Synthesis of microspheres stabilized sterically with two-component grafted chains by dispersion copolymerizations using mixture of two macromonomers in nonaqueous media

The polymer microspheres were synthesized by dispersion copolymerization of divinylbenzene (DVB) with two vinylbenzyl-terminated poly(ethylene glycol methylether) (PEG)/poly(t-butyl methacrylate) (PBMA) macromonomer blends in methanol. In these systems of two macromonomer blends as the emulsifier, the polymer microspheres formed had a very narrow particle size distribution. Two macromonomers formed comicelles with DVB monomer and acted not only as the comonomer but also as the stabilizer. Such polymer microspheres were stabilized sterically with two-component grafted chains, such as PEG and PBMA, in methanol.     

Side‐chain crystallization behavior of graft copolymers consisting of amorphous main chain and crystalline side chains: Poly(methyl methacrylate)‐graft‐poly(ethylene glycol) and poly(methyl acrylate)‐graft‐poly(ethylene glycol)

Graft copolymers consisting of amorphous main chain, poly(methyl methacrylate) (PMMA), or poly(methyl acrylate) (PMAc), and crystalline side chains, poly(ethylene glycol) (PEG), have been prepared by copolymerization of PEG macromonomers with methyl methacrylate or methyl acrylate (MMAx or MACx, respectively). Because of the compatibility of PMMA/PEG and PMAc/PEG, from small‐angle X‐ray scattering results, the main and side chains in graft copolymers were suggested to be homogeneous in the molten state. Differential scanning calorimetry (DSC) cooling scans revealed that PEG side chains for graft copolymers with large PEG fractions were crystallized when the sample was cooled, with a cooling rate of 10 °C/min. The spherulite pattern observed by a polarized optical microscope suggested the growth of PEG crystalline lamellae. Crystallization of PEG in MMAx was more restrained than in MACx. From these results, we have concluded that the crystallization behavior of the grafted side chains is strongly influenced by the glass transition of a homogeneously molten sample as well as dilution of the crystallizable chains. Domain spacings for isothermally crystallized graft copolymers were described by interdigitating chain packing in crystalline–amorphous lamellar structure. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 79–86, 2005     

Synthesis and characterization of novel pH-responsive microgels based on tertiary amine methacrylates

Emulsion polymerization of 2-(diethylamino)ethyl methacrylate (DEA) in the presence of a bifunctional cross-linker at pH 8-9 afforded novel pH-responsive microgels of 250-700 nm diameter. Both batch and semicontinuous syntheses were explored using thermal and redox initiators. Various strategies were evaluated for achieving colloidal stability, including charge stabilization, surfactant stabilization, and steric stabilization. The latter proved to be the most convenient and effective, and three types of well-defined reactive macromonomers were examined, namely, monomethoxy-capped poly(ethylene glycol) methacrylate (PEGMA), styrene-capped poly[2-(dimethylamino)ethyl methacrylate] (PDMA50-St), and partially quaternized styrene-capped poly[2-(dimethylamino)ethyl methacrylate] (10qPDMA50-St). The resulting microgels were pH-responsive, as expected. Dynamic light scattering and 1H NMR studies confirmed that reversible swelling occurred at low pH due to protonation of the tertiary amine groups on the DEA residues. The critical pH for this latex-to-microgel transition was around pH 6.5-7.0, which corresponds approximately to the known pKa of 7.0-7.3 for linear PDEA homopolymer. The microgel particles were further characterized by electron microscopy and aqueous electrophoresis studies. Their swelling and deswelling kinetics were investigated by turbidimetry. The PDEA-based microgels were compared to poly[2-(diisopropylamino)ethyl methacrylate] (PDPA) microgels prepared with identical macromonomer stabilizers. These PDPA-based microgels had a lower critical swelling pH of around pH 5.0-5.5, which correlates with the lower pKa of PDPA homopolymer. In addition, the kinetics of swelling for the PDPA microgels was somewhat slower than that observed for PDEA microgels; presumably this is related to the greater hydrophobic character of the former particles.     

