Modified poly(ϵ-caprolactone)s and their use for drug-encapsulating nanoparticles

Poly(ϵ-caprolactone) (PCL)-polydimethylsiloxane diblock and triblock copolymers and poly(ϵ-caprolactone-co-4-ethylcaprolactone) random copolymers were prepared through the homogeneously catalyzed coordination anionic polymerization of ϵ-caprolactone (CL) and the copolymerization of CL with 4-ethyl-ϵ-caprolactone (EtCL) in the presence of hydroxy-terminated polysiloxanes or allyl alcohol as chain-transfer agents, respectively. Polysiloxane precursors with hydroxypropyl or hydroxyethyl propyl ether end groups were obtained by the hydrosilation of the appropriate unsaturated alcohol with monofunctional or difunctional hydro-terminated polysiloxanes of different molecular weights. As proven by differential scanning calorimetry analysis, the presence of siloxane blocks and EtCL units determined the diminished copolymer crystallinity, which was shown by the reduced melting temperatures and enthalpy of fusion with respect to those of pure PCL. Both types of copolymers were found to form, in the presence of a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) emulsifier, monodisperse and stable nanoparticles able to encapsulate different types of bioactive compounds (Vitamin E and indomethacin). © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 689–700, 2004     

Micelle or polymersome formation by PCL-PEG-PCL copolymers as drug delivery systems

Polymeric micelles and polymersomes may have great potential as the drug delivery vehicles for solubilization of hydrophobic drugs.     

Synthesis of an amphiphilic triarm star copolymer based on polystyrene,poly(ethylene oxide) and poly(ε-caprolactone)

The synthesis of an amphiphilic triarm star copolymer based on polystyrene, poly(ethylene oxide) and poly(ε-caprolactone) block has been achieved by a novel strategy which consists in the preparation of a diblock copolymer, polystyrene-block-poly(ethylene oxide), having a protected anionic initiator group at the junction of the two blocks. After deprotection, this function is activated by a coloured and weakly basic carbanion. The generated alcoholate initiates the ε-caprolactone anionic polymerization.     

Water-dispersible Fe3O4 nanoparticles stabilized with a biodegradable amphiphilic copolymer

In this work, we report a green synthetic method using water-dispersible magnetite nanoparticles containing oleic acid and poly(2-ethyl-2-oxazoline)-poly(ɛ-caprolactone) diblock copolymer as the magnetite nanoparticle dispersants. The Fe₃O₄ nanoparticles were prepared by co-precipitation and had a bilayer surface with a hydrophobic inner poly(ɛ-caprolactone) (PCL) layer and hydrophilic corona poly(2-ethyl-2-oxazoline) (POX) blocks. Also, the role of the ultrasonicating treatment's duration on the percent of magnetite in the complex and on its magnetic properties was investigated. Transmission electron microscopy (TEM) showed the average particle size to be about 10–20 nm in diameter for nanoparticles.     

Gold-copolymer nanoparticles: Poly(ε-caprolactone)/poly(N-vinyl-2-pyrrolydone) Biodegradable triblock copolymer as stabilizer and reductant

Block copolymers have been extensively used in the synthesis of many types of nanoparticles, where generally are considered as stabilizer and protective agent. In this work a double function of the biodegradable triblock copolymer poly(N-vinyl-2-pyrrolidone)-b-poly(ε-caprolactone)-b-poly(N-vinyl-2-pyrrolidone), (PVP–PCL–PVP) in the gold nanoparticle-copolymer synthesis is reported.Gold-copolymer composed nanoparticles were synthesized using the triblock copolymer (PVP–PCL–PVP) and potassium tetrachloro aurate (III), both in aqueous solution. The copolymer work as both, reductant and stabilizer agent. The obtained nanoparticles were characterized by FT-IR, dynamic light scattering (DLS), atomic force microscopy (AFM) and transmission electron microscopy (TEM). The shape and the size of the obtained nanoparticles are dependent on the copolymer/salt of gold concentration ratio used in the synthesis.To complement the experimental results about the copolymer role in the nanoparticles synthesis, computational tools were used to characterize the reactivity of the reactant species.     

