Preparation of biodegradable microspheres by anionic dispersion polymerization with PLA copolymeric dispersion stabilizer

We prepared poly(d,l-lactide) (PLA) microspheres by anionic dispersion polymerization of d,l-lactide. The polymerization was carried out in xylene/heptane (1:2 in v/v) mixture solution at 368 K for 9 h, with poly(dodecyl methacrylate)-co-poly[α-methacryloxyethoxy-poly(l-lactide)] (PDMA-co-P(MA-PLLA)) synthesized in this study, as a dispersion stabilizer. The number-averaged diameter and diameter distribution (coefficient of variation) of obtained PLA microspheres ranged from 180 to 800 nm and 14–40%, respectively, depending on the preparation condition. Furthermore, the time courses of monomer conversion, particle diameter, and particle number were investigated to clarify the formation mechanism of microspheres with PDMA-co-P(MA-PLLA) as a dispersion stabilizer. From this experiment, we found that the aggregation of primary particles occurred in anionic dispersion polymerization, and the particle diameter of obtained PLA microspheres decreased with increasing PDMA-co-P(MA-PLLA) concentration. In conclusion, we clarified that PDMA-co-P(MA-PLLA) effectively contributed to the stability of primary particles.     

Preparation of nanoparticle colloids of methoxy poly(ethylene glycol)-<Emphasis Type="Italic">b</Emphasis>-poly(<Emphasis Type="SmallCaps">D</Emphasis>,<Emphasis Type="SmallCaps">L</Emphasis>-lactide): effects of surfactant and organic solvent

Nanoparticle colloids of methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (MPEG-b-PDLL) diblock copolymer were prepared by a modified spontaneous emulsification solvent diffusion method using acetone/ethanol as the mixture organic solvents. The MPEG-b-PDLL was synthesized by ring-opening polymerization of D,L-lactide using stannous octoate and MPEG with molecular weight of 5,000 g/mol as the initiating system. The MPEG-b-PDLL obtained was an amorphous polymer with molecular weight of 73,600 g/mol. Influences of acetone/ethanol (v/v) ratios and Tween 80 surfactant concentrations on characteristics of the colloidal nanoparticles were investigated and discussed. Light-scattering analysis showed that average diameters of the surfactant-free colloidal nanoparticles were in the range of 86–124 nm. The nanoparticle sizes decreased as the ethanol ratio increased. The Tween 80 did not show the significant effect on the nanoparticle sizes. Scanning electron micrographs of dried nanoparticles that demonstrated the aggregation of most particles suggested they were the soft nanoparticles. However, the dried nanoparticle morphology can be observed from scanning electron microscopy as having a spherical shape and smooth surfaces.     

Mechanism of particle formation and kinetics of the dispersion polymerization of cyclic esters

Pseudoanionic and anionic polymerizations of ε-caprolactone and lactides in 1,4-dioxane:heptane mixtures containing poly(dodecyl acrylate)-g-poly(ε-caprolactone) yield polyesters in form of microspheres. Monitoring partition of active centers between solution and microspheres revealed that particles are formed during initial period, when macromolecules reach their critical masses (ca. 1 000) and became insoluble. Then, propagation proceeds inside of microspheres into which monomer diffuses from solution. Monitoring of variation of the number of particles in a unit volume of reaction mixture with time indicated that after a primary nucleation the delayed nucleation and aggregation are absent. In effect, microspheres with narrow diameter distribution are obtained. Kinetic measurements revealed that in the dispersion pseudoanionic (initiator (CH₃CH₂)₂AlOCH₂CH₃) and anionic (initiator (CH₃)₃SiONa) polymerizations of ε-caprolactone the overall rates of monomer conversion are from 10 to 30 times higher than for the corresponding polymerizations in solution (THF solvent). Analysis of kinetic equations indicated that the observed faster monomer conversions in polymerizations in dispersed systems are due to the high local concentrations of active centers and monomer in growing microspheres.     

