Degradable polymer prodrugs with adjustable activity from drug-initiated radical ring-opening copolymerization.

Degradable polymer prodrugs based on gemcitabine (Gem) as an anticancer drug were synthesized by 'drug-initiated' nitroxide-mediated radical ring-opening copolymerization (NMrROP) of methacrylic esters and 2-methylene-4-phenyl-1,3-dioxolane (MPDL). Different structural parameters were varied to determine the best biological performances: the nature of the monomer [i.e., oligo(ethylene glycol) methacrylate (OEGMA) or methyl methacrylate (MMA)], the nature of the Gem-polymer linker (i.e., amide or amide and diglycolate) and the MPDL content in the copolymer. Depending on the nature of the methacrylate monomer, two small libraries of water-soluble copolymer prodrugs and nanoparticles were obtained (M n ∼10 000 g mol-1, D = 1.1-1.5), which exhibited tunable hydrolytic degradation under accelerated conditions governed by the MPDL content. Drug-release profiles in human serum and in vitro anticancer activity on different cell lines enabled preliminary structure-activity relationships to be established. The cytotoxicity was independently governed by: (i) the MPDL content - the lower the MPDL content, the greater the cytotoxicity; (ii) the nature of the linker - the presence of a labile diglycolate linker enabled a greater Gem release compared to a simple amide bond and (iii) the hydrophilicity of the methacrylate monomer-OEGMA enabled a greater anticancer activity to be obtained compared to MMA-based polymer prodrugs. Remarkably, the optimal structural parameters enabled reaching the cytotoxic activity of the parent (free) drug.

Fluorescent polymer prodrug nanoparticles with aggregation-induced emission (AIE) properties from nitroxide-mediated polymerization.

Aggregation-induced emission (AIE)-active polymer prodrug nanoparticles were readily prepared by growing short, well-defined polymer chains from an AIE dye by nitroxide-mediated polymerization, followed by co-nanoprecipitation of the resulting conjugates with similarly constructed anticancer polymer prodrugs. The nanoparticles had sharp fluorescence signal offering excellent imaging ability in living cells and their intra cellular localization to be accurately monitored.

Radical Ring-Opening Copolymerization of Cyclic Ketene Acetals and Maleimides Affords Homogeneous Incorporation of Degradable Units.

Radical copolymerization of donor-acceptor (D-A) monomer pairs has served as a versatile platform for the development of alternating copolymers. However, due to the use of conventional radical polymerization, the resulting copolymers have generally been limited to nondegradable vinyl polymers. By combining radical D-A copolymerization with radical ring-opening polymerization (rROP), we have synthesized an alternating copolymer with a high incorporation of degradable backbone units. Copolymerization of N-ethyl maleimide (NEtMI) with the cyclic ketene acetal (CKA) 2-methylene-4-phenyl-1,3-dioxolane (MPDL) was demonstrated to proceed in an alternating fashion, and controlled polymerization was achieved using reversible addition-fragmentation chain transfer (RAFT) polymerization. Spontaneous copolymerization, in the absence of an exogenous initiating source, occurred when the mixture of monomers was heated, presumably due to the large electron disparity between the comonomers. Chain-extension with styrene afforded well-defined P(MPDL-alt-NEtMI)-b-polystyrene copolymers, and degradation of the homopolymers and block copolymers showed complete breakdown of the alternating copolymer.

Correction: A ring to rule them all: a cyclic ketene acetal comonomer controls the nitroxide-mediated polymerization of methacrylates and confers tunable degradability.

Correction for 'A ring to rule them all: a cyclic ketene acetal comonomer controls the nitroxide-mediated polymerization of methacrylates and confers tunable degradability' by Vianney Delplace et al., Chem. Commun., 2015, DOI: 10.1039/c5cc04610f.

A ring to rule them all: a cyclic ketene acetal comonomer controls the nitroxide-mediated polymerization of methacrylates and confers tunable degradability.

2-Methylene-4-phenyl-1,3-dioxolane (MPDL) was successfully used as a controlling comonomer in NMP with oligo(ethylene glycol) methyl ether methacrylate (MeOEGMA) to prepare well-defined and degradable PEG-based P(MeOEGMA-co-MPDL) copolymers. The level of ester group incorporation is controlled, leading to reductions in molecular weight of up to 95% on hydrolysis. Neither the polymer nor its degradation products displayed cytoxicity. The method was also successfully applied to methyl methacrylate.

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.