Thesis

New Generation of Nanoseeds for Radiation Therapy of Unresectable Tumors

• Call:

  ProtoTera Call 2020

• Academic Year:

  2020/2021

• Supervisor:

  António Paulo

• Co-Supervisor:

  Maria Paula Cabral Campello

• Host Institution:

  C2TN - Centro de Ciências e Tecnologias Nucleares

• Granting Degree Institution:

  Instituto Superior Técnico (Universidade de Lisboa)

• Typology:

  National

• Abstract:

  This PhD research project will focus on the design and preclinical evaluation of a new generation of gold nanoseeds, which will be studied as nanoplatforms for the drug delivery of Pt(IV) prodrugs and as radiosensitizers in radiation therapy of cancer. The overall goal is to contribute for the development of innovative strategies for a more efficient treatment of unresectable solid tumor cancers with reduction of adverse side effects. The proposed research relies on our previous encouraging results with gold nanoparticles (AuNPs) carrying bombesin (BBN) peptides targeted at the gastrin releasing peptide receptor (GRPr) overexpressed in different cancer cells, namely prostate cancer (PCa) cells. We have found that these BBN-containing AuNPs undergo a specific and high uptake in PCa cells and radiosensitize these cancerous cells following exposure to high energy gamma photons (F. Silva et al., Bioconjugate Chemistry 2016, 27 (4), 1153-1164; F. Silva et al., Materials 2020, 13, 513). Herein, we propose to study the radiosensitizing properties of related AuNPs in proton therapy of prostate cancer, while comparing with traditional photon radiation. The originally designed AuNPs will be synthesized using different macrocyclic chelators suitable to coordinate 64Cu. This PET radionuclide will allow an image-guided approach of the intended radiation therapy involving the external irradiation with photon or proton beams of PCa cells or tissues accumulating the AuNPs. Some of the AuNPs will be also derivatized with Pt(IV) prodrugs. The presence of two different high-Z elements (Au and Pt) is expected to induce strongest radiosensitizing effects by intensifying the generation of low-energy electrons (e.g. photoelectrons or Auger electrons). Moreover, synergisms are anticipated between chemotherapeutic and radiotherapeutic effects in the case of the Pt-containing AuNPs, as they carry Pt(IV) prodrugs suffering intracellular glutathione-mediated activation with release of cisplatin or related Pt(II) anticancer metallodrugs. The PhD student will be involved in the different main steps of the devised multidisciplinary research plan, which are listed below. i) Synthesis and characterization of the AuNPs and their radiolabeling with Cu-64; ii) Determination of cellular uptake/subcellular distribution (Au and Pt content) and cytotoxicity of the AuNPs in PCa cell lines; iii) Cell irradiation experiments: irradiation of PCa cells with photon and proton beams (in the presence or absence of AuNPs); assessment of radiobiological effects and mechanisms of cell death; iv) PET imaging studies in PCa xenografts using the AuNPs labeled with 64Cu; v) Animal irradiation experiments: proton and photon irradiation of nude mice bearing PCa xenografts (treated or not with AuNPs); assessment of in vivo antitumoral effects and mechanisms of action. The PhD research work will be developed mainly at C2TN/IST within the framework of the ongoing projects TOP-PET (LISBOA-01-0247-FEDER-045904) and NANOGLIO (PTDC/MED-QUI/29649/2017), leaded in the latter case by the supervisor. The irradiation experiments with photons will be carried out at C2TN. The irradiation experiments with protons will be initially conducted at ICNAS with low energy protons using a 18 MeV cyclotron. As proposed in the TOF-PET project, irradiation experiments with high energy protons will be also performed at MD Anderson for the most promising AuNPs.