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Secondary Standards for Ra223

Summary:

223Ra is being evaluated as a radiopharmaceutical for the treatment of skeletal metastases.  As an alkaline earth metal, Ra exhibits intrinsic bone-seeking behavior, so that ligation to complex bioactive molecules is not required for efficient, targeted delivery to osseous sites.  Furthermore, while most commercial formulations currently available are β-emitters, the 223Ra decay chain includes four α emissions.  Alpha emitters are attractive for the treatment of metastases due to intrinsic high linear energy transfer and short path length, promoting strong, targeted cytotoxicity.

Description:

Secondary Standards for Ra223In order to conduct clinical trials in the United States, high standards of accuracy in dosage measurements must be met.  In clinical applications, activity measurements are most often achieved with commercially available reentrant ionization chambers, commonly referred to as "dose calibrators".  Accurate measurements require appropriate calibration factors, or "dial settings".  During the primary standardization of 223Ra at NIST, it was discovered that the calibration settings used in early trials give average readings that are 5.7 % to 8.7 % higher than the NIST calibrated activity.  These measurements were performed in the 5 mL NIST ampoule geometry, which is the standard geometry for all calibration settings published by the manufacturer of common dose calibrators, Capintec.

Because the characteristics (wall thickness, composition, etc.) of the sample container affect the extent to which source radiation is attenuated, accurate measurements require dial settings specific to a given clinical geometry.  Given the relatively low energy x-rays and bremsstrahlung characteristic of 223Ra decay, such effects were expected to be important, and so a series of experiments was undertaken to determine dial settings for several clinically relevant source geometries (dose vials and syringes) on a set of representative commercial dose calibrators.

Master solutions were dispensed gravimetrically into 5 mL NIST ampoules, 20 mL dose vials, and 2 mL, 5 mL and 20 mL syringes.  The massic activity of each master solution was determined by measuring an ampoule containing the solution in the NIST "4π"γ ionization chamber, using the previously derived calibration factor ("K value") and the appropriate radium (226Ra) reference source.  The determined massic activity for each solution had an expanded uncertainty of 1.1 %, with the largest uncertainty component arising from the uncertainty in the K value (0.53 %).  Each source was measured in the NIST-maintained Capintec (CRC-12, CRC-15R, and CRC-35R) and Atomlab-100 dose calibrators.  For each measurement sequence, readings were taken over a range of dial settings that included the value that returned the correct (known) activity.  Activity data were decay corrected to a common reference time assigned for each experiment, and the ratio Aobs/ANIST (Aobs = observed activity; ANIST = calibrated activity) was plotted against the dial setting.  The curves were fit and the NIST-determined dial setting is assigned when Aobs/ANIST = 1.  In most cases, the expanded uncertainty on the measured activity due to the dial setting uncertainty was similar to the expanded uncertainty on the activity.

It was discovered that samples in syringes produce higher currents than samples with the same activity in ampoules or dose vials; measuring at the NIST-determined dial settings for the ampoule (instead of the appropriate syringe settings) gives an activity reading that is up to 3.6 % too high.  For the 2 mL and 5 mL syringes, the difference between the dial setting determined for a "hanging" (from the dipper's syringe holder, as pictured) and a "bottom" geometry (in which the syringe simply rests at the bottom of the dipper) was within the expanded uncertainty.  Volume effects were found to be insignificant to within the uncertainty for the 20 mL dose vial and 2 mL syringe geometries, but led to errors as large as 2.9 % over the 5 mL to 20 mL volume range in the 20 mL syringe geometry.  The appropriate dial settings and relevant uncertainties were reported in Applied Radiation and Isotopes.