Thermal properties of amphiphilic biodegradable triblock copolymer of <Emphasis Type="SmallCaps">l</Emphasis>,<Emphasis Type="SmallCaps">l</Emphasis>-lactide and ethylene glycol

Samples of poly(l,l-lactide)-block-poly(ethylene glycol)-block-poly(l,l-lactide) (PLLA-PEG-PLLA) were synthesized from l,l-lactide polymerization using stannous 2-ethylhexanoate, Sn(Oct)₂ as initiator and di-hydroxy-terminated poly(ethylene glycol) (PEG) (M _n  = 4000 g mol⁻¹) as co-initiator. The chemical linkage between the PEG segment and the PLA segments was characterized by Fourier transform infrared spectroscopy (FTIR). Thermogravimetry analysis (TG) revealed the copolymers composition and was capable to show the deleterious effect of an excess of Sn(Oct)₂ in the polymer thermal stability, while Differential Scanning Calorimetry (DSC) allowed the observation of the miscibility between the PLLA and PEG segments in the different copolymers.     

Benzo-12-crown-4 modified N-heterocyclic carbene for organocatalyst: Synthesis,characterization and degradation of block copolymers of ϵ-caprolactone with L-lactide

A set of poly(L-lactide)-poly(?-caprolactone) diblock copolymers (AB) and poly(L-lactide)-poly(?-caprolactone)-poly(L-lactide) triblock copolymers (ABA) with predictable molecular weights and relatively narrow distributions were synthesized by ring-opening polymerization of successively added ?-caprolactone (?-CL) and L-lactide (LLA) using 4-methyl benzo-12-crown-4 imidazol-2-ylidene as catalyst. The effects of polymerization conditions, such as reaction time, temperature, monomer/catalyst molar ratio and monomer concentration on the copolymerization have been discussed in detail. The resulting copolymers were characterized by ¹H-NMR, ¹³C-NMR, IR, GPC and DSC methods which confirmed the successful synthesis of block copolymers of LLA and ?-CL. Hydrolytic degradation of the polymers showed that the PLLA-PCL-PLLA copolymer exhibited faster degradation as compared with the PCL homopolymer in alkaline medium at 37°C.     

Molecularly imprinted polymer based on chemiluminescence imaging for the chiral recognition of dansyl-phenylalanine

A new molecularly imprinted polymer (MIP)–chemiluminescence (CL) imaging detection approach towards chiral recognition of dansyl-phenylalanine (Phe) is presented. The polymer microspheres were synthesized using precipitation polymerization with dansyl-l-Phe as template. Polymer microspheres were immobilized in microtiter plates (96 wells) using poly(vinyl alcohol) (PVA) as glue. The analyte was selectively adsorbed on the MIP microspheres. After washing, the bound fraction was quantified based on peroxyoxalate chemiluminescence (PO-CL) analysis. In the presence of dansyl-Phe, bis(2,4,6-trichlorophenyl)oxalate (TCPO) reacted with hydrogen peroxide (H₂O₂) to emit chemiluminescence. The signal was detected and quantified with a highly sensitive cooled charge-coupled device (CCD). Influencing factors were investigated and optimized in detail. Control experiments using capillary electrophoresis showed that there was no significant difference between the proposed method and the control method at a confidence level of 95%. The method can perform 96 independent measurements simultaneously in 30 min and the limits of detection (LODs) for dansyl-l-Phe and dansyl-d-Phe were 0.025 μmol L⁻¹ and 0.075 μmol L⁻¹ (3σ), respectively. The relative standard deviation (RSD) for 11 parallel measurements of dansyl-l-Phe (0.78 μmol L⁻¹) was 8%. The results show that MIP-based CL imaging can become a useful analytical technology for quick chiral recognition.     