Nanosphere formation in copolymerization of methyl methacrylate with poly(ethylene glycol) macromonomers

Polymeric nanospheres consisting of poly(methyl methacrylate) (PMMA) cores and poly(ethylene glycol) (PEG) branches on their surfaces were prepared by free radical copolymerization of methyl methacrylate (MMA) with PEG macromonomers in ethanol/water mixed solvents. PEG macromonomers having a methacryloyl (MMA‐PEG) and p‐vinylbenzyl (St‐PEG) end group were used. It has become clear that the obtained polymer dispersions form three kinds of states, particle dispersion (milky solution), clear solution, and gel/precipitation. It was found that the reaction parameters such as MMA concentration, molecular weight, and concentration of PEG macromonomers, and water content can affect nanosphere formation in a copolymerization system. The water volume fraction of mixed ethanol/water solvents affected the particle size of the nanospheres. These differences in the formation of nanospheres were due to the solvophilic/solvophobic balance between the copolymers and solvents during the self‐assembling process of the copolymers. The sizes of nanospheres can be controlled by varying concentration of PEG macromonomer and water content in solvents. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1811–1817, 2000     

Surface-grafted polystyrene beads with comb-like poly(ethylene glycol) chains: preparation and biological application

We prepared surface-grafted polystyrene (PS) beads with comb-like poly(ethylene glycol) (PEG) chains. To accomplish this, conventional gel-type PS beads (35-75 microm) were treated with ozone gas to introduce hydroperoxide groups onto the surface. Using these hydroperoxide groups, poly(methyl methacrylate) (PMMA, Mn= 22,000-25,000) was grafted onto the surface of the PS beads. The ester groups of the grafted PMMA were reduced to hydroxyl groups with lithium aluminum hydride (LAH). After adding ethylene oxide (EO) to the hydroxyl groups, we obtained the PS-sg-PEG beads, which had a rugged surface and a diameter of 80-150 microm. We could obtain several kinds of the PS-sg-PEG beads by controlling the chain lengths of the grafted PMMA and the molecular weights of the PEG chains. The grafted PEG layer was about 30-50 microm thick, which was verified from the cross-sectioned views of the fluorescamine-labeled beads. These fluorescence images proved that the beads possessed a pellicular structure. Furthermore, we found that the surface-grafted PEG chains had the characteristic property of reducing non-specific protein adsorption on the beads.     

Synthesis of Porous PEG Microgels Using CaCO3 Microspheres as Hard Templates

Porous poly(ethylene glycol) (PEG) microgels of both 17.6 and 8.3 μm in diameter are synthesized via hard templating with calcium carbonate (CaCO₃) microparticles. The synthesis is performed in three steps: loading of PEG macromonomers into CaCO₃ microparticles, crosslinking via photopolymerization, and removal of the CaCO₃ template under acidic conditions. The resulting porous PEG microgels are inverse replicates of their templates as indicated by light microscopy, cryo‐scanning electron microscopy (cryo‐SEM), and permeability studies. Thus this process allows for the straightforward and highly reproducible synthesis of porous hydrogel particles of two different diameters and porosities that show great potential as carriers for drugs or nanomaterials.     

Effect of molecular weight on synthesis and surface morphology of high-density poly(ethylene glycol) grafted layers

This work describes studying the permanent grafting of carboxylic acid end-functionalized poly(ethylene glycol) methyl ether (PEG) chains of different molecular weights from the melt onto a surface employing poly(glycidyl methacrylate) ultrathin film as an anchoring layer. The grafting led to the synthesis of the complete PEG brushes possessing exceptionally high grafting density. The maximum thickness of the attached PEG films was strongly dependent on the length of the polymer chains being grafted. The maximum grafting efficiency was close to the critical entanglement molecular weight region for PEG. All grafted PEG layers were in the "brush regime", since the distance between grafting sites for the layers was lower than the end-to-end distance for the anchored macromolecules. Scanning probe microscopy revealed that the grafting process led to complete PEG layers with surface smoothness on a nanometric scale. Practically all samples were partly or fully covered with crystalline domains that disappeared when samples were scanned under water. Due to the PEG hydrophilic nature, the surface with the grafted layer exhibited a low (up to 21 degrees ) water contact angle.     

Brush‐like poly(ethylene glycol) grafting on SiO2 nanoparticles with in‐situ polymerization

This work presents the grafting of poly(ethylene glycol) (PEG) on the SiO₂ nanoparticles by the use of the azo‐groups bonded SiO₂ as a radical initiator and poly(ethylene glycol) methyl ether methacrylate (PEGMA) as a macromonomer, respectively. Then a kind of organic–inorganic composite particles with brush‐like PEG fixed covalently on the SiO₂ nanoparticles, SiO₂–PEG, is synthesized. The successful synthesis of SiO₂–PEG is confirmed by FT‐IR, XPS, and TEM techniques. Results show that the conversion degree of PEGMA can reach nearly 30% while the PEG graft amount accounts for ca. 43% of the total weight of the composite particles. After the PEG is grafted on the SiO₂ nanoparticles, the mobility of PEG chains is hindered by the proximity of oxide phase of SiO₂. As a result, PEG phase is strongly disturbed. Consequently, the grafted PEG melts at a low temperature with small quantity of heat enthalpy. Copyright © 2014 John Wiley & Sons, Ltd.     

