Fluorescent and Gadolinium-based Probes for the Targeted Surgery and Neutron Capture Therapy of Glioblastoma

The aim of this research proposal is to advance interventional procedures for glioblastoma (GBM) by developing two novel classes of either fluorescent or gadolinium-based probes. They are conceived for the targeted treatment of this disease allowing the precise surgical resection of the tumor and its targeted Neutron Capture therapy, respectively. GBM is the most aggressive primary brain tumor whose incidence is on the rise in many countries. As it still lacks an effective treatment, novel therapeutic approaches are urgently needed (1). It is known that the cytosolic aldehyde dehydrogenase 1A3 (ALDH1A3) is overexpressed in GBM, playing a crucial role in its progression. Therefore, compounds able to bind ALDH1A3 efficiently and with a long resident time may not only exert an anti-tumour activity per se, but also display additional functional activities by reason of their chemical characteristics. Actually, once tagged with suitable fluorescent residues, they can guide the surgical removal of GBM by highlighting malignant tissue. Instead, once complexed with suitable paramagnetic agents like the gadolinium-based ones, they allow the local and highly performant Neutron Capture therapy of GBM. We have already developed two examples of ALDH1A3 inhibitors, whose significance as prototypical compounds for the targeted treatment of GBM has been verified through in vitro and in vivo studies. These include a recently published imidazopyridine derivative, namely NR6, which showed a nanomolar antiproliferative efficacy when tested against U87MG cell line (2), and an alkyloxybenzaldehyde derivative labelled with a fluorescent tag, namely MD111, which proved to accumulate in the tumour mass when tested in a murine model of GBM (3).Moving from the existing data, and according to the workflow sketched in Figure 1, we now plan to:- design and synthesize novel fluorescent compounds by labelling NR6 with suitable tags through different linkers, to obtain a reference library of fluorescent imidazopyridines;- design and synthesize novel paramagnetic compounds by complexing NR6 with gadolinium, to obtain a reference library of paramagnetic imidazopyridines;- test in vitro the two libraries of either fluorescent or paramagnetic probes for their activity against the targetALDH1A3 and selectivity towards the other members of the ALDH1A family and the parent ALDH2A, as well as in properly chosen GBM cell lines, to select the most performing compounds;- test in vivo the most effective fluorescent and paramagnetic derivatives in a murine model of GBM, to investigate their usability for the precise surgery of glioblastoma and its Neutron Capture therapy, respectively, thus getting to two new lead candidates for the targeted treatment of GBM deserving of pre-clinical development.