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Göteborgs universitets publikationer

Development of targeted alpha therapy with Bi-213 and At-211 for the treatment of disseminated cancer

Författare och institution:
Anna Gustafsson (Institutionen för kliniska vetenskaper, sektionen för onkologi, radiofysik, radiologi och urologi, Avdelningen för radiofysik)
University of Gothenburg
Datum för examination:
Onsdagen den 23 mars 2016, kl. 9.00, Hörsal W. Sjölander, Medicinaregatan 7, Göteborg
Sammanfattning (abstract):
Radioimmunotherapy (RIT) is a type of targeted cancer therapy. The concept behind RIT is to deliver cytotoxic ionizing radiation to tumor cells by attaching radionuclides to tumor-specific antibodies. The radioimmunoconjugates identify and bind to tumor cells, isolated or in clusters, wherever located and possibly indistinguishable using imaging procedures. Thus, RIT is aimed to be an adjuvant treatment such as chemotherapy, but in contrast to chemotherapy specifically targeted to tumor cells, sparing healthy cells and tissues. RIT can however have unfavorable pharmacokinetics when administered systemically. To circumvent this problem, pretargeted RIT (PRIT) can be applied. In PRIT, administration of the therapeutic agents is divided into several steps. A modified antibody (pretargeting molecule) is first administered, and is allowed enough time (several hours) to localize the tumor cells. The unbound pretargeting molecules are then cleared from the circulation, either spontaneously or by the guidance of a clearing agent. As a final step, a radiolabeled molecule (effector) is administered, which has high affinity for the pretargeting molecule. The small size of the effector results in both rapid accumulation at the tumor site and fast blood clearance of unbound radioactivity. Thus, a higher tumor-to-normal tissue dose ratio is achievable with PRIT than RIT. Different radionuclides can be used for different purposes in targeted therapy. In the treatment of micrometastases, alpha-emitting radionuclides are well-suited because of their short path length and high linear energy transfer. These properties result in high relative biological effectiveness (RBE) as well as a reduced dependence of oxygenation and actively cycling cells when compared with nuclides emitting low-LET radiation. When properly targeted, alpha-emitters have high tumor-killing efficacy while sparing much of the normal healthy tissue due to their short range. In this work, molecules for RIT utilizing the alpha-emitters 213Bi and 211At were produced and tested in vitro and in vivo. The principal evaluations of these molecules were focused on ovarian cancer therapy, utilizing a preclinical ovarian cancer mouse model. Results showed a therapeutic efficacy and a favorable biodistribution for the intraperitoneally injected alpha-RIT molecules. A new site-selective reagent for coupling 211At to antibodies was also synthesized and evaluated. The resulting 211At-labeled antibody conjugate showed good binding properties both in vitro and in vivo. Finally, agents for PRIT were synthesized, which exhibited promising properties for further preclinical evaluation in full PRIT systems.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Klinisk medicin ->
Radiologi och bildbehandling ->
alpha particles, astatine, bismuth, MX35, ovarian cancer, polylysine, pretargeted radioimmunotherapy, radioimmunotherapy
Postens nummer:
Posten skapad:
2016-03-02 08:30

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