Development of CXCR4 targeting -nanosystem-imaging probes for molecular imaging of cancer cells and tumor microenvironment.

Immunotherapy, which consists in the use of the immune system to fight cancer has shown remarkable results in the treatment of liquid tumour such as leukaemia. Solid tumours have been more refractory to immunotherapy, this is due among others to the strong tumour microenvironment (TME) and their capacity to spread. The development of early diagnosis tools and precise follow-up represent the main avenue for successful cancer management. For diagnosis and follow up the majority of patients undergoes diagnostic imaging through computed tomography (CT) scan and Positron emitting tomography (PET) evaluation. Nevertheless, the widely utilized PET tracer, 18Fluorodeoxyglucose ([18F]-FDG), have several limitations in terms of specificity and sensitivity leading cancer lesions often undetectable. The use of next generation nano-tracer may allow tumour specific molecular targeting that could overcome [18F]-FDG limitations. The chemokine receptor C-X-C chemokine-receptor-4 (CXCR4) is overexpressed in the majority of solid tumours characterizing the cellular most aggressive components and their TME. We recently developed a new anti-CXCR4 PET probe ([68Ga]NOTA-Ahx-R54) able to detect CXCR4-expressing tumor lesions; coupling anti-CXCR4-PET probe with nanotechnology could magnify the specificity and the sensitivity through increased tumor accumulation, multiple targeting ligands per particle and amplification of contrast signal. In this project we aim to develop a new CXCR4 targeting nanovectors -specific PET tracer (CXCR4-PET-NAN) to improve early diagnosis of primary/secondary cancer lesions CXCR4 overexpressing such as breast, colon, melanoma, pancreas, lung and neuroendocrine tumors (NETs). Our work in Oslo was to detect the impact of using R54 inhibitor on immune cells and in particular if this inhibition was affecting immunotherapy. Indeed, immune cells, such as T cells or NK cells, also express variable amounts of CXCR4 which was proposed to participate to immune cell homing to the tumour. We have accumulate number of data showing that R54 is specific and might affect immune cell migration. In this line, we have also developed solutions to block this effect by genetically modifying immune cells.

Jobs: the project has involved 4 postdocs and one PhD student (Oslo) for its duration. The major developments are: delivery of a new method to create dendrimer (protocol and technique). Chemists have also created novel products based on the protocol which are dendrimers for bioimaging and drug delivery. These products have so far been used to visualize cancer lesion, the drug delivery is still pending. Finally a novel solution to overcome CXCR4 inhibition has been designed. The combination of visualization and drug deliver (two in one) will resolve unmet needs in hard-to-treat cancers such as ovarian cancer. Oslo's contribution was to validate the use in an immunology perspective and provide a solution for the combination of this treatment with immunotherapy. In the long term, it is predicted that combinatorial solutions will be the only treatments able to resolve relapse/refractory cancers, in particular solid ones.

Molecular imaging consists of noninvasive mapping of processes associated with disease progression in living systems. Although molecular imaging greatly improved cancer detection and diagnosis, tumor imaging still faces criticism in sensitivity, spatial resolution and depth penetration. Nanotechnology is an interdisciplinary area with broad applications in molecular imaging, molecular diagnosis, and targeted therapy. The use of nanoparticles as imaging agents for tumor lesions is expected to overcome cancer imaging limitations thus innovating cancer imaging, diagnosis and therapy. Nanoparticles offer several advantages compared to traditional imaging agents including but not limited to 1.different targeting strategies, 2. high avidity due the presence multiple ligands per particle, 3. amplification of contrast signal by incorporating thousands of reporting elements, 4. theranostic capabilities. Nanosystem delivery by active targeting through the conjugation of the functionalized nanoplatform with a targeting ligand, allow disease-specific characterization of malignant lesions at the molecular level that is a prerequisite for targeted therapy and personalized treatment. CXCR4 is an evolutionarily highly conserved G-protein coupled receptor (GPCR) expressed on monocytes, B cells and naive T cells. Its ligand, CXCL12, is a homeostatic chemokine which controls hematopoietic cell trafficking, adhesion, immune surveillance and development. CXCR4 is overexpressed in more than 20 different human cancers actively contributing to their metastatic dissemination and growth progression. Recent evidence shows that interrupting the interaction of CXCR4-expressing T cells with CXCL12-secreting cells in TME has a positive therapeutic effect. Accurate imaging of CXCR4 may provide relevant information serving as a new diagnostic or prognostic tool for the identification of aggressive tumor or the stratification of patients eligible for immunotherapy approaches.