Liposome-Mediated Delivery of MERS Antigen Induces Potent Humoral and Cell-Mediated Immune Response in Mice

The advancements in the field of nanotechnology have provided a great platform for the development of effective antiviral vaccines. Liposome-mediated delivery of antigens has been shown to induce the antigen-specific stimulation of the humoral and cell-mediated immune responses. Here, we prepared dried, reconstituted vesicles (DRVs) from DPPC liposomes and used them as the vaccine carrier system for the Middle East respiratory syndrome coronavirus papain-like protease (DRVs-MERS-CoV PLpro). MERS-CoV PLpro emulsified in the Incomplete Freund’s Adjuvant (IFA-MERS-CoV PLpro) was used as a control. Immunization of mice with DRVs-MERS-CoV PLpro did not induce any notable toxicity, as revealed by the levels of the serum alanine transaminase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) in the blood of immunized mice. Immunization with DRVs-MERS-CoV PLpro induced greater antigen-specific antibody titer and switching of IgG1 isotyping to IgG2a as compared to immunization with IFA-MERS-CoV PLpro. Moreover, splenocytes from mice immunized with DRVs-MERS-CoV PLpro exhibited greater proliferation in response to antigen stimulation. Moreover, splenocytes from DRVs-MERS-CoV PLpro-immunized mice secreted significantly higher IFN-γ as compared to splenocytes from IFA-MERS-CoV PLpro mice. In summary, DRVs-MERS-CoV PLpro may prove to be an effective prophylactic formulation to prevent MERS-CoV infection.     

Preparation of surfactant-free nanoparticles of methoxy poly(ethylene glycol)-<Emphasis Type="Italic">b</Emphasis>-poly(D,L-lactide-<Emphasis Type="Italic">co</Emphasis>-glycolide-<Emphasis Type="Italic">co</Emphasis>-ɛ-caprolactone)

Surfactant-free nanoparticles of methoxy poly(ethylene glycol)-b-poly(D,L-lactide-co-glycolide-co-ɛ-caprolactone) diblock copolymers (MPEG-b-PDLLGCL) with different DLL:G:CL ratios were prepared by modified-spontaneous emulsification solvent diffusion method. Sizes of resulted colloidal nanoparticles obtained from light-scattering analysis were in the range of 121–132 nm with narrow size distribution. The nanoparticle sizes depended on the composition of the PDLLGCL block. Scanning electron microscopy demonstrated that the nanoparticles were aggregated after drying process, suggested they were soft nanoparticles. However, their initial aggregates can be observed and it was shown that the nanoparticles have spherical shape with smooth surface. The text was submitted by the authors in English.     

New Segmented Copolymers by Combination of Atom Transfer Radical Polymerization and Ring Opening Polymerization

Atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP) were combined to synthesize various polymers with various structures and composition. Poly(ε-caprolactone)-b-poly(n-octadecyl methacrylate), PCL-PODMA, was prepared using both sequential and simultaneous polymerization methods. Kinetic studies on the simultaneous process were performed to adjust the rate of both polymerizations. The influence of tin(II) 2-ethylhexanoate on ATRP was investigated, which led to development of new initiation methods for ATRP, i.e., activators (re)generated by electron transfer (AGET and ARGET). Additionally, block copolymers with two crystalizable blocks, poly(ε-caprolactone)-b-poly(n-butyl acrylate)-b-poly(n-octadecyl methacrylate), PCL-PBA-PODMA, block copolymers for potential surfactant applications poly(ε-caprolactone)-b-poly(n-octadecyl methacrylate-co-dimethylaminoethyl methacrylate), PCL-P(ODMA-co-DMAEMA), and a macromolecular brush, poly(hydroxyethyl methacrylate)-graft-poly(ε-caprolactone), PHEMA-graft-PCL, were prepared using combination of ATRP and ROP.     

Microspheres by dispersion polymerization of lactides and ϵ-caprolactone

Polyester microspheres were synthesized by the ring-opening polymerization of lactides (racemate or optically active L,L-isomer) and ϵ-caprolactone. Polymerizations were carried out in the 1,4-dioxane-heptane mixed solvents in the presence of poly(dodecyl acrylate)-g-poly(ϵ-caprolactone) (poly(DA-CL)) used as surface-active agent. Polymerizations were initiated with tin(II) 2-ethylhexanoate (lactides), diethylaluminum ethoxide or sodium trimethylsilanolate (ϵ-caprolactone). In the studies of the polymerization of lactides, relations were determined between diameters, the distribution of diameters of synthesized microspheres, and the structure of poly(DA-CL). It was found that it is possible, depending on thermal treatment of microspheres after synthesis, to obtain polylactide microspheres differing in the degree of crystallinity. Kinetics of the dispersion pseudoanionic and anionic polymerizations of ϵ-caprolactone were also investigated and the results of these studies were compared with the data for the corresponding polymerizations of ϵ-caprolactone in solution.     

