Core‐shell microspheres with surface grafted poly(vinyl alcohol) as drug carriers for the treatment of hepatocellular carcinoma

Core(polyvinyl neodecanoate‐ethylene glycol dimethacrylate)‐shell(polyvinyl alcohol) (core (P(VND‐EGDMA))‐shell(PVA)) microspheres were developed by seeded polymerization with the use of conventional free radical and RAFT/MADIX mediated polymerization. Poly(vinyl pivalate) PVPi was grafted onto microspheres prepared via suspension polymerization of vinylneodecanoate and ethylene glycol dimethacrylate. The amount of grafted polymer was found to be independent from the technique used with conventional free radical polymerization and MADIX polymerization resulting into similar shell thicknesses. Both systems—grafting via free radical polymerization or the MADIX process—were found to follow slightly different kinetics. While the free radical polymerization resulted in a weight gain linear with the monomer consumption in solution the growth in the MADIX controlled system experienced a delay. The core‐shell microspheres were obtained by hydrolysis of the poly(vinyl pivalate) surface grafted brushes to form poly(vinyl alcohol). During hydrolysis the microspheres lost a significant amount of weight, consistent with the hydrolysis of 40–70% of all VPi units. Drug loading was found to be independent of the shell layer thickness, suggesting that the drug loading is governed by the amount of bulk material. The shell layer does not appear to represent an obstacle to the drug ingress. Cell testing using colorectal cancer cell lines HT 29 confirm the biocompatibility of the empty microspheres whereas the clofazimine loaded particles lead to 50% cell death, confirming the release of the drug. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 3256–3272, 2007     

Raft polymerization of N,N‐dimethylacrylamide from magnetic poly(2‐hydroxyethyl methacrylate) microspheres to suppress nonspecific protein adsorption

Nonspecific interaction is a key parameter affecting the efficiency of proteins, nucleic acids or cell separation. Currently, many approaches to introduce antifouling properties to materials have been developed. Among these, surface modification with polymer brushes plays a prominent role. The aim of this study was to synthesize new magnetic microspheres grafted with poly(N,N‐dimethylacrylamide) (PDMA) that resist nonspecific protein adsorption. Monodisperse macroporous poly(2‐hydroxyethyl methacrylate) (PHEMA) microspheres, 4 μm in size, were synthesized by a multiple swelling polymerization method. To render the microspheres magnetic, iron oxide was precipitated inside the microsphere pores. Functional carboxyl groups, introduced by the hydrolysis of the 2‐(methacryloyl)oxyethyl acetate (HEMA‐Ac) comonomer, were used to react with propargylamine, followed by coupling of a chain transfer agent via an azide‐alkyne click reaction. PDMA was grafted from the PHEMA microspheres using reversible addition‐fragmentation chain transfer polymerization (RAFT), resulting in surfaces with more than 81 wt % PDMA attached. The successful modification of the microspheres was confirmed by XPS. The magnetic microspheres grafted with PDMA showed excellent antifouling properties as tested in bovine serum protein solutions. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1036–1043     

Surface modification of polymeric microspheres using glycopolymers for biorecognition

We report the synthesis and characterization of sugar-containing microspheres consisting of poly(divinylbenzene) (PDVB) cores onto which chains of galactose- or mannose-bearing polymers have been grafted. PDVB particles prepared by distillation polymerization with a diameter of 2.4 μm containing residual surface vinyl groups were used as starting material. “Grafting from”, “grafting through” and “grafting to” techniques were performed and special interest was laid towards the resulting grafting densities. The surface modification via “grafting from” was conducted by reversible addition fragmentation chain transfer (RAFT) polymerization directly from the surface, whereas thiol-ene chemistry was used to affix glycopolymer chains onto the particle surface. The resulting sugar-covered microspheres were analyzed towards their protein recognition activity with a series of lectins.     

