HBP-MultiReact (2021-2025)

HBP-MultiReact: Hyperbranched polymers with multiple reactive terminal groups: toward multi-targeting therapeutic carriers

This research project directed by Dr Sagrario Pascual (IMMM, Le Mans) is granted by the French Research Agency (ANR) for the coming 4 years.

Hyperbranched polymers (HBPs) are highly branched macromolecules. In comparison with linear polymers, they have several advantages including an internal cavity and abundant functional groups with multivalent effect. HBP structures are irregular in comparison with dendrimers ones but offer advantages in terms of facile synthesis in one-pot reaction, low cost-efficient synthesis and flexible compositions. Among the various synthetic strategies to target HBPs, self-condensing vinyl polymerization (SCVP) is considered one of the most versatile because it employs vinyl monomers that can be polymerized via radical chemistry tolerant with a wide range of chemical functions. SCVP combined to reversible addition-fragmentation chain transfer polymerization (RAFT) can be employed under soft conditions (water, room temperature), using functional monomers including cationic monomers, and therefore offers access to a variety of HBP structures.

Despite their easy synthesis, HBPs are known to have a poor structural control and are limited to one kind of functional terminal groups. To tackle this limitation, the innovation of HBP-MultiReact project is to design and to synthesize structurally controlled HBPs with a variety of multiple reactive terminal groups through the combination of RAFT-SCVP in confined environments to structurally control the HBP cavity with a powerful chemical handle (azlactone derivatives) to target HBP with multiple chemoselective reactive functions at the periphery.

The azlactone chemistry has emerged as a powerful chemical handle for the synthesis of a wide library of functional linear polymers. The advantages of the azlactone group are a high reactivity towards amines in mild conditions with a total atom economy. In this project, the “click” amine-azlactone reaction is expected to enable HBP periphery with a variety of multiple reactive terminal groups. In addition, conducting RAFT-SCVP in confined environment may favor a tunable structure of HBP cavity thanks to the physical confinement of the growing radicals to regulate the polymer–polymer coupling reactions. Such physical confinement is reached through the compartmentalization of reactants within nanodomains, by relying on polymerization in aqueous dispersed media.

The ability of final cationic HBPs with multiple reactive terminal groups to conjugate targeting peptides and a therapeutic siRNA for preventing endothelium dysfunction associated with diabetes is assessed in this project.

To achieve the aims of this challenging HBP-MultiReact project, three partners (IMMM-Le Mans, CP2M-Villeurbanne and MINT-Angers) will combine their complementary expertise in: i) the azlactone chemistry, ii) polymer synthesis in dispersed media, and iii) nanomedicine and cardiovascular disease.

https://anr.fr/Project-ANR-21-CE06-0004