Actinium-225, allowing for efficient detection of gamma emissions at specific energy levels.
- Gamma counting of the resulting compounds demonstrates RCP of 94.2%, indicating effective processing.
High Purity Germanium Analysis
- High Purity Germanium detectors are utilized to evaluate processed peptide fractions over time.
- Quantification of decay products, such as radium and thorium isotopes, helps confirm the stability and purity during processing.
Quantification Techniques
- Bateman equations are employed for the quantification of 227Ac in labeled agents, establishing a relationship to 227Th ratios based on decay.
- After approximately 100 days, 227Th reaches equilibrium with 227Ac, allowing for accurate content determination.
Challenges in Detection and Discrimination
- Discrimination between Thorium-227 and Radium-223 poses significant challenges due to overlapping gamma emissions.
- Automated measurements are necessary for effective organ distribution evaluations of radiopharmaceuticals and understanding dosimetry.
Innovations in Detection Methods
- Combining gamma counting with spectral deconvolution techniques improves the ability to achieve exclusive detection of Thorium-227.
- Ongoing calibration and efficiency evaluations improve measurement accuracy against NIST standards for both 223Ra and 227Th.
Conclusion
- Quality control of long-lived alpha-emitting radiopharmaceuticals remains critical for safe and effective therapeutic applications.
- Advances in detection methodologies, alongside increased production capabilities, are essential to meet rising demand and enhance patient safety in targeted therapies.### Pharmacokinetics and Organ Distribution in Mice
- Used 227Th/223Ra discrimination to study in vivo 223Ra ingrowth.
- Administered [227Th]Th-Trastuzumab via intravenous injection to naive female Swiss/Webster mice.
Organ Uptake Observations
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227Th Uptake:
- Elevated in liver, decreased in spleen, low in bone.
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223Ra In Vivo Ingrowth:
- Accumulated significantly in spleen and bones, but remained low in liver.
Theranostic Capabilities
- 227Th and 89Zr labeled Trastuzumab utilized the same chemical precursor.
- Comparison of injected activity per gram (% Injected Activity/gram) at 24 hours and 14 days revealed similar patterns for 227Th and 89Zr.
Quality Control of Alpha Emitting Isotopes
- Quality control presents challenges specific to alpha-emitting isotopes due to potential radiation safety considerations and material handling.### Equipment Requirements
- Imaging radiopharmaceuticals laboratory requires a TLC reader, dose calibrator, and gamma counter.
- High Purity Germanium (HpGe) detector is essential for precise measurements.
- An alpha spectrometer may be utilized in certain situations.
Isotope Considerations
- Adjustments needed for each isotope and its progenies.
- Must respect secular and transient equilibrium for accurate results.
- Calibration and cross-instrument checks are crucial for reliability and consistency.
Team Composition
- A multidisciplinary team is necessary for effective operation and research.
- Team includes professionals from different backgrounds, enhancing collaboration and expertise.
Acknowledgements and Funding
- Thorek Laboratory and Program for Quantitative Molecular Therapeutics received recognition.
- Contributions from diverse experts in fields such as chemistry, engineering, and molecular therapeutics.
- Group includes individuals with advanced degrees and affiliations from institutions like Moffitt Cancer Center and University of Iowa.
Notable Contributors
- Key figures include Dr. Nadia Benabdallah, Dr. Peng Lu, Dr. Mark McLaughlin, and Dr. Richard L. Wahl.
- Various contributors from cyclotron facilities and the Department of Chemistry at Washington University in St. Louis.
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