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Development of immuno and nano PET/SPECT probes: towards novel theranostics for EGFR positive solid tumors

  • Author / Creator
    Sarrami, Nasim

  • Cancer continues to be a significant global public health issue, and regrettably, it remains one of the leading causes of death. Statistics indicate that 1 in 5 men or women will be diagnosed with cancer during their lifetime, resulting in 1 in 12 women and 1 in 9 men succumbing to the disease. Therefore, improving the current methods for diagnosis and treatment of cancer is a must. Time to first diagnosis plays an important role when it comes to managing cancer cases since as the cancer
    progresses its management will become more difficult, and the treatment of advanced cancers are not as effective. One possible solution to mange cancer cases faster than current practice, is to combine diagnosis and treatment steps into one. These compounds, known as theranostics, have attracted significant attention for the management of cancer in recent years. In this context, development of nanotheranostics, nanomedicine entities that can be tracked in real time and carry a high payload of medication to cancer lesions is expected to provide additional opportunities for the targeted and optimized treatment of tumor burden in patients. The hypothesis of this research was that antibodies and actively targeted nanoparticles against epidermal growth factor receptors (EGFR) labeled with radioactive traceable elements to home on EGFR positive tumors and provide means for tumor imaging in real time. To assess this hypothesis, we initially developed 64Cu labelled panitumumab, a clinically approved monoclonal antibody against EGFR. Further studies
    indicated that the 64Cu labelled panitumumab can be taken up by EGFR+ non-small cell cancer (NSCLC) cell lines. The radiolabelled panitumumab was able to detect EGFR+ subcutaneous and metastatic NSCLC xenografts in mice as shown by positron emission tomography (PET) imaging.
    Moreover, to assess the capability of radiolabelled panitumumab to detect other type of EGFR+ cancers and assess the capability of radiolabeled Pb as a radioisotope for developing theranostics, we developed 203Pb labeled panitumumab and assessed its capability on detecting EGFR+
    patient derived xenografts (PDX) of head and neck caner in mice using SPECT imaging. Our findings showed 203Pb-panitumumab to be capable of detecting EGFR+ head and neck cancer subcutaneous PDX. Furthermore, it can persist in the tumors for up to 120 hours after injection. We then worked on developing nanotheranostics by using poly (ethylene oxide)-poly(ε-benzylcarboxylate-εcaprolactone) nanoparticles (PEO-PBCL NPs) as the nano delivery system and the base of the intended nanotheranostic. The surface of PEO-PBCL NPs was modified with panitumumab and
    1,4,7-Triazacyclononane-1,4-bis (acetic acid)-7-(3 azidopropylacetamide) (NO2A-azide) chelator accommodate 64Cu. This modification was done on the Fc region of antibody, using glycan remodeling process. Despite preferential homing of panitumumab modified NPs on EGFR + NSCLC cell lines compared to plain NPs, the in vivo PET imaging and biodistribution studies did not indicate any advantage in terms of tumor homing and targeting for panitumumab modified NPs
    compared to plain NPs. In the final chapter of this thesis, we examined different cryoprotectants for long term storage of PEO-PBCL NPs using either freeze drying or freeze thaw methods. Our data showed the best condition for long-term storage of NPs to be provided by freeze-thawing
    method using polyethylene glycol (PEG)s at 3350 Da molecular weigh or higher leading to no aggregation of NPs upon storage. Sucrose was also found to be an effective cryoprotectant for this purpose. In conclusion, our presented research indicated that radiolabeled panitumumab can detect EGFR+ cancer and can be used for developing theranostics. We have also successfully developed radiolabelled PEO-PBCL NPs that can be tracked by PET imaging in real time in vivo, providing valuable information on the pharmacokinetic and biodistribution of NPs in different animal models of disease. Traceable NPs can be further developed for use in human patients to identify cancer patients who may benefit from NP drug delivery.

  • Subjects / Keywords
  • Graduation date
    Fall 2024
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/r3-907j-kq86
  • License
    This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.