Biodegradable lactone copolymers. I. Characterization and mechanical behavior of ε-caprolactone and lactide copolymers

Copolymers of ε-caprolactone and L-lactide (ε-CL/L-LA) and ε-caprolactone and DL-lactide (ε-CL/DL-LA) were synthesized with compositions 80/20, 60/40, and 40/60 (wt % in feed). The polymerization temperature was 140°C and Sn(II)octoate was used as a catalyst. The effect of the comonomer ratio on the thermal and mechanical properties of the copolymers was investigated by size-exclusion chromatography (SEC), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) spectrometry, and tensile testing. The copolymers differed widely in their physical characteristics, ranging from weak elastomers to tougher thermoplastics according to the ratio of ε-CL and LA in the copolymerization. Poly(L-lactide) (PLLA), poly(DL-lactide) (PDLLA), and poly(ε-caprolactone) (PCL) homopolymers were studied as references. The tensile modulus and tensile strength were much higher for PLLA, PDLLA, and PCL homopolymers than for the copolymers. The maximum strain was very low for PLLA and PDLLA, whereas the copolymers and PCL exhibited large elongation. © 1996 John Wiley & Sons, Inc.     

Synthesis,structure and behavior of new polycaprolactam copolymers based on poly (ethylene oxide)–poly (propylene oxide)–poly (ethylene oxide) macroactivators derived from Pluronic block copolymers

Novel series of poly (CL–co–Pluronic) polymers were successfully synthesized in situ by ring-opening polymerization (ROP) of ε-caprolactam (ε-CL). The copolymerization was activated by new type macroactivators (MAs) based on hydroxyl-terminated poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) [PEO-PPO-PEO] triblock copolymers, known under the trade name Pluronic^®. Toluene-2,4-diisocyanate (TDI) was used to obtain the isocyanate-terminated Pluronic prepolymers. The corresponding MAs were synthesized in situ with an N-carbamoyllactam structure. As an initiator of the copolymerization processes was used sodium lactamate (NaCL). To confirm the influence over the copolymerization process, microstructure, composition and molecular weight of the polymeric products two new types MAs based on Pluronic (P123 and F68) have been varied from 2 to 10 wt.% (vs. the monomer ε-CL). The structure of the both Pluronic based macroactivators (MAs) and accordingly obtained two series poly (CL-co-Pluronic) polymers were confirmed by ¹H NMR and FT-IR analyses. Additionally, the structure, molecular weight, physicomechanical behavior, thermal stability and morphology of the new synthesized poly (CL–co–Pluronic) polymers have been investigated by Differential Scanning Calorimetry (DSC), Wide-Angle X-ray Diffraction (WAXD), Thermogravimetric Analysis (TGA) and Scanning Electron Microscopy (SEM) analysis.     

Synthesis of poly(ε-caprolactone)-poly(L-lactide) block copolymers by melt or solution sequential copolymerization using nontoxic dibutylmagnesium as initiator

Summary  Poly(ε-caprolactone)-poly(L-lactide) (PCL-PLLA) block copolymers were synthesized via melt or solution sequential copolymerization of ε-caprolactone (ε-CL) and L-lactide (L-LA) using nontoxic dibutylmagnesium as initiator. The formation of block structure was confirmed by ¹H-, ¹³C NMR, GPC, and FT-IR, it can be concluded that the block copolymers PCL-PLLA have been successfully synthesized by both melt and solution sequential copolymerization methods. Two melting endothermic peaks (T_m) during heating and two crystallization exothermal peaks (T_c) during cooling were observed in DSC curves. XRD patterns of the copolymers were approximately the superposition of both the PCL and PLLA homopolymers. The results indicated the coexistence of both PCL and PLLA crystalline microdomains, and the microphase separation took place in the block copolymers.     

