Abstract
A poly(ethylene glycol) (PEG) macromolecular chain transfer agent (macro-CTA) is prepared in high yield (>95%) with 97% dithiobenzoate chain-end functionality in a three-step synthesis starting from a monohydroxy PEG113 precursor. This PEG113-dithiobenzoate is then used for the reversible addition–fragmentation chain transfer (RAFT) aqueous dispersion polymerization of 2-hydroxypropyl methacrylate (HPMA). Polymerizations conducted under optimized conditions at 50 °C led to high conversions as judged by 1H NMR spectroscopy and relatively low diblock copolymer polydispersities (Mw/Mn < 1.25) as judged by GPC. The latter technique also indicated good blocking efficiencies, since there was minimal PEG113 macro-CTA contamination. Systematic variation of the mean degree of polymerization of the core-forming PHPMA block allowed PEG113-PHPMAx diblock copolymer spheres, worms, or vesicles to be prepared at up to 17.5% w/w solids, as judged by dynamic light scattering and transmission electron microscopy studies. Small-angle X-ray scattering (SAXS) analysis revealed that more exotic oligolamellar vesicles were observed at 20% w/w solids when targeting highly asymmetric diblock compositions. Detailed analysis of SAXS curves indicated that the mean number of membranes per oligolamellar vesicle is approximately three. A PEG113-PHPMAx phase diagram was constructed to enable the reproducible targeting of pure phases, as opposed to mixed morphologies (e.g., spheres plus worms or worms plus vesicles). This new RAFT PISA formulation is expected to be important for the rational and efficient synthesis of a wide range of biocompatible, thermo-responsive PEGylated diblock copolymer nano-objects for various biomedical applications.
Highlights
Recent synthetic advances in polymerization-induced self-assembly (PISA) allow spherical micelles, worm-like micelles or vesicles composed of well-defined AB diblock copolymers to be prepared directly in concentrated aqueous solution via either reversible addition−fragmentation chain transfer (RAFT) dispersion or emulsion polymerization.[32−42] In particular, we have reported robust formulations comprising thermo-responsive PHPMA chains as the hydrophobic core-forming block and either poly(2-methacryloyloxy)ethyl phosphorylcholine (PMPC)[36] or poly(glycerol monomethacrylate) (PGMA)[33,35,41,42] as the hydrophilic stabilizer block
High copolymer concentrations (>17.5% w/w) and relatively long PHPMA blocks produced a remarkable range of nanostructures, including the first observation of oligolamellar vesicles formed during a PISA synthesis
Small-angle X-ray scattering (SAXS) confirms the thermo-responsive nature of these PEG113-PHPMAx nanoobjects, since partial fusion of spherical micelles can be induced by local heating caused by the synchrotron X-ray beam
Summary
It is well-known that conjugation of a hydrophilic poly(ethylene glycol) (PEG; known as poly(ethylene oxide) or PEO) chain to a biologically relevant molecule typically enhances its water solubility and hydrolytic stability.[1,2] In the case of proteins, this so-called ‘PEGylation’ approach can significantly reduce immunogenicity.[1−4] PEGylation can extend in vivo circulation lifetimes for important biomolecules such as insulin, allowing a lower dose frequency and greater patient compliance.[5,6] These attractive properties have led to the recent development of a number of FDA-approved PEGylated therapeutic entities.[1,5] Various PEGylation strategies have been developed, such as the site-specific attachment of PEG chains to proteins via disulfide linkages[6−8] or direct polymerization of oligo(ethylene glycol) methacrylate from specific surface sites on proteins.[3]. As far as we are aware, almost all previous PISA formulations have used macromolecular chain transfer agents (macro-CTAs) derived from various vinyl monomers.[34,36,37,39,43−45] the very few reports of the use of PEG macro-CTAs in heterogeneous media have often achieved only relatively low RAFT end-group functionality (∼85−90%), which inevitably reduces the blocking efficiency.[47−50] a commercially available near-monodisperse monohydroxy-terminated PEG precursor is efficiently converted into a well-defined PEGdithiobenzoate macro-CTA via a high-yielding multistep synthesis involving a monoaminated PEG113 intermediate (see Schemes 1 and S1) This macro-CTA is subsequently utilized to synthesize a wide range of well-defined diblock copolymer nano-objects via the RAFT aqueous dispersion polymerization of HPMA. In addition to the expected spheres, worms and vesicles, oligolamellar vesicles are obtained for the first time using PISA, and this phase is characterized together with a complete chain of self-assembled structural morphologies using transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS)
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