Antonina Simakova

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.

Bioinspired Iron‐Based Catalyst for Atom Transfer Radical Polymerization

Atom transfer radical polymerization (ATRP) provides welldefined polymers with predetermined molecular weight and narrow molecular weight distributions and precisely controlled architecture. Copper-based ATRP catalysts are the most efficient for the preparation of a broad range of welldefined polymers. However, the development of new transition-metal-based catalysts remains of great interest in order to extend the range of polymers that can be prepared by ATRP. Consequently, iron-mediated ATRP has been widely investigated because of its low toxicity and biocompatibility, especially advantageous when targeting biological applications. Despite these potential benefits of iron-based catalysts, their application in ATRP is quite limited because of their lower activity and selectivity. Therefore, the design and development of new iron-based catalysts comparable in activity to traditional catalysts and able to polymerize a broader range of monomers is critical for progress in this field. ATRP is typically performed in organic solvents, but performing ATRP in aqueous media provides several advantages. Water is an environmentally benign solvent, enabling direct polymerization of water-soluble monomers, faster reactions, and polymerization in the presence of biomolecules. Several methods for well-controlled Cu-based ATRP in water have been developed, but in the majority of reports a limited number of catalytic systems and narrow range of monomers are used. Difficulties with control of ATRP in aqueous media are associated with some side reactions including catalyst and chain-end instabilities, as well as a large equilibrium constant responsible for significantly increased rates of reaction. Our group has recently reported the synthesis of protein–polymer hybrids by ATRP under biologically relevant conditions, which were designed to sustain the structure of a protein during polymerization as well as provide good control. In this system, a protein served as an initiator, but recent publications by Bruns and diLena show that certain proteins/enzymes can also serve as catalysts for ATRP. Protein-based catalysts, so called ATRPases, with iron heme centers, such as horseradish peroxidase (HRP), catalase or hemoglobin (Hb) act as ATRP catalysts and can produce high molecular weight (MW) polymers with molecular weight distributions (MWDs) close to 1.5, indicative of some limited control. These catalytic systems can potentially expand the range of polymerizable monomers because of a different catalyst structure and tolerance to pH variation. However, a major drawback of using proteins for catalysis is their sensitivity to reaction conditions and high molecular weight. Therefore, the development of synthetic analogs that can reproduce or enhance the properties of native catalytic proteins without the need for such stringent conditions and high mass loading of the catalyst would allow for broader application of these bioinspired catalytic systems. Application of the naturally occurring hematin, the structure of which is similar to the prosthetic group of HRP, Hb, or catalase, for catalysis of radical polymerization reactions of vinyl monomers showed that it can successfully replace HRP. Indeed, some iron porphyrins can induce an atom transfer process, as in ATRP, and even provide a certain level of control indicated by a linear increase of molecular weight with conversion and moderate dispersity values (Mw/ Mn< 2; Mw = weight average molecular weight and Mn = number average molecular weight. Poly(N-isopropylacrylamide), poly(NIPAAm), prepared in the presence of alkyl halide initiator and hematin had relatively high Mw/Mn values (1.8–2.1). These results indicate that iron porphyrins can act as catalysts for ATRP, but significant improvements are needed to prepare well-defined materials. Hemin was chosen for initial testing as an iron-based catalyst for ATRP. Hemin is a ferric form of heme with a chloride ligand instead of hydroxyl group as in hematin. Hemin was used to catalyze activators generated by electron transfer (AGET) ATRP of oligo(ethylene oxide) methyl ether methacrylate (OEOMA475, average MW 475) [16] in aqueous media with ascorbic acid as reducing agent (see Scheme S1 in the Supporting Information). This method allows in situ generation of Fe species, thereby preventing the irreversible formation of m-oxo bisiron(III) complexes that can occur between two iron(II) porphyrins in the presence of oxygen. However, this catalyst has low halidophilicity, low solubility in water, and can itself polymerize because of the presence of vinyl moieties. Therefore, we developed a second generation of hemininspired catalysts that addressed these issues and provided significantly improved performance in the preparation of well-defined polymers (Scheme 1). We first attempted to improve the reported earlier catalase catalytic system, by addition of NaCl, yielding [*] A. Simakova, M. Mackenzie, S. E. Averick, S. Park, K. Matyjaszewski Department of Chemistry, Carnegie Mellon University 4400 Fifth Avenue, Pittsburgh, PA 15213 (USA) E-mail: km3b@andrew.cmu.edu

Covalently incorporated protein –nanogels using AGET ATRP in an inverse miniemulsion

Using a genetically engineered protein, containing a non-natural amino acid bearing an atom transfer radical polymerization (ATRP) initiator, protein–nanogel hybrids (PNHs) were synthesized by activator generated by electron transfer (AGET) ATRP in an inverse miniemulsion. The route presented is an appropriate synthetic strategy to covalently and site specifically incorporate green fluorescent protein (GFP) into well-defined nanogels. These PNHs were analyzed using dynamic light scattering (DLS), UV-visible fluorescence spectroscopy and confocal microscopy to confirm the successful integration of GFP proteins into each nanogel (NG), while preserving its native tertiary structure.

A brush-polymer/exendin-4 conjugate reduces blood glucose levels 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.

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 Đ < 1.5. Retention of halogen chain end was confirmed by successful chain extension of a poly-(methacrylic acid)-Br macroinitiator.

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.