Synthesis and characterization of poly(ϵ-caprolactone)-poly(ethylene glycol) block copolymer

Poly(ϵ-caprolactone)–poly(ethylene glycol)–poly(ϵ-caprolactone) triblock copolymers (PECL) covering a wide range of poly(ethylene glycol) (PEG) lengths were synthesized with alkali metal alkoxide derivatives of poly(ethylene glycol). The effects of various factors, such as amount of the initiator, reaction time and temperature, polarity of solvent, length of PEG segment, and counterion on the polymerization were investigated. The copolymers were characterized by ¹H-NMR, IR, GPC, and DSC. It was found that THF system is superior to toluene system. The conversion of the monomer increased with increase of the initiator concentration. High molecular weight of the copolymer and high conversion of the monomer was obtained at below 30°C within 5 min. The polymerization process was studied by GPC and the coexistence of propagation and transesterification reaction was found, which leaded to relatively broad molecular weight distribution of the copolymers. © 1997 John Wiley & Sons, Inc.     

Novel synthesis of biodegradable amphiphilic linear and star block copolymers based on poly(ε‐caprolactone) and poly(ethylene glycol)

Biodegradable, amphiphilic, diblock poly(ε‐caprolactone)‐block‐poly(ethylene glycol) (PCL‐b‐PEG), triblock poly(ε‐caprolactone)‐block‐poly(ethylene glycol)‐block‐poly(ε‐caprolactone) (PCL‐b‐PEG‐b‐PCL), and star shaped copolymers were synthesized by ring opening polymerization of ε‐caprolactone in the presence of poly(ethylene glycol) methyl ether or poly(ethylene glycol) or star poly(ethylene glycol) and potassium hexamethyldisilazide as a catalyst. Polymerizations were carried out in toluene at room temperature to yield monomodal polymers of controlled molecular weight. The chemical structure of the copolymers was investigated by ¹H and ¹³C NMR. The formation of block copolymers was confirmed by ¹³C NMR and DSC investigations. The effects of copolymer composition and molecular structure on the physical properties were investigated by GPC and DSC. For the same PCL chain length, the materials obtained in the case of linear copolymers are viscous whereas in the case of star copolymer solid materials are obtained with low T_g and T_m temperatures. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 3975–3985, 2007     

Methylated and pegylated PLA–PCL–PLA block copolymers via the chemical modification of di‐hydroxy PCL combined with the ring opening polymerization of lactide

Methylated and pegylated poly(lactide)‐block‐poly(ε‐caprolactone)‐block‐poly(lactide) copolymers, PLA–P(CL‐co‐CLCH₃)–PLA and PLA–P(CL‐co‐CLPEG)–PLA, were prepared in three steps: combining the formation of carbanion‐bearing dihydroxylated‐PCL, the coupling of iodomethane or bromoacetylated α‐hydroxyl‐ω‐methoxy‐poly(ethylene glycol) onto the carbanionic PCL, and finally the ring opening polymerization of DL ‐lactide initiated by the preformed grafted diOH‐PCL copolymers. The resulting block copolymers exhibited lower crystallinity, melting temperature, and hydrophobicity with respect to the original PCL. Degradation of the grafted copolymers was investigated in the presence of Pseudomonas cepacia lipase and compared with that of the triblock copolymer precursor. It is shown that the presence of the grafted substituents affected the enzymatic degradation of PCL segments. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4196–4205, 2005     

Novel pentablock copolymer (PLA–PCL–PEG–PCL–PLA)-based nanoparticles for controlled drug delivery: effect of copolymer compositions on the crystallinity of copolymers and in vitro drug release profile from nanoparticles

The purpose of this investigation was to design novel pentablock copolymers (polylactide–polycaprolactone–polyethylene glycol–polycaprolactone–polylactide) (PLA–PCL–PEG–PCL–PLA) to prepare nanoparticle formulations which provide continuous delivery of steroids over a longer duration with minimal burst effect. Another purpose was to evaluate the effect of poly(l-lactide) (PLLA) and poly(d,l-lactide) (PDLLA) incorporation on crystallinity of pentablock copolymers and in vitro release profile of triamcinolone acetonide (selected as model drug) from nanoparticles. PLA–PCL–PEG–PCL–PLA copolymers with different block ratio of PCL/PLA segment were synthesized. Release of triamcinolone acetonide from nanoparticles was significantly affected by crystallinity of the copolymers. Burst release of triamcinolone acetonide from nanoparticles was significantly minimized with incorporation of proper ratio of PDLLA in the existing triblock (PCL–PEG–PCL) copolymer. Moreover, pentablock copolymer-based nanoparticles exhibited continuous release of triamcinolone acetonide. Pentablock copolymer-based nanoparticles can be utilized to achieve continuous near–zero-order delivery of corticosteroids from nanoparticles without any burst effect.     