Influence of a reversible addition–fragmentation chain transfer agent in the dispersion polymerization of styrene

Dispersion polymerization was applied to the controlled/living free‐radical polymerization of styrene with a reversible addition–fragmentation chain transfer (RAFT) polymerization agent in the presence of poly(N‐vinylpyrrolidone) and 2,2′‐azobisisobutyronitrile in an ethanol medium. The effects of the polymerization temperature and the postaddition of RAFT on the polymerization kinetics, molecular weight, polydispersity index (PDI), particle size, and particle size distribution were investigated. The polymerization was strongly dependent on both the temperature and postaddition of RAFT, and typical living behavior was observed when a low PDI was obtained with a linearly increased molecular weight. The rate of polymerization, molecular weight, and PDI, as well as the final particle size, decreased with an increased amount of the RAFT agent in comparison with those of traditional dispersion polymerization. Thus, the results suggest that the RAFT agent plays an important role in the dispersion polymerization of styrene, not only reducing the PDI from 3.34 to 1.28 but also producing monodisperse polystyrene microspheres. This appears to be the first instance in which a living character has been demonstrated in a RAFT‐mediated dispersion polymerization of styrene while the colloidal stability is maintained in comparison with conventional dispersion polymerization. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 348–360, 2007     

Chromatographic performance of molecularly imprinted polymers: Core‐shell microspheres by precipitation polymerization and grafted MIP films via iniferter‐modified silica beads

In this work, two different surface imprinting formats have been evaluated using thiabendazole (TBZ) as model template. The first format is a thin film of molecularly imprinted polymer (MIP) grafted from preformed silica particles using an immobilized iniferter‐type initiator (inif‐MIP). The second format is molecularly imprinted polymer microspheres with narrow particle size distribution and core‐shell morphology prepared by precipitation polymerization in a two‐step procedure. For the latter format, polymer microspheres (the core particles) were obtained by precipitation polymerization of divinylbenzene‐80 (DVB‐80) in acetonitrile. Thereafter, the core particles were used as seed particles in the synthesis of MIP shells by copolymerization of DVB‐80 and methacrylic acid in the presence of TBZ in a mixed solvent porogen (acetonitrile/toluene). The materials were characterized by elemental microanalysis, nitrogen sorption porosimetry and scanning (and transmission) electron microscopy. Thereafter, the imprinted materials were assessed as stationary phases in liquid chromatography. From this study it can be concluded that grafted MIP beads can be obtained in a simple and direct manner, consuming only a fraction of the reagents used typically to prepare imprinted particles from a monolithic imprinted polymer. Such materials can be used in the development of in‐line molecularly imprinted solid‐phase extraction methods. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1058–1066, 2010     

Reversible addition fragmentation chain transfer polymerization of sterically hindered monomers: Toward well‐defined rod/coil architectures

The sterically hindered monomers dibutyl itaconate (DBI) and dicyclohexyl itaconate (DCHI) were polymerized via reversible addition fragmentation chain transfer (RAFT) free‐radical polymerization. S,S′‐Bis(α,α′‐dimethyl‐α″‐acetic acid) trithiocarbonate, cumyl dithiobenzoate, and cumyl phenyldithioacetate have been used as RAFT agents to mediate a series of polymerizations at 65 °C yielding rod polymers ranging in number average molecular weight from 9000 to 92,000 g mol^?1. The progress of the polymerization was followed via online Fourier transform–near infrared spectroscopy. The polydispersity indices of the obtained rod polymers were relatively high at 1.4–1.7. The RAFT polymerizations of the hindered monomers used in the present study displayed both ideal living and hybrid behavior between conventional and living polymerization, depending on the RAFT agent used. DCHI rod polymers generated via the RAFT process were subsequently reinitiated in the presence of styrene to produce a range of BAAB and A‐B rod‐coil block copolymers of molecular weights up to 164,000 g mol^?1. The chain extension yields molecular weight distributions that progressively shift to higher molecular weights and are unimodal. Thermogravimetric analysis of the pDCHI‐block‐pStyrene copolymers indicates thermal degradation in two separate steps for the pDCHI and pStyrene blocks. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2432–2443, 2004     