Plum-pudding gels as a platform for drug delivery: understanding the effects of the different components on the diffusion behavior of solutes

The internal structure of composite gels made of responsive microgel particles inserted into a bulk hydrogel (N-isopropylacrylamide microgel particles in a cross-linked dimethylacrylamide matrix) has been investigated from the diffusion behavior of poly(ethylene glycol) (PEG) probes through the network, in the absence of specific interactions between the diffusing molecules and the system. The effect of the different components has been examined, for example, the size of the probe, the bulk structure, and the microgel nature. Particles were characterized prior to their insertion into the hydrogel in order to describe their properties as a function of size and cross-linker content, thus revealing different swelling behaviors. The biggest effects on the diffusion of the PEG probes were related to the bulk structure, and no major effects were registered by the addition of different microgels into the hydrogel network. We attempt to rationalize this behavior in terms of the composite gel structure and discuss the results in terms of their meaning for controlled drug delivery strategies.     

Synthesis and characterization of PEGylated comb-like cationic polymer by polycondensation and ATRP

PEGylated poly(2-(dimethylamino)ethyl methacrylate) with comb-like architecture was synthesized by two-step polymerization. First,poly(oligo(ethylene glycol) malicate)(POEGMA) bearing pendant hydroxyl groups was prepared by direct polycondensation of oligo(ethylene glycol) and malic acid in the presence of scandium triflate as chemoselective catalyst.Then the poly(2- (dimethylamino)ethyl methacrylate) side chains were grafted from the POEGMA backbone by atom transfer radical polymerization (ATRP) after the hydroxyl groups were modified into bromo-ester form,resulting in a PEGylated cationic copolymer with branched architecture.     

Synthesis and Characterization of Novel pH‐Responsive Polyampholyte Microgels

Summary: We synthesized for the first time novel pH‐responsive polyampholyte microgels consisting of poly(methacrylic acid) and poly(2‐(diethylamino)ethyl methacrylate) (PMAA‐PDEA) that are sterically stabilized with poly(ethylene glycol) methyl ether methacrylate (PEGMEM). These microgels showed enhanced hydrophilic behavior in aqueous medium at low and high pH but become hydrophobic and compact between pH 4 and 6 near the isoelectric point. Dynamic‐light scattering measurements showed that the hydrodynamic radius, R_h of these microgels is approximately 100 nm between pH 4 and 6 and increases to around 140 and 170 nm at pH 2 and 10, respectively. It is evident that the cross‐linked MAA‐DEA microgel that is sterically stabilized with PEGMEM retains the polyampholyte properties in solution.

Sterically stabilized cross‐linked MAA‐DEA microgel.     

Inverse microemulsion polymerization of sterically stabilized polyampholyte microgels

Polyampholyte microgels consisting of various compositions of poly(methacrylic acid) and poly(2-(dimethylamino)ethyl methacrylate) (PMAA-PDMA) cross-linked with allyl methacrylate (AM) were synthesized via the inverse microemulsion polymerization (IMEP) technique. To improve colloidal stability at the isoelectric point (IEP), steric stabilization via the grafting of poly(ethylene glycol) methyl ether methacrylate (PEGMA) on the surface of the microgel was performed. Potentiometric and conductometric titration showed good agreement between the targeted and experimental compositions of the microgel systems. The microgel swelled at low and high pH and possessed a compact structure near the IEP, and the diameter were in good agreement with data from the transmission electron microscopic (TEM) analyses. With increasing pH, the mobility decreased from +2 m(2)s(-1)V (1) at pH 2 to -2 m(2)s(-1)V (1) at pH 10. An empirical relationship describing the PMAA composition and IEP was proposed, where the IEP decreased with increasing PMAA content. The microgel exhibited thermal-responsive properties at high pH, which is dictated by the lower critical solution temperature of PDMA.     

Connection of poly(methyl methacrylate) microgel particles dispersed in poly(vinyl alcohol) matrix by seed polymerization

Poly(methyl methacrylate) microgels covered with poly(hydroxyethyl methacrylate) thin layer was dispersed in poly(vinyl alcohol) matrix. Homogeneous and regular arrangement of the microgel particles was suggested by Bragg diffraction for the films prepared by varying the PVA/microgel ratio (from 6/4 to 3/7 (w/w)). It was proved that the regular arrangement and connection of the microgels by seeded polymerization in poly(vinyl alcohol) were possible. © 1996 John Wiley & Sons, Inc.     