Thermogelling hydrogels of poly(ε-caprolactone-co-D,L-lactide)–poly(ethylene glycol)–poly(ε-caprolactone-co-D,L-lactide) and poly(ε-caprolactone-co-L-lactide)–poly(ethylene glycol)–poly(ε-caprolactone-co-L-lactide) aqueous solutions

Thermogelling poly(ε-caprolactone-co-D,L -lactide)–poly(ethylene glycol)–poly(ε-caprolactone-co-D,L -lactide) and poly(ε-caprolactone-co-L -lactide)–poly(ethylene glycol)–poly(ε-caprolactone-co-L -lactide) triblock copolymers were synthesized through the ring-opening polymerization of ε-caprolactone and D,L -lactide or L -lactide in the presence of poly(ethylene glycol). The polymerization reaction was carried out in 1,3,5-trimethylbenzene with Sn(Oct)₂ as the catalyst at various temperatures, and the yields were about 96%. The molecular weights and polydispersities (M_w/M_n) by gel permeation chromatography were in the ranges of 5140–6750 and 1.35–1.45, respectively. The differential scanning calorimetry results showed that the melting temperatures of the poly(ε-caprolactone) components were between 30 and 40 °C. By the subtle tuning of the chemical compositions and microstructures of these triblock copolymers, the aqueous solutions underwent sol–gel transitions as the temperature increased, with the suitable lower critical solution temperature in the range of 17–28 °C at different concentrations. Transesterification in the polymerization process generated the redistribution of sequences, which remarkably affected the sol–gel transition temperature. The amphiphilic copolymers formed micelles in aqueous solutions with a diameter of 62 nm and a critical micelle concentration of about 0.032 wt % at 20 °C. Micelles aggregated as the temperature increased, leading to gel formation. The sol–gel transition was studied, with a focus on the structure–property relationship. It is expected to have potential applications in drug delivery and tissue engineering. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4091–4099, 2007     

Melt block copolymerization of ϵ-caprolactone and L-lactide

AB block copolymers of ϵ-caprolactone and (L )-lactide could be prepared by ring-opening polymerization in the melt at 110°C using stannous octoate as a catalyst and ethanol as an initiator provided ϵ-caprolactone was polymerized first. Ethanol initiated the polymerization of ϵ-caprolactone producing a polymer with ϵ-caprolactone derived hydroxyl end groups which after addition of L -lactide in the second step of the polymerization initiated the ring-opening copolymerization of L -lactide. The number-average molecular weights of the poly(ϵ-caprolactone) blocks varied from 1.5 to 5.2 × 10³, while those of the poly(L -lactide) blocks ranged from 17.4 to 49.7 × 10³. The polydispersities of the block copolymers varied from 1.16 to 1.27. The number-average molecular weights of the polymers were controlled by the monomer/hydroxyl group ratio, and were independent on the monomer/stannous octoate ratio within the range of experimental conditions studied. When L -lactide was polymerized first, followed by copolymerization of ϵ-caprolactone, random copolymers were obtained. The formation of random copolymers was attributed to the occurrence of transesterification reactions. These side reactions were caused by the ϵ-caprolactone derived hydroxyl end groups generated during the copolymerization of ϵ-caprolactone with pre-polymers of L -lactide. The polymerization proceeds through an ester alcoholysis reaction mechanism, in which the stannous octoate activated ester groups of the monomers react with hydroxyl groups. © 1997 John Wiley & Sons, Inc.     

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.     

Synthesis of poly(ethylene glycol)/polypeptide/poly(D,L‐lactide) copolymers and their nanoparticles

