Simon Harrisson

Nanoparticles with in vivo anticancer activity from polymer prodrug amphiphiles prepared by living radical polymerization.

impor-tant limitations, which may explain the lower number ofsuccessful in vivo studies, still remain. The “burst release”, inwhich a large fraction of chemotherapeutic agent is quicklyreleased post-administration, can be harmful to patients.Poorly soluble drugs exhibit a high tendencyto crystallizationupon encapsulation. Finally, maximum achievable drug load-ings are generally only a few percent, thus the use of a largeamount of nanocarrier is required and this can lead toprohibitive toxicity in vivo.To overcome these obstacles, inspiration can be takenfrom the prodrug approach, whereby the drug is covalentlylinked to a (macro)molecule. The inactive prodrug is metab-olized in vivo into an active metabolite.

Degradable and comb-like PEG-based copolymers by nitroxide-mediated radical ring-opening polymerization.

Three cyclic ketene acetals, 2-methylene-1,3-dioxepane (MDO), 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), and 2-methylene-4-phenyl-1,3-dioxolane (MPDL), have been copolymerized with oligo(ethylene glycol) methyl ether methacrylate and a small amount of acrylonitrile (or styrene) at 90 °C by nitroxidemediated radical ring-opening polymerization, as a convenient way to prepare degradable PEG-based copolymers for biomedical applications. MPDL was the best candidate, enabling high monomer conversions to be reached and well-defined PEG-based copolymers with adjustable amount of ester groups in the main chain to be synthesized, leading to nearly complete hydrolytic degradation (5% KOH aqueous solution, ambient temperature). The noncytotoxicity of the obtained copolymers was shown on three different cell lines (i.e., fibroblasts, endothelial cells and macrophages), representing a promising approach for the design of degradable precursors for PEGylation and bioconjugation via the NMP technique.

Polymer Prodrug Nanoparticles Based on Naturally Occurring Isoprenoid for Anticancer Therapy

The synthesis of a novel class of polymer prodrug nanoparticles with anticancer activity is reported by using squalene, a naturally occurring isoprenoid, as a building block by the reversible addition-fragmentation (RAFT) technique. The RAFT agent was functionalized by gemcitabine (Gem) as anticancer drug, and the polymerization of squalenyl-methacrylate (SqMA) led to well-defined macromolecular prodrugs comprising one Gem at the extremity of each polymer chain. The amphiphilic nature of the resulting Gem-PSqMA conjugates allowed them to self-assemble into long-term stable and narrowly dispersed nanoparticles with significant anticancer activity in vitro on various cancer cell lines. To confer stealth properties on these nanoparticles, their PEGylation was successfully performed, as confirmed by X-ray photoelectron spectroscopy (XPS) and complement activation assay. It was also shown that the PEGylated nanoparticles could be internalized in cancer cells to a greater extent than their non-PEGylated counterparts.

Simple and efficient copper metal-mediated synthesis of alkoxyamine initiators

A simple and efficient method is presented for the preparation of a wide range of alkoxyamines from nitroxide radicals and activated alkyl bromides at room temperature. The reaction requires a stoichiometric amount of copper metal (0.5 mol mol−1 alkyl bromide) and proceeds most rapidly in polar solvents such as acetonitrile, dimethyl sulfoxide or ethanol. No addition of copper(I) or copper(II) salts is necessary. Isolated yields of 71–94% were obtained across a range of alkyl bromide and nitroxide substrates, with reaction times of 1–16 h. The method is compatible with carboxylic acid and amine functionalities.

Nitroxide-Mediated Radical Ring-Opening Copolymerization: Chain-End Investigation and Block Copolymer Synthesis

Well-defined, degradable copolymers are successfully prepared by nitroxide-mediated radical ring opening polymerization (NMrROP) of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) or methyl methacrylate (MMA), a small amount of acrylonitrile (AN) and cyclic ketene acetals (CKAs) of different structures. Phosphorous nuclear magnetic resonance allows in-depth chain-end characterization and gives crucial insights into the nature of the copoly-mer terminal sequences and the living chain fractions. By using a small library of P(OEGMA-co-AN-co-CKA) and P(MMA-co-AN-co-CKA) as macroinitiators, chain extensions with styrene are performed to furnish (amphiphilic) block copolymers comprising a degradable segment.

