Thesis

Tumor-derived Exosomes as Nanotheranostic Tools for Lung Metastasis Detection and Treatment

• Call:

  ProtoTera Call 2020

• Academic Year:

  2020/2021

• Supervisor:

  Antero Abrunhosa

• Co-Supervisor:

  Celia Gomes

• Host Institution:

  ICNAS - Instituto de Ciências Nucleares Aplicadas à Saúde

• Granting Degree Institution:

  Universidade de Coimbra

• Typology:

  National

• Abstract:

  This project aims to develop an exosome-based theranostic nanoplatform for non-invasive early detection and treatment of lung metastasis, using tumor-derived exosomes (EXs) as natural delivery vehicles of radionuclides with diagnostic (64Cu) or therapeutic (177Lu) purposes. This represents a new functionality for EXs integrating advanced molecular imaging technology in early diagnosis and treatment of metastatic tumors and with increased clinical translation potential. The intrinsic advantages of EXs as endogenous nanocarriers featuring excellent biocompatibility and low immunogenicity, and the easy functionalization make them exquisite nanoplatforms for radionuclide-based theranostic for lung metastasis. EXs derived from metastatic cell lines will be used as core platforms for linking with cyclotron produced radionuclides. Copper-64 (64Cu), a longer-lived positron-emitter (t1/2=12.7h), will be conjugated at the surface of EVs following a protocol already established by our group. This targeting ability for metastatic lesions will be extended for radionuclide therapy by functionalizing EXs with 177Lu, which delivers cytotoxic radiation with a maximal tissue penetration of 2mm and a shorter emission range of 1.6mm, which makes it ideal for irradiation of smaller lesions. The therapeutic efficacy of 177Lu-labelled EXs will be tested in mice bearing lung metastasis. We have already established a set of animals’ models modeling lung metastatic disease suitable for this study and have available a broad set of small animal imaging modalities, among which stand out the microPET scanner based on resistive plate chambers with submillimeter spatial resolution (0.3mm) able to detect a small cluster of cells within the range size of the micrometastases.