Efficient Surface Modification of Divinylbenzene Microspheres via a Combination of RAFT and Hetero Diels‐Alder Chemistry

A combination of reversible addition fragmentation chain transfer (RAFT) polymerization and hetero Diels‐Alder (HDA) chemistry has been utilized to successfully generate functional core‐shell microspheres. Initially, precipitation polymerization in conjunction with the RAFT technique has been employed to synthesize divinylbenzene (DVB) microspheres with surface expressed RAFT groups. Subsequently, HDA cycloaddition has been performed under mild reaction conditions (50 °C, 24 h) with a diene‐functionalized poly(ε‐caprolactone) (PCL). While the successful grafting is immediately evident by optical inspection of the microspheres (color change from purple to white), X‐ray photoelectron spectroscopy (XPS), and attenuated total reflectance spectroscopy (ATR) were additionally employed to characterize the chemical composition and surface functionalization of the microspheres. Further, confocal microscopy was used to confirm the presence of grafted PCL chains after labeling them with rhodamine B.

     

Functionalized multi‐walled carbon nanotubes with poly(N‐(2‐hydroxypropyl)methacrylamide) by RAFT polymerization

In this study, we grafted water‐soluble biocompatible polymer, poly(N‐(2‐hydroxypropyl)methacrylamide) (PHPMA), onto the surface of multi‐walled carbon nanotubes (MWNTs). The reversible addition‐fragmentation chain transfer (RAFT) agents, dithioesters, were successfully immobilized onto the surface of MWNTs first, PHPMA chains were then subsequently grafted onto MWNTs via RAFT polymerization by using dithioesters immobilized on MWNTs as RAFT agent. FTIR, XPS, ¹H NMR, Raman and TGA were used to characterize the resulting products and to determine the content of water‐soluble PHPMA chains in the product. The MWNTs grafted with PHPMA chains have good solubility in distilled water, PBS buffer, and methanol. TEM images of the samples provide direct evidence for the formation of a nanostructure that MWNTs coated with polymer layer. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 2419–2427, 2006     

RAFT of sulfobetaine for modifying poly(glycidyl methacrylate) microspheres to reduce nonspecific protein adsorption

The minimization of nonspecific protein adsorption is a crucial step in the development of bioseparation processes, immunoassays, and affinity diagnostics. Among the numerous biomaterials, polyzwitterions are known to effectively suppress protein and cell adhesion. This article describes the formation of monodisperse polymer microspheres coated with polysulfobetaine with the aim to limit nonspecific adsorption of bovine serum albumin (BSA) as a model protein. In this process, 2‐μm poly(glycidyl methacrylate) (PGMA) microspheres were prepared by dispersion polymerization. To render the microspheres hydrophilic and biocompatible, [3‐(methacryloylamino)propyl]dimethyl(3‐sulfopropyl)ammonium hydroxide (MPDSAH) was grafted from the surface by reversible addition‐fragmentation chain transfer (RAFT) polymerization. Elemental analysis of the modified microspheres revealed up to 20 wt % of poly{[3‐(methacryloylamino)propyl]dimethyl(3‐sulfopropyl)ammonimum hydroxide} (PMPDSAH). The microspheres were characterized in terms of particle size, morphology, and zeta potential. The amount of BSA nonspecifically adsorbed on the PMPDSAH‐modified microspheres decreased to half of that captured on the unmodified PGMA microspheres. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2273–2284     

Effect of rate retardation in RAFT grafting polymerization from silicon wafer surface

Polystyrene and poly(butyl acrylate) were grafted from silicon wafer surface by reversible addition‐fragmentation chain transfer (RAFT) polymerization. Three RAFT agents were immobilized onto silicon wafer through their leaving/initiating groups (R group). Grafting polymerization of butyl acrylate (BA) and styrene (St) was then carried out from the immobilized RAFT agents. The immobilization of the RAFT agents and the subsequent grafting polymerization of St and BA were evaluated by ellipsometry and X‐ray photoelectron spectroscopy. It was found that type of monomer, structure of RAFT agent, and local RAFT concentration on the surface have dramatic influences on the thickness of grafted polymer layer. The grafting polymerization with more severe rate retardation effect yielded thinner polymer films on the silicon wafer. Selection of a RAFT agent with little rate retardation was critical in the grafting polymerization to achieve thick films. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 970–978, 2008     

