RotaxImage

[Non-confidential summary] This project addresses the call of the Action Plan 2016 of ANR for Nanomaterials and nanotechnologies for tomorrow products - Innovative nano-objects for health. The main objective is the development of a supramolecular platform for biomedical applications such as multimodal imaging, early stage diagnosis and ultimately medical treatment of arthritis. Our method holds promises for future extensions to other diseases, because of its innovative modular approach. Building on a polyrotaxane platform that was adapted from literature by the principal investigator during preliminary work, we plan to synthesize versatile building block molecules that self-assemble to yield large supramolecular architectures. These building block molecules are functionalized individually with markers for imaging, or vectors for targeting. The self-assembly procedure thus yields multifunctional agents which fulfill the features for modern cutting edge vectors for diagnosis and monitored therapy. The key advantages of our strategy consist in i) its exceptional modularity as different combinations can be obtained easily from the same set of building blocks; and ii) its high flexibility because the functions and their synthesis can be optimized individually and separately on each building block. Thus, our project goes beyond existing systems as it combines molecularly defined synthesis with the biomedical advantages of macromolecular assemblies. We will focus on biocompatible and biodegradable molecules, in contrast to nanoparticles, to obtain a powerful nanometric imaging agent. The chemistry part of the project consists of organic synthesis, coordination chemistry and characterization of molecular and supramolecular compounds. The project is target oriented towards arthritis, with the ultimate goal for early stage diagnosis and monitoring disease progression. Within this project, we plan to optimize key functions and properties, and to improve the pharmacokinetics and pharmacodynamics of our supramolecular compounds. Therefore we will assess physicochemical behavior in solutions and biological media (charge, size, stability). We will check on a routine base the toxicity of all new compounds by MTT conversion assay, before studying the biodistribution in animal models. We will develop multimodal imaging by combining at least two different markers, in particular fluorescence labels and MRI contrast agents to benefit from their complementary sensitivity and resolution to ensure quantitative diagnosis. Their potential for combined imaging experiments will be evaluated in optical imaging platforms (quantum yield, stability) equipped with the latest technologies (3D) and in micro MR imaging systems at high magnetic field (relaxivity). After optimization of all biodistribution and sensitivity features of our platform in healthy animals, we will use it for the study of inflammatory arthritis in a transgenic mouse model in a non-targeted and TNF-a targeted form. Thus, an interdisciplinary consortium of chemists, biophysicists, pharmacologists and physicians has joined together to generate novel probes for clinical applications that require the detection of specific biochemical signatures. The proposal is upstream of clinical research. It consists mainly in the development of a conceptually new, supramolecular theranostic agent. It requires new chemical synthesis for compounds with specific properties, and their characterization in biological and biophysical tests for diagnosis. For this, we request funding for a PhD student, a post-doctoral associate and laboratory expenses.