Tri-component diblock copolymers of poly(ethylene glycol)–poly(ε-caprolactone-<Emphasis Type="Italic">co</Emphasis>-lactide): synthesis,characterization and loading camptothecin

Biodegradable tri-component diblock copolymer was synthesized by bulk copolymerization of ε-caprolactone (CL) and D, L-lactide (LA) in the presence of methoxy poly(ethylene glycol) (MePEG), using stannous octoate as catalyst. Their chemical structure and physical properties were investigated by GPC, NMR, DSC, TGAand XRD. The increase of CL/LA ratio in the diblock copolymer leads to lower T _g, higher decomposition temperature and crystallinity. Nanoparticles formulated from MePEG–poly(CL-co-LA) (PCAE) possess spherical structure, which was characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The DLS results indicate that the particle size increased with the increase of CL/LA ratio and the hydrophobic fragment length in the copolymer. The drug encapsulation efficiency and the drug release behavior in vitro conditions of camptothecin were measured by high performance liquid chromatography (HPLC). The encapsulation efficiency can be achieved as high as 84.4% and the release behavior can be made well-controlled. MePEG–poly(CL-co-LA) nanoparticles might have a great potential as carriers for hydrophobic drugs.     

Chiral effects of alkyl-substituted derivatives of N,O-bismethacryloyl ethanolamine on the performance of one monomer molecularly imprinted polymers (OMNiMIPs)

New monomers were synthesized and evaluated for their molecular imprinting performance by a recently discovered methodology referred to as one monomer molecularly imprinted polymers (OMNiMIPs). The structural design of the new monomers was based on a lead compound methacrylamidoethyl methacrylate (1) used for the synthesis of OMNiMIP1, and introduced alkyl groups of various sizes at the α-amino position of the lead compound. Enantioselectivity, determined by liquid chromatography, was used to compare the performance of the imprinted polymers. Methyl substitution provided crosslinker 5 (2-methacrylamidopropyl methacrylate), which upon imprint polymerization afforded OMNiMIP5 with approximately the same enantioselectivity (α = 3.8) as OMNiMP1 (α = 3.7) made with the lead compound (1). The other two monomers (6 and 7) with larger alkyl substitutions (isopropyl and sec-butyl respectively) resulted in OMNiMIPs with low selectivity values (α = 1.0 and 1.2 respectively). Last, a strong influence of diastereomeric complexes on OMNiMIP5 selectivity was determined, with L/L and D/D monomer/template pairs giving α values of 3.6–3.8, while L/D and D/L monomer/template pairs had α values of 2.3–2.4. There is no intrinsic enantioselectivity seen for the OMNiMIP5 control polymer made without template at all, giving an α value of 1.03. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Synthesis of monodispersed poly(acrylonitrile) microspheres by dispersion polymerization in compressed liquid dimethyl ether

In this study, monodispersed spherical particles of poly(acrylonitrile) were synthesized via dispersion polymerization in compressed liquid dimethyl ether using 2,2′-azobisisobutyronitrile (AIBN) as an initiator and five kinds of surfactants: PDMS-g-pyrrolidonecarboxylic acid (Monasil PCA™), PDMS modified surfactants, SS-5050K™, KF-6017™, poly(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10- heptadecafluorodecyl acrylate), and poly(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate). Using Monasil PCA as a surfactant, uniform and spherical polymer particles were generated. The size of the microsphere particles was reduced via an increase in the concentration of Monasil PCA and a reduction in the monomer concentration. Increases in the concentration of AIBN resulted in a broad distribution of microspheres. Reaction temperature and pressure did not exert significant effects on the size and size distribution of the polymer particles.     

Shape-memory and biocompatibility properties of segmented polyurethanes based on poly(L-lactide)

A series of segmented poly(L-lactide)-polyurethanes (PLA-PUs) were synthesized by a two-step method, with oligo-poly(L-lactide) (PLA) as the soft segments and the reaction product of 2,4-toluene diisocyanate (TDI) and ethylene glycol (EG) as the hard segments. The shape-memory properties and biocompatibility of PLA-PUs were examined. The 50% compressed PLA-PUs could recover almost 100% to their original shape within 10°C from the lowest recovery temperature (22°C–37°C). In the recovery process the PLA-PU showed a maximum contracting stress in the range of 1.5–4 MPa. Cell incubation experiments show that PLA-PU has biocompatibility comparable to that of pure PLA. Therefore, this kind of polyurethane can be used for implanted medical devices with shape memory requirements. __________ Translated from Chemical Journal of Chinese Universities, 2007, 28(2): 371–375 [译自: 高等学校化学学报]     

