Paul Schaffer

Associate Professor

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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Dosimetry and biodistribution of actinium radiopharmaceuticals for targeted alpha therapy (2024)

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.

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Nuclide production and imaging applications of ??uAc for targeted alpha therapy (2021)

Targeted alpha therapies using actinium-225 (²²⁵Ac, t₁/₂ = 9.9 d) can treat advanced metastatic disease, yet insufficient ²²⁵Ac availability limits their development (63 GBq/year is produced globally via ²²⁹Th generators). This thesis describes efforts to produce ²²⁵Ac and apply multi-nuclide SPECT imaging in preclinical evaluation of ²²⁵Ac-radiopharmaceuticals. Initial ²²⁵Ac production used ᴺᵃᵗU-spallation-produced and mass-separated ion beams, producing up to 8.6 MBq of ²²⁵Ra (an ²²⁵Ac parent) and 18 MBq of ²²⁵Ac. This material helped characterize the performance of ²²⁵Ac decay chain imaging on a microSPECT/PET/CT scanner in terms of contrast recovery, spatial resolution, and noise. Larger ²²⁵Ac quantities were produced via thorium target irradiation with a 438 MeV, 72 μA proton beam for 36 hours, producing (521 ±18) MBq of ²²⁵Ac and (91 ± 14) MBq of ²²⁵Ra. These irradiations enabled ²³²Th(p,x) cross sections measurements for ²²⁵Ac, ²²⁵Ra, and ²²⁷Ac: (13.3 ± 1.2) mb, (4.2 ± 0.4) mb, and (17.7 ± 1.7) mb, respectively. Thirty-five other cross sections were measured and compared to FLUKA simulations; measured and calculated values generally agree within a factor of two. Ac separation from irradiated thorium and co-produced radioactive by-products used a thorium peroxide precipitation followed by cation exchange and extraction chromatography. Studies showed this method separates Ac from most elements, providing a directly-produced Ac product (²²⁷˒²²⁵Ac†) with measured ²²⁷Ac content of (0.15 ± 0.04)%, a hazardous long-lived (t₁/₂ = 21.8 y) impurity with prohibitively low waste disposal limits. A second, indirectly-produced ²²⁵Ra/²²⁵Ac-generator-derived Ac product (²²⁵Ac*) with ²²⁷Ac content of
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Radiofluorinated amino acids for oncological positron emission tomography imaging (2020)

Cancer progression and metastasis are driven by certain molecular features that are either non-existent or abnormally active in normal cells. These features are often exploited by medical scientists for the development of targeted therapies and/or imaging probes to better diagnose and stratify patients. In this thesis, we report the investigation of novel radiotracers designed to measure oxidative stress and the use of amino acids as alternative sources of energy, both associated with malignant transformation and resulting in upregulation of different amino acid transporters (AATs). Oxidative stress has been implicated as a feature of aggressive cancer types, particularly those with poor prognosis. System xC- is an antiporter of cystine and glutamate, which is upregulated under oxidative stress and overexpressed in many cancers including triple-negative breast cancer and glioblastoma. System xC- provides cells with a substrate for antioxidant synthesis. This transporter can be studied by positron emission tomography (PET) using ¹⁸F-fluoroaminosuberic acid ([¹⁸F]FASu). [¹⁸F]FASu is hypothesized to be a specific substrate for system xC- activity. The work herein explores the relationship between [¹⁸F]FASu uptake and system xC- transporter activity, and whether this can be used for cancer diagnosis and treatment response monitoring. We studied system xC- activity and overexpression in vitro and used [¹⁸F]FASu in vivo to monitor intratumoural changes following radiotherapy. We evaluated a novel [¹⁸F]FASu analogue, [¹⁸F]ASu-BF3, synthesized via an alternative radiolabelling method. Additionally, we compared [¹⁸F]FASu to two other PET radiopharmaceuticals in vivo, one of which also targets system xC-. Finally, this thesis also explores a novel radiolabelling methodology and biological characterisation of a number of radiofluorinated leucine derivatives, substrates for another AAT, LAT1. LAT1 is highly upregulated in several cancers and at metastatic sites. LAT1 is a poor prognostic biomarker in cancer patients. It is associated with mTOR pathway activation, through which amino acids are being imported and used as substrates for protein biosynthesis. This research presents effective methodology for producing LAT1 substrates for the purposes of cancer imaging with PET. Collectively, this research provides a non-invasive platform for the characterization of two AAT proteins, both of which play a role in cancer development and progression.

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