Synthesis and aqueous solution properties of sterically stabilized pH-responsive polyampholyte microgels

Emulsion copolymerization of poly(methacrylic acid) and poly(2-(diethylamino)ethyl methacrylate) (PMAA/PDEA) yielded pH-responsive polyampholyte microgels of 200-300 nm in diameter. These microgels showed enhanced hydrophilic behavior in aqueous medium at low and high pH, but formed large aggregates of approximately 2500 nm at intermediate pH. To achieve colloidal stability at intermediate pH, a second batch of microgels of identical monomer composition were synthesized, where monomethoxy-capped poly(ethylene glycol)methacrylate (PEGMA) was grafted onto the surface of these particles. Dynamic light-scattering measurements showed that the hydrodynamic radius, Rh, of sterically stabilized microgels was approximately 100 nm at intermediate pH and increased to 120 and 200 nm at pH 2 and 10, respectively. Between pH 4 and 6, these microgels possessed mobility close to zero and a negative second virial coefficient, A2, due to overall charge neutralization near the isoelectric pH. From the Rh, mobility, and A2, cross-linked MAA-DEA microgels with and without PEGMA retained their polyampholytic properties in solution. By varying the composition of MAA and DEA in the microgel, it is possible to vary the isoelectric point of the colloidal particles. These new microgels are being explored for use in the delivery of DNA and proteins.     

New Biocompatible Microgels

Summary: Microgel particles have received an increasing interest in the biomedical field. Temperature-sensitive microgels gained particular interest due to their potential use as controlled drug delivery systems. With the objective to produce new thermoresponsive biocompatible microgels, the synthesis and characterization of two families of microgel particles obtained by using N-vinylcaprolactam (VCL) as main monomer and N,N′-methylenbisacrylamide (BA) or poly(ethylene glycol) diacrylate (PEGDA) as crosslinkers are described. Evidence of hydrolysis VCL during polymerization is also presented.     

Poly(ethylene glycol) as a biointeractive electron‐beam resist

Poly(ethylene glycol) (PEG) can serve as an electron‐beam (e‐beam) resist to modulate protein adsorption on and cell adhesion to surfaces. PEG preferentially crosslinks under e‐beam irradiation to create microgels with controllable properties. Here, atomic‐force, scanning electron, and confocal microscopies are used to study discrete microgels formed from solvent‐cast PEG thin films by focused e‐beams with energies between 2 and 30 keV and point doses between 10 and 1000 fC. Consistent with experimental findings, Monte Carlo simulation of electron energy deposition identifies three structures within each microgel: a highly crosslinked core near the point of electron incidence; a lightly crosslinked near corona surrounding the core; and a far corona at the PEG–Si interface. The nature and relative sizes of these three regions and, hence, the microgel–protein interactions depend on the incident electron energy and dose. The far corona creates protein‐repulsive surface hundreds of nanometers or more from the microgel core. The highly crosslinked core is largely shielded by the near corona. These findings can help guide the choice of irradiation conditions to most effectively modulate protein–surface interactions via PEG microgels patterned by e‐beam lithography. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2013 , 51, 1543–1554     

Side‐chain crystallization behavior of graft copolymers consisting of an amorphous main chain and crystalline side chains. II. Poly(n‐hexyl methacrylate)‐graft‐poly(ethylene glycol)

The phase behavior and crystallization of graft copolymers consisting of poly(n‐hexyl methacrylate) (PHMA) as an amorphous main chain and poly(ethylene glycol) (PEG) as crystallizable side chains (HMAx with 15 ≤ x ≤ 73, where x represents the weight percentage of PEG) were investigated. Small‐angle X‐ray scattering profiles measured above the melting temperature of PEG suggested that a microdomain structure with segregated PHMA and PEG domains was formed in HMA40 and HMA46. This phase behavior was qualitatively described by a calculated phase diagram based on the mean‐field theory. Because of the segregation of PEG into microdomains, the crystallization temperature of the PEG side chains in HMAx was higher than that in poly(methyl acrylate)‐graft‐poly(ethylene glycol) having a similar value of x, which was considered to be in a disordered state above the melting temperature. In HMAx with x ≤ 40, PEG crystallization was strongly restricted, probably because the PEG microdomains were isolated in the PHMA matrix. As a result, the growth of PEG spherulite was not observed because the PEG crystallization occurred after vitrification of the PHMA segregated domains. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 45: 129–137, 2007     