Synthesis and Characterization of Triblock Terpolymers with three Potentially Crystallisable Blocks: Polyethylene-b-poly(ethylene oxide)-b-poly(ε-caprolactone)

A first attempt was made to produce novel ABC triblock terpolymers with three potentially crystallisable blocks: polyethylene (PE), poly(ethylene oxide) (PEO), and poly(ε-caprolactone) (PCL). Polybutadiene-b-poly(ethylene oxide) diblock copolymers were synthesized by living anionic polymerization. Then, a non-catalyzed thermal polymerization of ε-caprolactone from the hydroxyl end group of the PB-b-PEO diblock precursors was performed. Finally, hydrogenation by Wilkinson catalyst produced PE-b-PEO-b-PCL triblock terpolymers. Side reactions were detected that lead to the formation of undesired PCL-b-PEO diblock copolymers, however, these impurities were successfully removed by purification. A range of triblock terpolymers with PCL and PEO minor components were prepared. Topological restrictions on the PEO middle block prevented this block from crystallizing while the complex crystallization behavior of the PE and PCL blocks was documented by DSC and WAXS measurements.     

Uniform antibacterial cylindrical nanoparticles for enhancing the strength of nanocomposite hydrogels

Crystallization-driven self-assembly (CDSA) was employed for the preparation of monodisperse cationic cylindrical nanoparticles with controllable sizes, which were subsequently explored for their effect on antibacterial activity and the mechanical properties of nanocomposite hydrogels. Poly(ɛ-caprolactone)-block-poly(methyl methacrylate)-block-poly[2-(tert-butylamino) ethyl methacrylate] (PCL-b-PMMA-b-PTA) triblock copolymers were synthesized using combined ring-opening and RAFT polymerizations, and then self-assembled into polycationic cylindrical micelles with controllable lengths by epitaxial growth. The polycationic cylinders exhibited intrinsic cell-type-dependent antibacterial capabilities against gram-positive and gram-negative bacteria under physiological conditions, without quaternization or loading of any additional antibiotics. Furthermore, when the cylinders were combined into anionic alginate hydrogel networks, the mechanical response of the hydrogel composite was tunable and enhanced up to 51%, suggesting that cationic polymer fibers with controlled lengths are promising mimics of the fibrous structures in natural extracellular matrix to support scaffolds. Overall, this polymer fiber/hydrogel nanocomposite shows potential as an injectable antibacterial biomaterial, with possible application in implant materials as bacteriostatic agents or bactericides against various infections.     

Preparation and Characterization of PEGylated Thiophilic Nanoparticles for Rapid Antibody Separation

Magnetic nanoparticles with novel core-shell structure were prepared for immunoglobulin (IgG) separation, in which thiophilic property of sulfone groups and protein resistance of poly(ethylene glycol) (PEG) moieties were integrated. The step-wise surface reactions on the nanoparticles were characterized by ¹H nuclear magnetic resonance (NMR) and surface zeta potential measurements. With human IgG and bovine serum albumin (BSA) as model proteins, the effects of PEG chain length, conjugation group, solution pH and salt concentration on IgG selectivity were investigated using static adsorption experiments. The experiment results showed that mPEG2000-NH₂ modified magnetic nanoparticles had an adsorption capacity of 132.8 mg g^?1 and selectivity of 32.5 towards IgG under the condition of pH 7.45 and 0.15 M NaCl. In complex biological fluids, the PEG modified magnetic nanoparticles could separate IgG from fetal calf serum and Omalizumab from cell culture supernatant with purities of 96% and 99%, respectively. Moreover, the binding affinities of the proposed core-shell structure towards IgG from four animal species (human, bovine, rabbit and goat) were quantified by bio-layer interferometer (BLI). The results showed that the selectivity of this structure towards IgG varied from traditional Protein A method, suggesting its potentials in rapid separation and purification of IgG with low affinity towards Protein A.     