Enzymatic hydrolysis of poly(D, L-lactide) spread monolayers by cutinase

 The enzymatic hydrolysis of a model poly(D,L-lactide) by cutinase was studied by using a barostat surface balance. A theoretical approach based on the adaptation of the Michaelis–Menten scheme at the interface and a process of random fragmentation of the macromolecules was developed. The role of the interfacial organisation of the reaction products was discussed. Hydrolysis rate constant values and the specific activity were estimated and compared with those obtained for the hydrolysis of lipid monolayers. The process of fragmentation of the interfacial polymer structures was visualised by using AFM imaging. Received: 19 August 1996 Accepted: 13 December 1996     

Synthesis and characterization of a functionalized amphiphilic diblock copolymer: MePEG-b-poly(DL-lactide-co-RS-β-malic acid)

A class of novel amphiphilic diblock copolymer of MePEG-b-poly(DL-lactide-co-RS-β-malic acid) has been synthesized via the hydrogenation over palladium on charcoal of MePEG-b-poly(DL-lactide-co-RS-β-benzyl malolactonate), which was prepared by ring-opening copolymerization of DL-lactide and RS-β-benzyl malolactonate (MABz) using methyl-polyethylene glycol (MePEG) as the initiator and stannous octoate as the catalyst. The influence of copolymerization temperature, reaction time, macro-initiator (MePEG-5000) proportion and monomer ratio was studied. Gel permeation chromatography measurements revealed that the molecular weight decreased with increasing MABz feeding dose. The configurational structures of the protected and de-protected copolymers were determined by ¹³C nuclear magnetic resonance (NMR), ¹H NMR and Fourier transform infrared. A water-swollen core of the nanospheres formed from the de-protected copolymer was discovered by transmission electron microscopy measurement. Additionally, the degradation experiments indicated that more hydrophilic malic acid content led to higher degradation rate.     

Synthesis and characterization of poly(styrene/α-t-butoxy-ω-vinylbenzyl-polyglycidol) microspheres

Polystyrene microspheres with polyglycidol (polyGL) in a surface layer were synthesized in batch radical emulsifier-free emulsion copolymerizations of styrene and surfmers, α-t-butoxy-ω-vinylbenzyl-polyGL macromonomers (VB-polyGL). Macromonomers with number-average molecular weight Mˉ _n=950 (VB-polyGL950) and Mˉ _n=2700 (VB-polyGL2700) were used for these polymerizations. In all syntheses the initial concentrations of styrene and initiator (K₂S₂O₈) were constant. The initial macromonomer-to-styrene ratios were varied from 1.10 × 10⁻³ to 1.64 × 10⁻² mol/mol and from 3.46 × 10⁻⁴ to 3.47 × 10⁻³ mol/mol for VB-polyGL950 and VB-polyGL2700, respectively. The diameters of microspheres obtained were smaller for the syntheses with higher concentrations of macromonomers. Syntheses with VB-polyGL950 yielded microspheres with number-average diameters (Dˉ _n) from 216 to 900 nm and with a bimodal diameter distribution. The number-average diameters of microspheres obtained with VB-polyGL2700 varied from 220 to 650 nm, depending on the initial concentration of macromonomer. Their diameter distributions were monomodal, with a diameter polydispersity parameter (ratio of weight-average and number-average diameters) in the range 1.007≤Dˉ _w/Dˉ _n≤1.022. For each type of microsphere the fraction of polyGL in a surface layer and the surface concentration of sulfate anions were determined. The fraction of polyGL in the surface layer was related to the initial monomer composition in the polymerizing mixture. Adsorption of human serum albumin onto surfaces of some poly(styrene/VB-polyGL) microspheres was up to 10 times lower than for the polystyrene microspheres obtained in a similar emulsifier-free emulsion polymerization of styrene. Received: 26 September 2000/Accepted: 19 February 2001     

Preparation and optical properties of novel bioactive photonic crystals obtained from core-shell poly(styrene/α-<Emphasis Type="Italic">tert</Emphasis>-butoxy-ω-vinylbenzyl-polyglycidol) microspheres

