Axially Ligated Mesohemins as Bio-Mimicking Catalysts for Atom Transfer Radical Polymerization.

Copper is the most common metal catalyst used in atom transfer radical polymerization (ATRP), but iron is an excellent alternative due to its natural abundance and low toxicity compared to copper. In this work, two new iron-porphyrin-based catalysts inspired by naturally occurring proteins, such as horseradish peroxidase, hemoglobin, and cytochrome P450, were synthesized and tested for ATRP. Natural protein structures were mimicked by attaching imidazole or thioether groups to the porphyrin, leading to increased rates of polymerization, as well as providing polymers with low dispersity, even in the presence of ppm amounts of catalysts.

Biocompatible Polymeric Analogues of DMSO Prepared by Atom Transfer Radical Polymerization.

The synthesis of a sulfoxide-based water-soluble polymer, poly(2-(methylsulfinyl)ethyl acrylate) (polyMSEA), a polymeric analogue of DMSO, by atom transfer radical polymerization (ATRP) is reported. Well-defined linear polymers were synthesized using relatively low amounts of copper catalyst (1000 or 100 ppm). Two types of star polymers were synthesized by either an "arm-first" approach or a "core-first" approach using a biodegradable ß-cyclodextrin core. The glass transition temperatures of both the linear polymer (16 °C) and star polymer (32 °C) were determined by differential scanning calorimetry (DSC). The lower critical solution temperature (LCST) of poly(MSEA) was estimated to be ca. 140 °C by extrapolating the LCST of a series of copolymers with NIPAM. Cytotoxicity tests revealed that both the linear and star polymers have low toxicity, even at concentrations up to 3 mg/mL.

Degradable copolymers with incorporated ester groups by radical ring-opening polymerization using atom transfer radical polymerization.

Preparation of degradable materials using reversible deactivation radical polymerizations (RDRP) is of particular interest for biomedical applications. In this paper we report preparation of degradable copolymers of 2-methylene-4-phenyl-1, 3-dioxolane (MPDL), monomer which undergoes ring-opening reaction and forms ester bond upon radical polymerization, with hydrophobic and hydrophilic methacrylate monomers using atom transfer radical polymerization (ATRP). Copolymers composition and degradation were evaluated upon varied temperature and monomer type.

Photoinduced Atom Transfer Radical Polymerization with ppm-Level Cu Catalyst by Visible Light in Aqueous Media.

Photoinduced ATRP was successfully performed in aqueous media. Polymerization of oligo(ethylene oxide) methyl ether methacrylate (OEOMA) in the presence of CuBr2 catalyst and tris(2-pyridylmethyl)amine ligand when irradiated with visible light of 392 nm wavelength at 0.9 mW/cm(2) intensity was well controlled. Linear semi-logarithmic kinetic plots and molecular weights increasing with conversion were observed. Polymers of OEOMA were synthesized with low dispersity (Mw/Mn = 1.12) using only 22 ppm of copper catalyst in the presence of excess bromide anions in highly diluted (90% v/v) aqueous media. The effects of copper concentration, salt, and targeted degrees of polymerization were investigated. The polymerization could be directly regulated by external stimulation, i.e., switching the irradiation on/off, with a good retention of chain-end functionality, as proved by clean chain extension of the OEOMA polymers. This new system could enable applications for controlled aqueous radical polymerization due to its low catalyst loading in the absence of any other chemicals.

Direct ATRP of Methacrylic Acid with Iron-Porphyrin Based Catalysts.

An iron porphyrin catalyst, derived from the active center of proteins such as horseradish peroxidase and hemoglobin, was successfully used for the atom transfer radical polymerizations (ATRP) of methacrylic acid. ATRP of methacrylic acid and other acidic monomers is challenging due to Cu complexation by carboxylates, protonation of the ligand, and displacement of the halogen chain end. A robust mesohemin-based catalyst provided controlled ATRP of methacrylic acid, yielding poly(methacrylic acid) with Mn ≥ 20000 and dispersity D < 1.5. Retention of halogen chain end was confirmed by successful chain extension of a poly-(methacrylic acid)-Br macroinitiator.

Synthesis of Polymer Bioconjugates via Photoinduced Atom Transfer Radical Polymerization under Blue Light Irradiation.

A rapid blue-light-induced atom transfer radical polymerization (ATRP) was conducted in a biologically friendly environment. Well-controlled polymerization of oligo(ethylene oxide) methyl ether methacrylate (OEOMA) was successfully performed in aqueous media (1X PBS) under irradiation by blue LED strips. With 10.0 mW/cm2 intensity output at 450 nm, >90% conversion was achieved in 2 h in the presence of a system comprising glucose, glucose oxidase, and sodium pyruvate. Poly-(OEOMA) was synthesized with predetermined M n and low dispersities using low ppm of Cu catalysts. Importantly, secondary structures of proteins, as analyzed by circular dichroism (CD), were preserved under blue-light irradiation due to its lower energy output. The aqueous blue-light ATRP technique was applied to biological systems by synthesizing well-defined protein-polymer and DNA-polymer hybrids by the "grafting-from" method.

A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity.

The delivery of therapeutic peptides and proteins is often challenged by a short half-life, and thus the need for frequent injections that limit efficacy, reduce patient compliance and increase treatment cost. Here, we demonstrate that a single subcutaneous injection of site-specific (C-terminal) conjugates of exendin-4 (exendin) - a therapeutic peptide that is clinically used to treat type 2 diabetes - and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) with precisely controlled molecular weights lowered blood glucose for up to 120 h in fed mice. Most notably, we show that an exendin-C-POEGMA conjugate with an average of 9 side-chain ethylene glycol (EG) repeats exhibits significantly lower reactivity towards patient-derived anti-poly(ethylene glycol) (PEG) antibodies than two FDA-approved PEGylated drugs, and that reducing the side-chain length to 3 EG repeats completely eliminates PEG antigenicity without compromising in vivo efficacy. Our findings establish the site-specific conjugation of POEGMA as a next-generation PEGylation technology for improving the pharmacological performance of traditional PEGylated drugs, whose safety and efficacy are hindered by pre-existing anti-PEG antibodies in patients.

ATRP under Biologically Relevant Conditions: Grafting from a Protein.

Atom transfer radical polymerization (ATRP) methods were developed in water-based media, to grow polymers from proteins under biologically relevant conditions. These conditions gave good control over the resulting polymers, while still preserving the protein's native structure. Several reaction parameters, such as ligand structure, halide species, and initiation mode were optimized in water and PBS buffer to yield well-defined polymers grown from bovine serum albumin (BSA), functionalized with cleavable ATRP initiators (I). The CuCl complex with ligand 2,2'-bipyridyne (bpy) provides the best conditions for the polymerization of oligo(ethylene oxide) methacrylate (OEOMA) in water at 30 °C under normal ATRP conditions (I/CuCl/CuCl2/bpy = 1/1/9/22), while the CuBr/bpy complex gave better performance in PBS. Activators generated by electron transfer (AGET) ATRP gave well-controlled polymerization of OEOMA at 30 °C with the ligand tris(2-pyridylmethyl)amine (TPMA), (I/CuBr2/TPMA = 1/10/11). The AGET ATRP reactions required slow feeding of a very small amount of ascorbic acid into the aqueous reaction medium or buffer. The reaction conditions developed were used to create a smart, thermoresponsive, protein-polymer hybrid.