Degradation behaviors of star-shaped poly(ethylene glycol)-poly(?-caprolactone) nanoparticles in aqueous solution

Star-shaped poly(ethylene glycol) (PEG)-poly(?-caprolactone) (?-PCL) block copolymers were synthesized via a ring-opening polymerization. Nanoparticles prepared by the precipitation/solvent evaporation technique exhibit a core-shell structure. The hydrolytic degradation of 3-arm PEG-PCL copolymeric nanoparticles was studied by dynamic light scattering (DLS), nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC). It was found that copolymers with shorter PCL block length degraded faster. The sizes of nanoparticles fluctuated during the initial degradation period, and then increased slightly before finally dropping off. The degradation mainly occurred at CL-CL linkages firstly then at the EO-CL linkages. The CL/EO molar ratios and the molecular weights of copolymers decreased as degradation time and a zero-order degradation behavior was observed.     

Synthesis and characterization of aba-type block copolymer of poly(ϵ-caproplactone) with poly(ethylene glycol), by mean of activation end groups

Poly(?-caprolactone)-b-poly(ethylene glycol)-b-poly(?-caprolactone) (PCL-b-PEG-b-PCL) triblock copolymer were synthesized by mean anionic activation of the hydroxyl end groups of poly(ethylene glycol) in presence of diphenylmethylsodium. Copolymers were characterized by SEC, FT-IR and ¹H-NMR spectroscopy, TGA and DSC. Size exclusion chromatographic analysis of obtained copolymers indicated incorporation of CL monomer into PEG without formation of PCL homopolymer. Characterization by FT-IR and ¹H NMR spectroscopy of the resulting polymeric products, with respect to their structure, end-groups and composition, showed that they are best described as ester-ether-ester triblock copolymers, whose compositions can be adjusted changing the feeding molar ratio of PEG to CL. The thermal stability of triblock copolymers was less that PEG precursor, but higher that PCL homopolymer. Analysis by mean DSC showed that all copolymers were semi-crystalline and their thermal behavior depending on their composition.     

MEKC determination of IgG in human serum via a pH‐mediated acid stacking method

An on‐column preconcentration technique, pH‐mediated acid stacking, was used in this study to improve the sensitivity of MEKC‐UV analysis of IgG in human serum. Various parameters affecting pH‐mediated acid stacking were optimized systematically. To eliminate the matrix interferences of human serum and to combine the sample pretreatment procedure with the detection methodology, silica‐coated Fe₃O₄ magnetic nanoparticles modified with N‐(2‐aminoethyl)‐3‐aminopropyl‐trimethoxysilane were prepared and employed as solid phase extraction adsorbent to remove the abundant HSA from human serum. HSA was quantitatively removed by silica‐coated Fe₃O₄ magnetic nanoparticles modified with N‐(2‐aminoethyl)‐3‐aminopropyl‐trimethoxysilanes without retaining IgG at pH 9.3. Under the optimum conditions, the sensitivity of IgG was improved 40.3‐fold using a 100 s electrokinetic injection as compared with a 6 s hydrodynamic injection. The detection limit of IgG was found to be 0.1 mg/L, and the proposed method was successfully applied for the determination of IgG in human serum with satisfactory results.     

Gold-copolymer nanoparticles: Poly(ε-caprolactone)/poly(N-vinyl-2-pyrrolydone) Biodegradable triblock copolymer as stabilizer and reductant

Block copolymers have been extensively used in the synthesis of many types of nanoparticles, where generally are considered as stabilizer and protective agent. In this work a double function of the biodegradable triblock copolymer poly(N-vinyl-2-pyrrolidone)-b-poly(ε-caprolactone)-b-poly(N-vinyl-2-pyrrolidone), (PVP-PCL-PVP) in the gold nanoparticle-copolymer synthesis is reported.Gold-copolymer composed nanoparticles were synthesized using the triblock copolymer (PVP-PCL-PVP) and potassium tetrachloro aurate (III), both in aqueous solution. The copolymer work as both, reductant and stabilizer agent. The obtained nanoparticles were characterized by FT-IR, dynamic light scattering (DLS), atomic force microscopy (AFM) and transmission electron microscopy (TEM). The shape and the size of the obtained nanoparticles are dependent on the copolymer/salt of gold concentration ratio used in the synthesis.To complement the experimental results about the copolymer role in the nanoparticles synthesis, computational tools were used to characterize the reactivity of the reactant species.     