Optical properties of polymer microspheres with polystyrene cores and polyglycidol-enriched shells poly(styrene/α-tert-butoxy-ω-vinylbenzyl-polyglycidol) (P(S/PGL) particles with number average diameters D _n determined by scanning electron microscopy equal 237 and 271 nm), were studied before and after immobilization of ovalbumin. The particles were synthesized by emulsifier-free emulsion copolymerization of styrene and polyglycidol macromonomer (poly(styrene/α-tert-butoxy-ω-vinylbenzyl-polyglycidol)) initiated with potassium persulfate. Molar fraction of polyglycidol units in the interfacial layer of the microspheres determined by XPS was equal 42.6 and 34.0%, for the particles with D _n equal 137 and 271 nm, respectively. Colloidal crystals from the aforementioned particles were prepared by deposition of particle suspensions on the glass slides and subsequent evaporation of water. It was found that optical properties of colloidal crystals from the P(S/PGL) microspheres strongly depend on modification of their interfacial layer by covalent immobilization of ovalbumin. The coating of particles with ovalbumin resulted in decreasing their refractive index from 1.58 to 1.52.     

Mixtures poly((<Emphasis Type="Italic">R</Emphasis>)-3-hydroxybutyrate) and poly(<Emphasis Type="SmallCaps">l</Emphasis>-lactic acid) subjected to DSC

Blends of bacterial poly((R)-3-hydroxybutyrate) (PHB) and poly(l-lactic acid) (PLLA) synthesized by polycondensation of l-lactic acid or by ring-opening polymerization of l-lactide were studied. Miscibility was investigated through both conventional differential scanning calorimetry (DSC) and temperature-modulated DSC (TMDSC). PHB and low-molar mass PLLA were miscible in a whole concentration range, and a single glass transition temperature was observed. On the other hand, PHB/high-molar mass PLLA mixtures phase separate, giving rise to two glass transition temperatures corresponding to PHB and PLLA. A treatment of blends at 190 °C leads to formation of block/multiblock/random copolymers, and blends become miscible.     

Magnetic microsphere-based methods to study the interaction of teicoplanin with peptides and bacteria

Teicoplanin (teic) from Actinoplanes teichomyceticus is a glycopeptide antibiotic used to treat many Gram-positive bacterial infections. Glycopeptide antibiotics inhibit bacterial growth by binding to carboxy-terminal d-Ala-d-Ala intermediates in the peptidoglycan of the cell wall of Gram-positive bacteria. In this paper we report the derivatization of magnetic microspheres with teic (teic-microspheres). Fluorescence-based techniques have been developed to analyze the binding properties of the microspheres to two d-Ala-d-Ala terminus peptides. The dissociation constant for the binding of carboxyfluorescein-labeled d-Ala-d-Ala-d-Ala to teic on microspheres was established via fluorimetry and flow cytometry and was determined to be 0.5 × 10⁻⁶ and 3.0 × 10⁻⁶ mol L⁻¹, respectively. The feasibility of utilizing microparticles with fluorescence methods to detect low levels (the limit of bacterial detection was determined to be 30 colon-forming units; cfu) of Gram-positive bacteria has been demonstrated. A simple microfluidic experiment is reported to demonstrate the possibility of developing microsphere-based affinity assays to study peptide–antibiotic interaction.     

Effects of the reaction parameters on the properties of thermosensitive poly(N‐isopropylacrylamide) microspheres prepared by precipitation and dispersion polymerization