PPEGMEA‐g‐PDEAEMA: Double hydrophilic double‐grafted copolymer stimuli‐responsive to both pH and salinity

A series of well‐defined double hydrophilic double‐grafted copolymers, consisting of polyacrylate backbone, hydrophilic poly(2‐(diethylamino)ethyl methacrylate) and poly(ethylene glycol) side chains, were synthesized by successive atom transfer radical polymerization. The backbone, poly[poly(ethylene glycol) methyl ether acrylate] (PPEGMEA) comb copolymer, was firstly prepared by ATRP of PEGMEA macromonomer via the grafting‐through route followed by reacting with lithium diisopropylamide and 2‐bromopropionyl chloride to give PPEGMEA‐Br macroinitiator of ATRP. Finally, poly[poly(ethylene glycol) methyl ether acrylate]‐g‐poly(2‐(diethylamino)ethyl methacrylate) graft copolymers were synthesized by ATRP of 2‐(diethylamino)ethyl methacrylate using PPEGMEA‐Br macroinitiator via the grafting‐from route. Poly(2‐(diethylamino)ethyl methacrylate) side chains were connected to polyacrylate backbone through stable C? C bonds instead of ester connections, which is tolerant of both acidic and basic environment. The molecular weights of both backbone and side chains were controllable and the molecular weight distributions kept relatively narrow (M_w/M_n ≤ 1.39). The results of fluorescence spectroscopy, dynamic laser light scattering and transmission electron microscopy showed this double hydrophilic copolymer was stimuli‐responsive to both pH and salinity. It can aggregate to form reversible micelles in basic surroundings which can be conveniently dissociated with the addition of salt at room temperature. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3142–3153, 2009     

Synthesis and mass cytometric analysis of lanthanide-encoded polyelectrolyte microgels

This article describes the synthesis and characterization of two series of functional polyelectrolyte copolymer microgels intended for bioassays based upon mass cytometry, a technique that detects metals by inductively coupled plasma mass spectrometry (ICP-MS). The microgels were loaded with Eu(III) ions, which were then converted in situ to EuF(3) nanoparticles (NPs). Both types of microgels are based upon copolymers of N-isopropylacrylamide (NIPAm) and methacrylic acid (MAA), poly(NIPAm/VCL/MAA) (VCL = N-vinylcaprolactam, V series), and poly(NIPAm/MAA/PEGMA) (PEGMA = poly(ethylene glycol)methacrylate, PG series). Very specific conditions (full neutralization of the MAA groups) were required to confine the EuF(3) NPs to the core of the microgels. We used mass cytometry to measure the number and the particle-to-particle variation of Eu ions per microgel. By controlling the amount of EuCl(3) added to the neutralized microgels. we could vary the atomic content of individual microgels from ca. 10(6) to 10(7) Eu atoms, either in the form of Eu(3+) ions or EuF(3) NPs. Leaching profiles of Eu ions from the hybrid microgels were measured by traditional ICP-MS.     

Synthesis of double hydrophilic graft copolymer containing poly(ethylene glycol) and poly(methacrylic acid) side chains via successive ATRP

A well‐defined double hydrophilic graft copolymer, with polyacrylate as backbone, hydrophilic poly(ethylene glycol) and poly(methacrylic acid) as side chains, was synthesized via successive atom transfer radical polymerization followed by the selective hydrolysis of poly(methoxymethyl methacrylate) side chains. The grafting‐through strategy was first used to prepare poly[poly(ethylene glycol) methyl ether acrylate] comb copolymer. The obtained comb copolymer was transformed into macroinitiator by reacting with lithium diisopropylamine and 2‐bromopropionyl chloride. Afterwards, grafting‐from route was employed for the synthesis of poly[poly(ethylene glycol) methyl ether acrylate]‐g‐poly(methoxymethyl methacrylate) amphiphilic graft copolymer. The molecular weight distribution of this amphiphilic graft copolymer was narrow. Poly(methoxymethyl methacrylate) side chains were connected to polyacrylate backbone through stable C? C bonds instead of ester connections. The final product, poly[poly(ethylene glycol) methyl ether acrylate]‐g‐poly(methacrylate acid), was obtained by selective hydrolysis of poly(methoxymethyl methacrylate) side chains under mild conditions without affecting the polyacrylate backbone. This double hydrophilic graft copolymer was found be stimuli‐responsive to pH and ionic strength. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4056–4069, 2008