Core‐shell structured nanoparticles of poly(ethylene glycol) (PEG)/polypeptide/poly(D ,L ‐lactide) (PLA) copolymers were prepared and their properties were investigated. The copolymers had a poly(L ‐serine) or poly(L ‐phenylalanine) block as a linker between a hydrophilic PEG and a hydrophobic PLA unit. They formed core‐shell structured nanoparticles, where the polypeptide block resided at the interface between a hydrophilic PEG shell and a hydrophobic PLA core. In the synthesis, poly(ethylene glycol)‐b‐poly(L ‐serine) (PEG‐PSER) was prepared by ring opening polymerization of N‐carboxyanhydride of O‐(tert‐butyl)‐L ‐serine and subsequent removal of tert‐butyl groups. Poly(ethylene glycol)‐b‐poly(L ‐phenylalanine) (PEG‐PPA) was obtained by ring opening polymerization of N‐carboxyanhydride of L ‐phenylalanine. Methoxy‐poly(ethylene glycol)‐amine with a MW of 5000 was used as an initiator for both polymerizations. The polymerization of D ,L ‐lactide by initiation with PEG‐PSER and PEG‐PPA produced a comb‐like copolymer, poly(ethylene glycol)‐b‐[poly(L ‐serine)‐g‐poly(D ,L ‐lactide)] (PEG‐PSER‐PLA) and a linear copolymer, poly(ethylene glycol)‐b‐poly(L ‐phenylalanine)‐b‐poly(D ,L ‐lactide) (PEG‐PPA‐PLA), respectively. The nanoparticles obtained from PEG‐PPA‐PLA showed a negative zeta potential value of ?16.6 mV, while those of PEG‐PSER‐PLA exhibited a positive value of about 19.3 mV. In pH 7.0 phosphate buffer solution at 36 °C, the nanoparticles of PEG/polypeptide/PLA copolymers showed much better stability than those of a linear PEG‐PLA copolymer having a comparable molecular weight. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Amphiphilic Biodegradable Poly(ϵ-caprolactone)-Poly(ethylene glycol) – Poly(ϵ-caprolactone) Triblock Copolymer Synthesis by Maghnite-H+ as a Green Catalyst

Amphiphilic biodegradable (PCL-PEG-PCL) triblock copolymers have been successfully prepared by the ring opening polymerization of ?-caprolactone (CL) in the presence of poly(ethylene glycol) (PEG) at 80°C employing Maghnite-H⁺ a non-toxic Montmorillonite clay as catalyst. Maghnite-H⁺ reacts as a solid source of protons to induce ?-caprolactone polymerization. The triblock architecture, molecular weight and thermal properties of the copolymers were characterized by NMR spectra, GPC and DSC analyses. The effect of Maghnite-H⁺ proportion and PEGs on the rate of copolymerization and on average molecular weight of resulting copolymers was studied. A cationic mechanism for the copolymerization reaction was proposed.     

Electrospun Aligned Poly(L-lactide)/Poly(ϵ-caprolactone) /Poly(ethylene glycol) Blend Fibrous Membranes

Aligned poly(L-lactide) (PLLA)/poly(?-caprolactone) (PCL)/poly(ethylene glycol)(PEG) fibrous membranes were fabricated by electrospinning. Their morphology, thermal stability, mechanical properties, hydrophilic properties and in vitro degradation behaviors were investigated. With increasing the content of PEG, the PLLA/PCL/PEG blend fibers become thinner due to the increment in solution conductivity and decrease in solution viscosity. The thermal stability, hydrophilic properties, the tensile strength and elongation-at-break of PLLA/PCL/PEG blend fibrous membranes were improved, but porosity were decreased with the content of PEG changing from 10 wt% to 30 wt%. Furthermore, the incorporation of PEG enhanced the degradation of the PLLA/PCL/PEG fibrous membranes due to the better hydrophilic properties. In addition, the PLLA/PCL/PEG fibrous membranes have no toxic effect on proliferation of adipose-derived stem cells.     

Novel synthesis of biodegradable star poly(ethylene glycol)‐block‐poly(lactide) copolymers

Biodegradable star‐shaped poly(ethylene glycol)‐block‐poly(lactide) copolymers were synthesized by ring‐opening polymerization of lactide, using star poly(ethylene glycol) as an initiator and potassium hexamethyldisilazide as a catalyst. Polymerizations were carried out in toluene at room temperature. Two series of three‐ and four‐armed PEG‐PLA copolymers were synthesized and characterized by gel permeation chromatography (GPC) as well as ¹H and ¹³C NMR spectroscopy. The polymerization under the used conditions is very fast, yielding copolymers of controlled molecular weight and tailored molecular architecture. The chemical structure of the copolymers investigated by ¹H and ¹³C NMR indicates the formation of block copolymers. The monomodal profile of molecular weight distribution by GPC provided further evidence of controlled and defined star‐shaped copolymers as well as the absence of cyclic oligomeric species. The effects of copolymer composition and lactide stereochemistry on the physical properties were investigated by GPC and differential scanning calorimetry. For the same PLA chain length, the materials obtained in the case of linear copolymers are more viscous, whereas in the case of star copolymer, solid materials are obtained with reduction in their T_g and T_m temperatures. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 3966–3974, 2007     

