P2X7 and P2X4 Receptors in Cancer and Inflammation: Drug Development, Bioimaging, and Targeted Drug Delivery

Basic data for this project

Description

The P2X7 receptor (P2X7R) is emerging as a promising target for the treatment of breast cancer, pancreas cancer, and inflammatory diseases, whereas the pharmacologically less explored P2X4 receptor (P2X4R) displays promising potential for the therapy of neuropathic pain and prostate cancer. The proposed project aims to develop potent and selective P2X7R and P2X4R ligands as innovative drugs for bioimaging, and targeted drug delivery. For the P2X7R novel, selective agonists with enhanced metabolic stability are proposed. Those compounds will not only improve our understanding of agonist recognition by the receptor but are also highly desired as pharmacological tools for P2X7R research. On the other hand, development of new P2X7R antagonists is envisaged as well. The structure-activity relationships (SAR) of new P2X7R antagonists will be implemented into the development of a quantitative structure-activity relationships (QSAR) model and the most potent and selective receptor antagonists will be optimized pharmacokinetically to generate compounds suitable for drug development, targeted drug delivery, and bioimaging. The research in the field of P2X4R is lacking potent and selective antagonists. Therefore, new piperazine-based P2X4R antagonists are proposed. The generated SAR will be implemented into the development of a QSAR model and will help to elucidate pharmacophoric elements required for selective binding to the P2X4R. In vitro and in vivo imaging plays an important role in the understanding of mechanisms leading to the development and progression of many human diseases. The diagnostic potential of the P2X7R as tumor marker will be explored using 3 different imaging techniques: positron emission tomography (PET), fluorescence imaging and photoacoustic (PA) tomography. First, development of P2X7R targeting PET tracers based on the structure of two highly potent P2X7R antagonists is proposed. The new PET tracers will be evaluated in disease animal models in dual PET/MRI combining molecular and anatomical imaging. The main challenge facing bioimaging is the ability to bridge from single cell to whole-body imaging through the development of more efficient probes or a combination of various imaging modalities. Therefore, fluorescence and photoacoustic (PA) imaging probes utilizing novel fluorescent, conjugated polymer nanoparticles (P-dots) for the in vitro and in vivo imaging of P2X7Rs will be developed. In addition to the imaging of P2X7Rs, we are highly interested in exploring the therapeutic potential of targeted receptor antagonist delivery to the site of bone metastases in breast cancer and into inflamed, rheumatic joints. Therefore, the development of bispecific conjugates through the incorporation of P2X7R antagonists on one site and bisphosphonates, targeting bone tissue, on the other site are envisaged. Hereby metabolically stable multivalent dendrimeric conjugates and enzymatically degradable conjugates are proposed.