Elise Guégain

Nitroxide-Mediated Polymerization of Methacrylic Esters: Insights and Solutions to a Long-Standing Problem.

Nitroxide-mediated polymerization (NMP) is one of the most powerful reversible deactivation radical polymerization techniques and has incredibly gained in maturity and robustness over the last decades. However, control of methacrylic esters is one of the different aspects of NMP that still requires improvement. This family of monomers always represented an important challenge for NMP, despite the many different nitroxide structures that have been designed over the course of time. This Review aims to present the most successful strategies directed toward the control of the NMP technique of methacrylic esters and especially methyl methacrylate. NMP-derived materials comprising uncontrolled methacrylate segments will also be discussed.

On the structure–control relationship of amide-functionalized SG1-based alkoxyamines for nitroxide-mediated polymerization and conjugation

The functionalization of alkoxyamines prior to nitroxide-mediated polymerization (NMP) induces important structural variations when compared to the parent molecules. This may have important consequences on the design of functionalized materials by pre-functionalization. In this context, a wide range of amide-functionalized alkoxyamines (a functionality often obtained after conjugation from COOH– and N-succinimidyl-containing alkoxyamines) based on the nitroxide SG1 (N-tert-butyl-N-(1-diethyl phosphono-2,2-dimethylpropyl) nitroxide) have been synthesized and their dissociation rate constants (kd) have been determined. To rationalize their reactivity, a multi-parameter procedure was applied and enabled to discriminate disubstituted amide-functionalized alkoxyamines from monosubstituted ones. Monosubstituted alkoxyamines exhibited lower kd than their disubstituted counterparts (Ea increase of ∼7–10 kJ mol−1) because of the occurrence of intramolecular hydrogen bonding (IHB) between the alkyl and the nitroxide fragments. NMP of styrene, n-butyl acrylate and methyl methacrylate with a small amount of acrylonitrile was then successfully performed from two representative secondary SG1-based alkoxyamines employed for conjugation: namely AMA (COOH-containing) and AMA-NHS (N-succinimidyl derivative), and compared to polymerizations initiated with AMA-Gem, an AMA-based alkoxyamine pre-functionalized with the anticancer drug Gemcitabine (Gem) and subjected to IHB. Although AMA-NHS showed the best results due to its lower Ea, the strong polarity of the Gem moiety that counter-balanced the detrimental effect of IHB over its kd still allowed for a reasonable control.

Efficient synthesis of 2-methylene-4-phenyl-1,3-dioxolane, a cyclic ketene acetal for controlling the NMP of methyl methacrylate and conferring tunable degradability

The efficient and reliable synthesis of 2-methylene-4-phenyl-1,3-dioxolane (MPDL), a highly effective cyclic ketene acetal for radical ring-opening polymerization, was reported from three different acetal halides and thoroughly characterized by 1H and 13C NMR spectroscopy, IR spectroscopy, elemental analysis and mass spectrometry. MPDL was then employed as a controlling comonomer for nitroxide-mediated polymerization using methyl methacrylate (MMA) as the principal monomer to produce well-defined, degradable PMMA-rich copolymers (Mn ∼ 20–30 kg mol−1, Đ = 1.3–1.4) when sufficient MPDL was initially introduced into the monomer feed (fMPDL,0 > 0.2). Hydrolytic degradation was tuned by varying the amount of MPDL in the monomer feed. The insertion of MPDL into the polymethacrylate backbone only moderately affected the glass transition temperature compared to the poly(methyl methacrylate) homopolymer, while giving low molar mass degradation products after hydrolysis.

Self-stabilized, hydrophobic or PEGylated paclitaxel polymer prodrug nanoparticles for cancer therapy

Facile derivatization of paclitaxel (Ptx) and subsequent “drug-initiated” synthesis of well-defined Ptx-polymer prodrugs was performed from nitroxide-mediated polymerization or reversible addition–fragmentation chain transfer polymerization. Short polyisoprene (Mn = 2640–4310 g mol−1, Đ ∼ 1.1) or poly[(oligo(ethylene glycol) methyl ether methacrylate)] (Mn = 5580–7530 g mol−1, Đ ∼ 1.2) chains were grown from Ptx in a controlled fashion and enabled, for the first time, the formation of either self-stabilized, all-hydrophobic Ptx-polymer prodrug nanoparticles or their PEGylated counterparts. They exhibited average diameters in the 110–235 nm range, great colloidal stability in PBS and cell culture medium, high drug loadings (up to 32 wt%) and cytotoxicity similar to that of the parent drug on three different cancer cell lines (A549, L1210 and MCF-7). This versatile approach is expected to provide more potent anticancer nanocarriers and rejuvenate the development of Ptx-based nanomedicines.

Chapter 7:NMP of Methacrylic Esters: How to Circumvent a Long-time Obstacle

Despite recent intensive research, especially focused on the design of different nitroxide structures, the control of methacrylic esters is still an important challenge for NMP. This chapter aims at covering not only the main reasons for the difficulty achieving NMP of methacrylates but also the most successful strategies that have been developed to control the polymerization of such monomers by NMP.