Ring-opening homo- and copolymerization of lactones. Part 1. Homo- and copolymerization of racemic β-butyrolactone with ε-caprolactone and δ-valerolactone by tetraisobutyldialuminoxane (TIBAO) catalyst

Copolymers of racemic β-butyrolactone (β-BL) with ε-caprolactone (ε-CL) (P(BL-co-CL)) and δ-valerolactone (δ-VL) (P(BL-co-VL)) were prepared by ring-opening polymerization reactions using the commercial aluminoxane catalyst tetraisobutyldialuminoxane (TIBAO). The yields, molecular weights, compositions and crystallinities were determined for both copolymers by gel permeation chromatography (GPC), nuclear magnetic resonance (¹H NMR) spectroscopy and differential scanning calorimetry (DSC). A detailed study by ¹³C NMR spectroscopy has been made to determine monomer diad sequence distributions. These results and those of reactivity ratios indicate that the co-polymers may consist of compatible blocks of BL units and VL units of variable size. © 1998 SCI.     

两亲扩展型共聚物的合成及中间极性嵌段对乳化性能的影响

采用聚乙二醇单甲醚(Mn=1 900,5 000)分别引发丙交酯和ε-己内酯开环聚合合成了中间嵌段(PLA)聚合度递增的聚乙二醇-聚丙交酯-聚己内酯(MPEG-PLA-PCL)两亲扩展型共聚物和相应的聚乙二醇-聚己内酯(MPEG-PCL)两嵌段共聚物。用FTIR、1HNMR和GPC对产物结构进行了表征,研究了共聚物和常规低分子表面活性剂的乳化性能,探讨了中间极性嵌段的长度对共聚物乳化性能的影响。结果表明,对于甲苯/水体系,共聚物可用于制备稳定的O/W型乳液,且三嵌段共聚物的乳化性能优于低分子表面活性剂;随着引入PLA嵌段聚合度的增加,共聚物的乳化能力呈先增加后减小的趋势;相对于MPEG1900系列共聚物,MPEG5000系列共聚物中需要引入更长的中间嵌段才能获得最佳乳化性能。     

Novel poly(ε-caprolactone)s bearing amino groups: Synthesis,characterization and biotinylation

A novel functional ε-caprolactone monomer containing protected amino groups, γ-(carbamic acid benzyl ester)-ε-caprolactone (γCABεCL), was successfully synthesized. A series of copolymers [poly(CL-co-CABCL)] were prepared by ring-opening polymerization of ε-caprolactone (CL) and γCABεCL in bulk using tin (II)-2-ethylhexanoate [Sn(Oct)₂] as catalyst. The morphology of the copolymers changed from semi-crystalline to amorphous with increasing γCABεCL monomer content. They were further converted into deprotected copolymers [poly(CL-co-ACL)] with free amino groups by hydrogenolysis in the presence of Pd/C. After deprotection, the free amino groups on the copolymer were further modified with biotin. The monomer and the corresponding copolymers were characterized by ¹H NMR, ¹³C NMR, FT-IR, mass, GPC and DSC analysis. The obtained data have confirmed the desired monomer and copolymer structures.     

Synthesis of biodegradable poly(trans-4-hydroxy-N-benzyloxycarbonyl-l-proline)-block-poly(ε-caprolactone) copolymers and micellar characterizations

A series of novel types of diblock poly(trans-4-hydroxy-N-benzyloxycarbonyl-l-proline)-block-poly(ε-caprolactone) (PHpr10-b-PCL) copolymers were synthesized by ring-opening polymerization from macroinitiator poly(trans-4-hydroxy-N-benzyloxycarbonyl-l-proline) (PHpr10) and ε-caprolactone (ε-CL) in the presence of organocatalyst dl-lactic acid (dl-LA). The M_n of the copolymers increased from 3370 to 19,040 g mol⁻¹ with the molar ratio (10-100) of ε-CL to PHpr10. These products were characterized by differential scanning calorimetry (DSC), ¹H NMR, and gel permeation chromatography. According to DSC, the glass-transition temperature (T_g) of the diblock copolymers depend on the molar ratio of monomer/initiator that were added. The hydrolytic degradation behavior of PHpr-b-PCLs was evaluated from weight-loss measurements and the change of M_n and M_w/M_n. With higher PCL contents resulted in a slower weight loss, while having a higher molecular weight loss percentage. Their micellar characteristics in an aqueous phase were investigated by fluorescence spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The block copolymers formed micelles in the aqueous phase with critical micelle concentrations (CMCs) in the range of 1.33-4.22 mg L⁻¹. The micelles exhibited a spindly shape and showed a narrow monodisperse size distribution. The obtained micelles have a relatively high drug-loading of about 26% when the feed weight ratio of amitriptyline hydrochloride (AM) to polymer was 1/1. An increase of molecular weight and hydrophobic components in copolymers produced a higher CMC value and greater loading efficiencies were observed.     