Preparation of nanocomposites by reversible addition‐fragmentation chain transfer polymerization from the surface of quantum dots in miniemulsion

Herein, we report the synthesis of quantum dots (QDs)/polymer nanocomposites by reversible addition‐fragmentation chain transfer (RAFT) polymerization in miniemulsions using a grafting from approach. First, the surfaces of CdS and CdSe QDs were functionalized using a chain transfer agent, a trisalkylphosphine oxide incorporating 4‐cyano‐4‐(thiobenzoylsulfanyl)pentanoic acid moieties. Using a free radical initiator (AIBN) to activate the RAFT process, a polystyrene (PS) block was grafted from the surface of the QDs. Quantum confinement effects were identified for the nanocomposite obtained, so attesting to the integrity of the QDs after the polymerization. Free PS chains were also present in the final nanocomposite, indicating that the RAFT polymerization from the surface of the QDs was accompanied by conventional free radical polymerization. After isolating the nanocomposite particles, a second poly(n‐butyl acrylate) block was tentatively grown from the initial PS block. The first results indicated a successful polymerization of the second polymer and show the potential of the current strategy to prepare block copolymers from the surface of the RAFT‐modified QDs. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5367–5377, 2009     

Polymerization of styrene in alcohol/water mediated by a macro‐RAFT agent of poly(N‐isopropylacrylamide) trithiocarbonate: From homogeneous to heterogeneous RAFT polymerization

The reversible addition fragmentation chain transfer (RAFT) polymerization of styrene in alcohol/water mixture mediated with the poly(N‐isopropylacrylamide) trithiocarbonate macro‐RAFT agent (PNIPAM‐TTC) is studied and compared with the general RAFT dispersion polymerization in the presence of a small molecular RAFT agent. Both the homogeneous/quasi‐homogeneous polymerization before particle nucleation and the heterogeneous polymerization after particle nucleation are involved in the PNIPAM‐TTC‐mediated RAFT polymerization, and the two‐stage increase in the molecular weight (M_n) and nanoparticle size of the synthesized block copolymer is found. In the initial homogeneous/quasi‐homogeneous polymerization, the M_n and nanoparticle size slowly increase with monomer conversion, whereas the M_n and particle size quickly increase in the subsequent heterogeneous RAFT polymerization, which is much different from those in the general RAFT dispersion polymerization. Besides, the PNIPAM‐TTC‐mediated RAFT polymerization runs much faster than the general RAFT dispersion polymerization. This study is anticipated to be helpful to understand the polymer chain extension through RAFT polymerization under dispersion conditions. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Immobilization of RAFT agents on silica nanoparticles utilizing an alternative functional group and subsequent surface‐initiated RAFT polymerization

Silica–polystyrene core‐shell particles were successfully prepared by surface‐mediated reversible addition fragmentation chain transfer (RAFT) polymerization of styrene monomer from the surfaces of the silica‐supported RAFT agents. Initially, macro‐RAFT agents were synthesized by RAFT polymerization of γ‐methacryloxypropyltrimethoxysilane (MPS) in the presence of chain transfer agents (CTAs). Immobilization of CTAs onto the silica surfaces was then performed by reacting silica with macro‐RAFT agents via a silane coupling. Grafting of polymer onto silica forms core‐shell nanostructures and shows a sharp contrast between silica core and polymer shell in the phase composition. The thickness of grafted‐polymer shell and the diameter of core‐shell particles increase with the increasing ratio of monomer to silica. A control experiment was carried out by conventional free radical emulsion copolymerization of MPS‐grafted silica and styrene under comparable conditions. The resulting data provide further insight into the chemical composition of grafted‐polymers that are grown from the silica surface through RAFT process. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 467–484, 2009     

