Biodegradable, PEGylating polymers: application to the synthesis of nanoparticles and bioconjugates – BioPolyPEG

The idea is to advantageously combine the nitroxide-mediated radical polymerization (NMP) technique with the possibility to perform the copolymerization of vinyl monomers with cyclic ketene acetal (CKA) derivatives, which can act as precursors of biodegradable monomer units. In this case, the resulting radical ring opening polymerization (rROP) mechanism gathers both the advantages of ring opening polymerization and radical polymerization. It enables the synthesis of biodegradable polymers comprising ester moieties in the main chain by a radical pathway. NMP has been chosen for its numerous advantages such as its ability to control the polymerization of many monomers, its non-cytotoxicity and its flexibility concerning the precise insertion of functional groups. The influence of the nature of the CKA derivatives on its ability to copolymerize has first been investigated. To do so, we prepared a small library of CKA derivatives and studied their copolymerization with PEG-based macromonomers (acrylate or methacrylate) by NMP. The idea was to develop new PEGylating copolymer building blocks for application in the synthesis of nanoparticles and polymer-protein bioconjugates.

A library of PEG-based copolymers has been prepared by nitroxide-mediated controlled radical ring opening polymerization. These copolymers were well-defined and exhibited tunable amounts of biodegradable units of different nature in the main chain, leading to degradation ranging from 20 to 90% compared to the initial molar mass. Further biological evaluations demonstrated the noncytotoxicity of the obtained copolymers on different cell lines, representing a promising approach for the
design of degradable precursors for PEGylation and bioconjugation. Nanoparticles and polymer-protein bioconjugates were successfully obtained.

This projected enabled the synthesis of fully degradable vinyl polymers by a environmentally-friendly polymerization method as building block for the design of biomaterials such as nanoparticles of protein-polymer bioconjugates. Envisioned application are therefore numerous, especially in the field of nanomedicine. Besides, this approach could be applied to many other vinyl monomers, thus opening the door to applications in the field of sustained development.

Most of the results have been published in high impact factor polymer journals (Polym. Chem. 2013, 4, 4776, Biomacromolecules 2013, 14, 3769, Polym. Chem. 2014, 5, 1529, Macromol. Rapid Commun. 2014, 35, 484) and 3 submitted (Nature Chem. (proposition de revue acceptée, Polym. Chem. et Chem. Commun.).
The obtained results have been disseminated through oral communications and poster presentations during prestigious international congresses (ACS Meeting, EPF, etc.).

In the fields of biomaterials, the pool of synthetic biodegradable polymers is somehow limited to two main categories of polymers; namely polyesters (such as polycaprolactones, polylactides, polyglycolides and their copolymers) and poly(alkyl cyanoacrylate)s. Although they represent well-established classes of biomaterials, severe drawbacks and limitations usually hamper the easy design of complex and functionalized materials. In this view, the aim of this project is to broaden this limited range of synthetic biodegradable polymers intended to be used for biomedical applications, by means of controlled/living radical polymerization. The idea is to advantageously combine nitroxide-mediated polymerization (NMP) together with the ability of cyclic ketene acetal (CKA) monomers, as precursors of biodegradable functions, to be copolymerized under a radical ring-opening process (rROP). In this case, rROP presents the advantages of both ring-opening polymerization and radical polymerization, that is, the production by a radical process of biodegradable polymers comprising ester functions in the polymer backbone. NMP was chosen due to its numerous benefits such as its ability to control a broad range of monomer with certain ease, its non-totoxicity and its flexibility regarding the insertion of functionalities. We first propose to synthesize three small libraries of CKA derivatives: (i) hydrophobic, (ii) hydrophilic and (iii) hydrophilic + functionalized, able to strictly polymerize under rROP. By copolymerization of CKAs with vinylic PEG macromonomers (acrylate or methacrylate), we plan to design novel, biodegradable and non-cytotoxic PEGylating polymers further involved in the production of amphiphilic block copolymers, PEGylated nanoparticles and bioconjugates (i.e., PEGylated proteins). Due to the controlled polymerization process, they will exhibit well-defined architectures, biodegradable features and easy-to-insert functional groups for further coupling to biomolecules of interest. This will be illustrated by the insertion on the CKA structure of azide or alkene moieties involved in “click chemistry” reactions with model biomolecules. This project could pave the way to a new class of well-defined and readily functionalizable synthetic biomaterials with unique biodegradation features.