Segmented block copolymers of poly(ethylene glycol) and poly(ethylene terephthalate)

A new series of segmented copolymers were synthesized from poly(ethylene terephthalate) (PET) oligomers and poly(ethylene glycol) (PEG) by a two‐step solution polymerization reaction. PET oligomers were obtained by glycolysis depolymerization. Structural features were defined by infrared and nuclear magnetic resonance (NMR) spectroscopy. The copolymer composition was calculated via ¹H NMR spectroscopy. The content of soft PEG segments was higher than that of hard PET segments. A single glass‐transition temperature was detected for all the synthesized segmented copolymers. This observation was found to be independent of the initial PET‐to‐PEG molar ratio. The molar masses of the copolymers were determined by gel permeation chromatography (GPC). © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4448–4457, 2004     

Quadruple click reactions for the synthesis of cysteine‐terminated linear multiblock copolymers

Synthesis of cysteine‐terminated linear polystyrene (PS)‐b‐poly(ε‐caprolactone) (PCL)‐b‐poly(methyl methacrylate) (PMMA)/or poly(tert‐butyl acrylate)(PtBA)‐b‐poly(ethylene glycol) (PEG) copolymers was carried out using sequential quadruple click reactions including thiol‐ene, copper‐catalyzed azide–alkyne cycloaddition (CuAAC), Diels–Alder, and nitroxide radical coupling (NRC) reactions. N‐acetyl‐L ‐cysteine methyl ester was first clicked with α‐allyl‐ω‐azide‐terminated PS via thiol‐ene reaction to create α‐cysteine‐ω‐azide‐terminated PS. Subsequent CuAAC reaction with PCL, followed by the introduction of the PMMA/or PtBA and PEG blocks via Diels–Alder and NRC, respectively, yielded final cysteine‐terminated multiblock copolymers. By ¹H NMR spectroscopy, the DP_ns of the blocks in the final multiblock copolymers were found to be close to those of the related polymer precursors, indicating that highly efficient click reactions occurred for polymer–polymer coupling. Successful quadruple click reactions were also confirmed by gel permeation chromatography. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Thermoplastic elastomers based on poly(l‐Lysine)‐Poly(ε‐Caprolactone) multi‐block copolymers

Novel thermoplastic elastomers based on multi‐block copolymers of poly(l ‐lysine) (PLL), poly(N‐ε‐carbobenzyloxyl‐l ‐lysine) (PZLL), poly(ε‐caprolactone) (PCL), and poly(ethylene glycol) (PEG) were synthesized by combination of ring‐opening polymerization (ROP) and chain extension via l ‐lysine diisocyanate (LDI). SEC and ¹H NMR were used to characterize the multi‐block copolymers, with number‐average molecular weights between 38,900 and 73,400 g/mol. Multi‐block copolymers were proved to be good thermoplastic elastomers with Young's modulus between 5 and 60 MPa and tensile strain up to 1300%. The PLL‐containing multi‐block copolymers were electrospun into non‐woven mats that exhibited high surface hydrophilicity and wettability. The polypeptide–polyester materials were biocompatible, bio‐based and environment‐friendly for promising wide applications. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3012–3018     

A facile approach to biodegradable poly(ε-caprolactone)-poly(ethylene glycol)-based polyurethanes containing pendant amino groups

A novel biodegradable poly(ε-caprolactone)-poly(ethylene glycol)-based polyurethanes (PCL-PEG-PU) with pendant amino groups was synthesized by direct coupling of PEG ester of NH₂-protected-(aspartic acid) (PEG-Asp-PEG diols) and poly(ε-caprolactone) (PCL) diols with hexamethylene dissocyanate (HDI) under mild reaction conditions and by subsequent deprotection of benzyloxycarbonyl (Cbz) groups. GPC, ¹H NMR, and ¹³C NMR studies confirmed the polymer structures and the complete deprotection. DSC and WXRD results indicated that the crystallinity of the copolymer was enhanced with increasing PCL diols in the copolymer. The content of amino group in the polymer could be adjusted by changing the molar ratio of PEG-Asp-PEG diols to PCL diols. Thus the results of this study provide a good way to prepare polyurethanes bearing hydrophilic PEG segments and reactive amino groups without complicated synthesis.     