Poly(N‐isopropylacrylamide) (PNIPAAm)‐based microspheres were prepared by precipitation and dispersion polymerization. The effects of several reaction parameters, such as the type and concentration of the crosslinker (N,N′‐methylenebisacrylamide or ethylene dimethacrylate), medium polarity, concentration of the monomer and initiator, and polymerization temperature, on the properties were examined. The hydrogel microspheres were characterized in terms of their chemical structure, size and size distribution, and morphological and temperature‐induced swelling properties. A decrease in the particle size was observed with increasing polarity of the reaction medium or increasing concentration of poly(N‐vinylpyrrolidone) as a stabilizer in the dispersion polymerization. The higher the content was of the crosslinking agent, the lower the swelling ratio was. Too much crosslinker gave unstable dispersions. Although the solvency of the precipitation polymerization mixture controlled the PNIPAAm microsphere size in the range of 0.2–1 μm, a micrometer range was obtained in the Shellvis 50 and Kraton G 1650 stabilized dispersion polymerizations of N‐isopropylacrylamide in toluene/heptane. Typically, the particles had fairly narrow size distributions. Copolymerization with the functional glycidyl methacrylate monomer afforded microspheres with reactive oxirane groups. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 968–982, 2006     

Spirocyclic bisphenoxides of Ge,Zr, and Sn as catalysts for ring-expansion polymerizations of l- and meso-lactide

Spirocyclic phenoxides of germanium, zirconium, and tin were prepared from 2,2′-dihydroxybiphenyl and 2,2′-dihydroxy-1,1′-binaphthyl. Ring-expansion polymerizations of l -lactide are mainly studied at 160 or 180 °C. The reactivity of the catalysts increases in the order: Zr < Ge < Sn. Regardless of catalyst, the weight-average molecular weights (M_w) never exceed 50,000 g mol⁻¹. The resulting poly(l -lactide)s are optically pure and have a cyclic architecture. Decreasing temperature and time favor formation of even-numbered cycles, and at 102° cyclics, almost free of odd-numbered rings are obtained. Analogous polymerizations of meso-lactide give similar results >120 °C, but different results at 100 or 80 °C. Surprisingly, bell-shaped narrow molecular weight distributions are obtained <140 °C, resembling the pattern of living polymerizations found for alcohol-initiated polymerizations. An unusual transesterification mechanism yielding narrow distributions of odd-numbered cycles is discovered too. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2730–2738     

Precipitation polymerization of <Emphasis Type="Italic">N-tert</Emphasis>-butylacrylamide in water producing monodisperse polymer particles

The precipitation polymerizations of N-tert-butylacrylamide (NtBAM) in water are demonstrated; for example, the polymerization with potassium peroxodisulfate using a 15 g L⁻¹ (118 mmol L⁻¹) concentration of NtBAM in the feed ([NtBAM]₀) was performed at 70 °C for 12 h, quantitatively producing poly(N-tert-butylacrylamide) particles with a number-average diameter (d _n) of 203 nm and a coefficient of variation (C _v) of 4.7%. The particle sizes were controlled in the d _ns range between 75 and 494 nm by changing the monomer feeds or adding an electrolyte such as NaCl. The solid contents in the resulting aqueous latex solutions ranged from 0.1 to 1.5%, whereas it increased to 4.8% by applying a “shot-growth” technique. The polymerization in water under a somewhat unique condition is described, which was started from a heterogeneous system due to the presence of significantly large amounts of monomers ([NtBAM]₀ = 50 g L⁻¹). This also provided monodisperse latexes with the d _n of 370 nm in 96% yield, in which the solid content reached 4.9%.     

Poly(<Emphasis Type="SmallCaps">l</Emphasis>-lactide) networks with tailored water sorption

A poly(l-lactide) diol was obtained through ring opening polymerization of l-lactide, using 1,6 hexanediol and tin(II) 2 ethylhexanoate as a catalyst. In the second step, the poly(l-lactide) macromer (mLA) was obtained by the reaction of poly(l-lactide) diol with methacrylic anhydride. The effective incorporation of the polymerizable end groups was assessed by Fourier transform infrared spectroscopy and nuclear magnetic resonance (¹H NMR). Besides, poly(l-lactide) networks (pmLA) were prepared by photopolymerization of mLA. Further, the macromer was copolymerized with 2-hydroxyethyl acrylate seeking to tailor the hydrophilicity of the system. A set of hydrophilic copolymer networks were obtained. The phase microstructure of the new system and the network architecture was investigated by differential scanning calorimetry, infrared spectroscopy, dynamic mechanical spectroscopy, thermogravimetry, and water sorption studies.