Use of Solvent Effects to Improve Control Over Nitroxide-Mediated Polymerization of Isoprene

The use of 1,4-dioxane or pyridine as solvents for the polymerization of isoprene mediated by the acid-functional SG1-based alkoxyamines N-(2-methylpropyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)-O-(2-carboxylprop-2-yl)hydroxylamine (BlocBuilder MA) and N-(2-methylpropyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)-O-(2-carboxyleth-2-yl)hydroxylamine results in an increase in the rate of consumption of the initiator and narrower molecular weight distributions of the resulting polymer. In pyridine, an improved control of the polymerization was also obtained for a non-acid-functional initiator, and the overall rate of polymerization increased. These effects are likely to be the result of the disruption of intramolecular hydrogen bonding and, in the case of pyridine, stabilization of the polar SG1 free radical.

Unprecedented solvent-induced acceleration of free-radical propagation of methyl methacrylate in ionic liquids

The rate of propagation in the free-radical polymerization of methyl methacrylate in an ionic liquid has been determined and shows unprecedented solvent-induced acceleration, partially explaining the surprising increase in overall rates of polymerization and molecular weights in these solvents.

Scope and limitations of the nitroxide-mediated radical ring-opening polymerization of cyclic ketene acetals

The ring-opening polymerization of cyclic ketene acetals (CKAs) by controlled radical mechanisms represents an alternative route for the synthesis of aliphatic polyesters. For the first time, 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) and 2-methylene-4-phenyl-1,3-dioxolane (MPDL) were homopolymerized by nitroxide mediated polymerization (NMP), from the commercially available SG1-based BlocBuilder MA alkoxyamine. Various experimental conditions (i.e., reaction temperature, nature of solvent, and nature of the alkyl initiating radical) were varied to determine the optimized conditions in terms of polymerization kinetics and living character of the final polymer. Chain-end extensions from either PS-SG1 or PBMDO-SG1 were also performed in order to furnish PS-b-PBMDO and PBMDO-b-PS, respectively, thus demonstrating the synthesis of block copolymers comprising a CKA block. In order to have a better insight into the polymerization mechanism, the occurrence of side reactions was analyzed by 31P NMR spectroscopy and ESI-MS. It was supposed that the ketal-based macroradical could be irreversibly trapped by nitroxide and thus the corresponding macroalkoxyamine decomposed by CO–N bond dissociation. DFT calculations as well as PREDICI modeling were also undertaken in order to support this hypothesis.

Copper mediated living radical polymerisation: interactions between monomer and catalystBased on the presentation given at Dalton Discussion No. 6, 9?11th September 2003, University of York, UK.

The mechanism of copper(I) mediated living radical polymerisation (ATRP) of vinyl monomers has been widely assumed to be relatively simple. However, monomer reactivity ratios in ATRP can be significantly different from those in conventional radical polymerisation, and the exact nature of the catalyst is not well understood due to rapid exchange of ligand and monomer at the copper centre under the polymerisation conditions. This paper illustrates aspects of this catalyst system, which complicate the accepted mechanism of this new and important reaction. Coordination of aminoethyl methacrylates and methoxy[poly(ethylene glycol)] methacrylate monomers is demonstrated by NMR with rMMA = 0.96(2), 0.98(1) and 0.97(1) for dimethylaminoethyl methacrylate (DMAEMA), (diethylamino)ethyl methacrylate (DEAEMA) and (tert-butylamino)ethyl methacrylate (TBAEMA) under free radical polymerisation and 0.74(3), 0.79(3) and 0.69(3) for transition-metal mediated polymerisation.

Synthesis of functional polymers by living radical polymerisationBasis of a presentation given at Materials Discussion No. 6, 12?14th September 2003, Durham, UK.Electronic supplementary information (ESI) available: synthesis and characterization of initiators 2, 3 and 5?7. See http://www.rsc.org/suppdata/jm/b3/b303759b/

The use of copper(I) halides in conjunction with pyridine imine ligands is reported to lead to a range of controlled molecular weight and architecture polymers. The use of multifunctional initiators leads to di-, tri- and tetra-functional star polymers based on pentaerythritol cores. The polymerisations all follow excellent first order kinetics with Mn increasing linearly with conversion. The polymerisation is first order in copper halide. A range of α-functional polymers with 4-[(4-chloro-6-methoxy-1,3,5-triazin-2-yl)amino]phenyl 2-bromo-2-methylpropionate, N-hydroxysuccinimide and phthalimide have been prepared which introduce terminal functionality into polymers for subsequent coupling and potential synthesis of conjugates for biologically active compounds. Finally block/graft amphiphilic copolymers are demonstrated via the preparation of a statistical copolymer macroinitiator containing a hydroxy functionality which is used for the polymerisation of dimethylaminoethyl methacrylate prior to esterification of the hydroxy functionality to give living radical polymerisation initiators which are used subsequently in the polymerisation of methyl methacrylate. Copper(I) mediated living radical polymerisation is shown to be an effective method for the synthesis of a range of functional synthetic polymers.