Facile Access to Hydroxy‐Functional Core–Shell Microspheres via Grafting of Ethylene Oxide by Anionic Ring‐Opening Polymerization

We present a facile access route to hydroxy‐functional narrow disperse microspheres of well‐defined grafting density (GD). Ethylene oxide has been grafted from highly crosslinked poly(divinyl benzene) microspheres by anionic ring‐opening polymerization using sec‐butyllithium as activator together with the phosphazene base t‐BuP₄. Initially, core microspheres have been prepared by precipitation polymerization utilizing divinyl benzene (DVB, 80 wt.‐%). The grafting of poly(ethylene oxide) (PEO) from the surface resulted in the formation of functional core–shell microspheres with hydroxy‐terminal end groups. The number average particle diameter of the grafted microspheres was 3.6 µm and the particle weight increased by 5.7%. The microspheres were characterized by SEM, FT‐IR spectroscopy, elemental analysis, and fluorescence microscopy. The surface GD (determined via two methods) was 1.65 ± 0.06 and 2.09 ± 0.08 chains · nm⁻², respectively.

     

Synthesis of densely grafted comblike copolymers

Densely grafted copolymers were synthesized using the “grafting from” approach via the combination of reversible addition‐fragment chain transfer polymerization (RAFT) and atom transfer radical polymerization (ATRP). First, a novel functional monomer, 2,3‐di(2‐bromoisobutyryloxy)ethyl acrylate (DBPPA), with two initiating groups for ATRP was synthesized. It was then polymerized via RAFT polymerization to give macroinitiators for ATRP with controlled molecular weights and narrow molecular weight distributions. Last, ATRP of styrene was carried out using poly(DBPPA)s as macroinitiators to prepare comblike poly(DBPPA)‐graft‐polystyrenes carrying double branches in each repeating unit of backbone via “grafting from” approach. Furthermore, poly(DBPPA)‐graft‐[polystyrene‐block‐poly(t‐BA)]s and their hydrolyzed products poly(DBPPA)‐graft‐[polystyrene‐block‐poly(acrylic acid)]s were also successfully prepared. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 362–372, 2008     

Kinetic modeling of controlled living microemulsion polymerizations that use reversible addition–fragmentation chain transfer

Reversible addition–fragmentation chain transfer (RAFT) polymerization is a useful technique for the formation of polymers with controlled architectures and molecular weights. However, when used in the polymerization of microemulsions, RAFT agents are only able to control the polymer molecular weight only at high RAFT concentrations. Here, a kinetic model describing RAFT microemulsion polymerizations is derived that predicts the reaction rates, molecular weight polydispersities, and particle size. The model predicts that at low RAFT concentrations, the RAFT agent will be consumed early in the reaction and that this will result in uncontrolled polymerization in particles nucleated late in the reaction. The higher molecular weight polydispersity that is observed in RAFT microemulsion polymerizations is the result of this uncontrolled polymerization. The model also predicts a shift in the conversion at which the maximum reaction rate occurs and a decrease in the particle size with increasing RAFT concentration. Both of these trends are also consistent with those observed experimentally. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6055–6070, 2006     

Atom‐transfer radical grafting polymerization of 2‐methacryloyloxyethyl phosphorylcholine from silicon wafer surfaces

2‐Methacryloyloxyethyl phosphorylcholine (MPC), a biomimetic monomer, was grafted from silicon wafer surfaces at room temperature by combining self‐assembly of initiator and surface‐initiated atom transfer radical polymerization. Two methods were used to control the grafting process. One was to add free initiator to the reaction system; the other was to add excess deactivator. The grafting densities up to 0.3 chains/nm² were obtained. The surface thickness increased linearly with MPC conversion. The thickness depended on catalyst and monomer concentrations, as well as activator/deactivator ratio. Poly(MPC) layers of >100 nm thick were obtained by optimizing the polymerization conditions. A second block of either poly(MPC) or poly[2‐(dimethylamino)ethyl methacrylate] was also grown from the grafted poly(MPC), demonstrating the system livingness. X‐ray photoelectron spectroscopy was used to examine the surface chemical compositions showed good agreement with the theoretical values. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2931–2942, 2004     

