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Koniar, Helena Marie

University of British Columbia

Targeted alpha therapy (TAT) combines an alpha emitting radioisotope with an appropriate biological targeting molecule to selectively bind to cancer cells and deliver highly localised cytotoxic radiation while sparing healthy non-targeted tissues. The alpha emitter actinium-225 (²²⁵Ac) has demonstrated promising clinical outcomes in patients with advanced metastatic disease, yet there remain unmet needs for quantitative and accurate methods to directly detect ²²⁵Ac-labelled radiopharmaceuticals in vivo. This thesis presents computational and experimental methods to evaluate the biodistribution and dosimetry of actinium radiopharmaceuticals. ²²⁵Ac (t₁⧸₂ = 9.9 d) is a potent therapeutic isotope due to the four α emissions in its decay chain, however, it is only detectable via gamma emissions from its progeny ²²¹Fr and ²¹³Bi, which can relocate from targeted sites. Monte Carlo simulations were conducted to evaluate dosimetry estimates in cancer cells and micrometastasis and to assess the effect of progeny retention on the absorbed therapeutic dose. Direct detection of actinium radiopharmaceuticals is required for accurately assessing absorbed dose and pharmacokinetics in vivo. ²²⁶Ac (t₁⧸₂ = 29.6 h) was selected as an ideal Ac-isotope for element-equivalent diagnostics of ²²⁵Ac due to its gamma emissions at 158 keV and 230 keV suitable for single photon emission computed tomography (SPECT) imaging. ²²⁶Ac was produced at TRIUMF with its Isotope Separator and Accelerator (ISAC) facility in quantities up to 37 MBq for proof-of-concept and feasibility studies. Quantitative ²²⁶Ac SPECT imaging was characterized with a small animal SPECT/CT scanner in a phantom study designed to assess its performance with respect to contrast, noise, and resolution. The feasibility of preclinical imaging with high quantitative accuracy and spatial resolution was established and motivated the first ever in vivo images with ²²⁶Ac. SPECT imaging with ²²⁶Ac was demonstrated in vivo with both a preclinical radiopharmaceutical and free ²²⁶Ac activity. Image-based activity measurements correlated well with ex vivo biodistribution measurements. As an alpha emitter itself, ²²⁶Ac was also evaluated for its standalone theranostic potential. Dosimetry from a preclinical ²²⁶Ac-labelled radiopharmaceutical was estimated with Monte Carlo simulations and ex vivo biodistribution measurements. A longitudinal therapy study demonstrated anti-tumour properties with no observable toxicities.

Text

2024-04-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87922

Medical Physics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/