Phase equilibria of poly(ɛ-caprolactone)-<Emphasis Type="Italic">co</Emphasis>-poly(acryl methacrylate)-methylene chloride systems and the phase structure of polymer binary mixtures

Isothermal cross sections of amorphous separation diagrams of the ternary systems poly(ɛ-caprolactone)-co-poly(acryl methacrylate) Eudragite RS-methylene chloride and poly(ɛ-caprolactone)-co-poly(acryl methacrylate) Eudragite E-methylene chloride are obtained via the experimental methods of turbidity points and analytical transmission electron microscopy and the calculation semi-empirical method of constructing boundary lines of phase diagrams. It is shown that the composition of copoly(acryl methacrylate) affects the length of the solubility region in the ternary phase diagram and the character of the anisotropy of films prepared via solvent evaporation. The determination of coordinates of figurative points corresponding to the completion of phase separation shows that the mechanism of phase separation for both systems is of the spinodal type. The specific orientation of polycaprolactone crystallites during film preparation from the poly(ɛ-caprolactone)-Eudragite RS mixture is determined by the morphology of the film formed during solvent evaporation and the phase composition.     

Thermal characterization of biodegradable methoxy poly(ethylene glycol)-b-poly(d,l-lactide)/methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) blend nanoparticles

Biodegradable methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (MPEG-b-PDLL) and methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (MPEG-b-PCL) diblock copolymers were synthesized by ring-opening polymerization of DLL and CL monomers in bulk using stannous octoate, and MPEG as the initiating system. Surfactant-free MPEG-b-PDLL/MPEG-b-PCL blend nanoparticles were prepared by the nanoprecipitation method. The influences of block length and blend ratio on morphology, average size, and thermal properties of the blend nanoparticles were determined. The blend nanoparticles were spherical in shape. The average particle sizes slightly decreased as the MPEG-b-PCL blend ratio increased. ¹H-NMR and thermogravimetry revealed the different MPEG-b-PDLL/MPEG-b-PCL blend ratios of the nanoparticles. Differential scanning calorimetry showed that the MPEG-b-PCL crystallinity steadily decreased as the MPEG-b-PDLL blend ratio increased, suggesting miscible blending between the MPEG-b-PDLL and MPEG-b-PCL in the amorphous phase of the nanoparticle matrix.     

New Functional Diblock Copolymers Through Radical Addition of Mercaptans

1,2-Polybutadiene-block-poly(ethylene oxide)s were prepared by anionic polymerization and were subsequently modified by radical addition of ω-functional mercaptans (functional groups: carboxylic acid, amine, ethylene glycol, and fluorocarbon). The degree of functionalization of the products at full conversion of double bonds is 60–80%, and the molecular weight distribution is as narrow as that of the precursor polymer. The modified block copolymers are amphiphilic in nature and form complex aggregates in dilute aqueous solution.     

Multifunctional surface modification of gold-stabilized nanoparticles by bioorthogonal reactions

Nanocarriers that combine multiple properties in an all-in-one system hold great promise for drug delivery. The absence of technology to assemble highly functionalized devices has, however, hindered progress in nanomedicine. To address this deficiency, we have chemically synthesized poly(ethylene oxide)-β-poly(ε-caprolactone) (PEO-b-PCL) block polymers modified at the apolar PCL terminus with thioctic acid and at the polar PEO terminus with an acylhydrazide, amine, or azide moiety. The resulting block polymers were employed to prepare nanoparticles that have a gold core, an apolar polyester layer for drug loading, a polar PEO corona to provide biocompatibility, and three different types of surface reactive groups for surface functionalization. The acylhydrazide, amine, or azide moieties of the resulting nanoparticles could be reacted with high efficiencies with modules having a ketone, isocyanate, or active ester and alkyne function, respectively. To demonstrate proof of principle of the potential of multisurface functionalization, we prepared nanoparticles that have various combinations of an oligo-arginine peptide to facilitate cellular uptake, a histidine-rich peptide to escape from lysosomes, and an Alexa Fluor 488 tag for imaging purposes. It has been shown that uptake and subcellular localization of the nanoparticles can be controlled by multisurface modification. It is to be expected that the modular synthetic methodology provides unique opportunities to establish optimal configurations of nanocarriers for disease-specific drug delivery.