Reactive poly(glycidyl methacrylate) microspheres prepared by dispersion polymerization

Poly(glycidyl methacrylate) [poly(GMA)] microspheres of narrow size distribution were prepared in a simple one‐step procedure by dispersion radical polymerization. Depending on the solvent used, poly(GMA) particle size could be controlled in the range of 0.5–4 μm by changing the solubility parameter of the reaction mixture. In N,N′‐dimethylformamide (DMF)/methanol mixture, the particle size increased and the size distribution broadened with decreasing initial solubility parameter. While in the DMF/methanol solvent system, hydroxypropyl cellulose (HPC) or cellulose acetate butyrate (CAB) were taken as steric stabilizers of the dispersion polymerization, poly(vinylpyrrolidone) (PVP) was used in alcoholic media. Contrary to the DMF/methanol system, narrow particle size distributions were obtained with PVP‐stabilized polymerizations in ethanolic, methanolic, propan‐1‐olic or butan‐1‐olic medium. Both the particle size and polydispersity were reduced with increasing stabilizer concentration. If lower molecular‐weight PVP was used, larger microspheres were obtained. Poly(GMA) samples prepared in a neat alcoholic medium virtually quantitatively retained oxirane group content after the polymerization. Reactivity of the poly(GMA) microspheres was confirmed by their hydrolysis and aminolysis. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3855–3863, 2000     

Well‐defined polyisoprene‐grafted silica nanoparticles via the RAFT process

The preparation of well‐defined polyisoprene‐grafted silica nanoparticles (PIP‐g‐SiO₂ NPs) was investigated. Surface initiated reversible addition fragmentation chain transfer (SI‐RAFT) polymerization was used to polymerize isoprene from the surface of 15 nm silica NPs. A high temperature stable trithiocarbonate RAFT agent was anchored onto the surface of particles with controllable graft densities. The polymerization of isoprene mediated by silica anchored RAFT with different densities were investigated and compared to the polymerization mediated by free RAFT agents. The effects of different temperatures, initiators, and monomer feed ratios on the kinetics of the SI‐RAFT polymerization were also investigated. Using this technique, block copolymers of polyisoprene and polystyrene on the surface of silica particles were also prepared. The well‐defined synthesized PIP‐g‐SiO₂ NPs were then mixed with a polyisoprene matrix which showed a good level of dispersion throughout the matrix. These tunable grafted particles have potential applications in the field of rubber nanocomposites. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 1493–1501     

Facile synthesis of core‐surface crosslinked nanoparticles by interblock RAFT polymerization

A new, efficient method for synthesizing stable nanoparticles with poly(ethylene oxide) (PEO) functionalities on the core surface, in which the micellization and crosslinking reactions occur in one pot, has been developed. First, amphiphilic PEO‐b‐PS copolymers were synthesized by reversible addition fragmentation chain transfer (RAFT) radical polymerization of styrene using (PEO)‐based trithiocarbonate as a macro‐RAFT agent. The low molecular weight PEO‐b‐PS copolymer was dissolved in isopropyl alcohol where the block copolymer self‐assembled as core‐shell micelles, and then the core‐shell interface crosslink was performed using divinylbenzene as a crosslinking agent and 2,2′‐azobisisobutyronitrile as an initiator. The design of the amphiphilic RAFT agent is critical for the successful preparation of core‐shell interface crosslinked micellar nanoparticles, because of RAFT functional groups interconnect PEO and polystyrene blocks. The PEO functionality of the nanoparticles surface was confirmed by ¹H NMR and FTIR. The size and morphology of the nanoparticles was confirmed by scanning electron microscopy, transmission electron microscopy, and dynamic laser light scattering analysis. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010