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.     

Stereocomplex formation in AB DI-block copolymers of poly(ϵ-caprolactone) (a) and poly(lactide)(B)

The thermal properties of two series of AB di-block copolymers of poly(ϵ-caprolactone) (A) and poly(lactide) (B) and their blends were studied. Each series contained poly(lactide) blocks of opposite chirality. The length of the poly(ϵ-caprolactone) blocks was not varied (DP = 70), whereas the poly(lactide) blocks were of varying length (DP = 5 − 80). Blends of polymers containing blocks of opposite chirality were prepared by mixing in solution. The melting temperature of the PLA phase was raised by approximately 55 °C in the blends due to stereocomplex formation. The melting temperatures of the crystalline PCL and PLA phases strongly depended on the composition of the block copolymers.     

ABCD 4‐miktoarm star quarterpolymers using click [3 + 2] reaction strategy

Two samples of ABCD 4‐miktoarm star quarterpolymer with A = polystyrene (PS), B = poly(ε‐caprolactone) (PCL), C = poly(methyl methacrylate) (PMMA) or poly(tert‐butyl acrylate) (PtBA), and D = poly(ethylene glycol) (PEG) were prepared using click reaction strategy (Cu(I)‐catalyzed Huisgen [3 + 2] reaction). Thus, first, predefined block copolymers of different polymerization routes, PS‐b‐PCL with azide and PMMA‐b‐PEG and PtBA‐b‐PEG copolymers with alkyne functionality, were synthesized and then these blocks were combined together in the presence of Cu(I)/N,N,N′,N″,N″‐pentamethyldiethylenetriamine as a catalyst in DMF at room temperature to give the target 4‐miktoarm star quarterpolymers. The obtained miktoarm star quarter polymers were characterized by GPC, NMR, and DSC measurements. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1218–1228, 2008     

Photocurable biodegradable poly(ɛ-caprolactone)/poly(ethylene glycol) multiblock copolymers showing shape-memory properties

Biodegradable multiblock copolymers were synthesized by a polycondensation of poly(ɛ-caprolactone) (PCL) diols of molecular weight (MW)=3,000 and poly(ethylene glycol)s (PEG) of MW=3,000 with 4,4′-(adipoyldioxy)dicinnamic acid (CAC) dichloride as a chain extender in diphenyl ether at 180 °C for 2 h, and were characterized by GPC, ¹H-NMR, FTIR, UV, DSC, and WAXS. These photosensitive copolymers were irradiated by a 400-W high-pressure mercury lamp (λ>280 nm) from 5–60 min to form a network structure. The gel contents increased with irradiation time, and attained ca. 90% after 60 min for all copolymers. The degree of swelling in a distilled water at ambient temperature, and the rate of degradation in a phosphate buffer solution (pH 7.2) at 37 °C increased with increasing PEG components. The shape-memory tests were performed by a cyclic thermomechanical experiments for the photocured CAC/PCL/PEG (75/25) films. The film with a gel content of 57% showed the best shape-memory property with strain fixity rate of 100% and strain recovery rate of 88%.     

Microporous structure and drug release kinetics of polymeric nanoparticles

The aim of the present study was to characterize pegylated nanoparticles (NPs) for their microporosity and study the effect of microporosity on drug release kinetics. Blank and drug-loaded NPs were prepared from three different pegylated polymers, namely, poly(ethylene glycol)1%-graft-poly(D,L)-lactide, poly(ethylene glycol)5%-graft-poly(D,L)-lactide, and the multiblock copolymer (poly(D,L)-lactide-block-poly(ethylene glycol)-block-poly(D,L)-lactide)n. These NPs were characterized for their microporosity using nitrogen adsorption isotherms. NPs of the multiblock copolymer showed the least microporosity and Brunauer-Emmett-Teller (BET) surface area, and that of PEG1%-g-PLA showed the maximum. Based on these results, the structural organization of poly(D,L)-lactide (PLA) and poly(ethylene glycol) (PEG) chains inside the NPs was proposed and was validated with differential scanning calorimetry (DSC) and X-ray photoelectron spectroscopy (XPS) surface analysis. An in vitro drug release study revealed that PEG1%-g-PLA NPs exhibited slower release despite their higher surface area and microporosity. This was attributed to the presence of increased microporosity forming tortuous internal structures, thereby hindering drug diffusion from the matrix. Thus, it was concluded that the microporous structure of NPs, which is affected by the molecular architecture of polymers, determines the release rate of the encapsulated drug.