A-B-A-Triblock and multiblock copolyesters prepared from ε-caprolactone, glycolide and l-lactide by means of bismuth subsalicylate

Bismuth (III) subsalicylate, a commercial drug, was used as catalyst for 1,4-butanediol-initiated copolymerizations of ε-caprolactone (εCL) and glycolide (GL). Telechelic copolyesters having two OH-endgroups and predominantly alternating sequences were obtained. These copolyesters are amorphous with glass transition temperatures (T_gs) below −30 °C. In a second series of polymerizations, in situ chain extension with l-lactide (LLA) was performed, whereby A-B-A triblock copolymers were obtained without significant transesterification between A- and B-blocks. Finally, these A-B-A triblock copolymers were transformed into multiblock copolymers by chain extension with 1,6-hexamethylene diisocyanate. The block copolymers were characterized by ¹H and ¹³C NMR spectroscopy, by viscosity, SEC and DSC measurements.     

Synthesis and characterization of four- and six-arm star-shaped poly(ε-caprolactone)-b-poly(N-vinylcaprolactam): Micellar and core degradation studies

Star-shaped copolymers with four and six poly(ε-caprolactone)-block-poly(N-vinylcaprolactam) (S(PCL-b-PNVCL)) arms were successfully synthesized by combining ring opening polymerization (ROP) of ε-caprolactone (CL) and reversible addition-fragmentation chain transfer (RAFT) polymerization of N-vinylcaprolactam (NVCL). The resulting star copolymers were characterized using ¹H NMR, GPC and UV–vis. The numbers of arms in the star-shaped PCL-b-PNVCL block copolymers were demonstrated using degradation studies under acidic conditions, and the individual PNVCL chains were characterized by GPC and ¹H NMR. In aqueous solution, star-shaped PCL-b-PNVCL block copolymers self-assembled into large aggregates or micelles with sizes varying from 54 to 300 nm, depending on the molecular weight of the copolymer and the relative lengths of the hydrophobic and hydrophilic segments. Micelles were characterized by atomic force microscopy (AFM), dynamic light scattering (DLS) and scanning electron microscopy (SEM).     

Amphiphilic biodegradable poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) triblock copolymers: synthesis, characterization and their use as drug carriers for folic acid

Amphiphilic biodegradable poly(ε-caprolactone)-poly(ethylene glycol)-poly (ε-caprolactone) (PCEC) triblock copolymers have been successfully synthesized by the ring-opening polymerization of ε-caprolactone (ε-CL) employing SnOct as catalyst and double-hydroxyl capped PEG (DHPEG) as macro-initiator. The triblock structure and copolymer composition were conformed by FT-IR, ¹H-NMR, and GPC. Using a membrane dialysis method, PCEC micelles were prepared with a core–shell type. The critical micelle concentration (CMC) of PCEC triblock copolymers was determined by fluorescence technique using pyrene as probe, and CMC values decreased with the increase of PCL chain length. From the observation of transmission electron microscopy (TEM), the morphology of polymer micelles was spherical in shape. Micelles size measured by dynamic light scattering (DLS) exhibited a narrow size distribution. Folic acid (FA) was then used as a model drug to incorporate into PCEC micelles. The diameter, drug loading, and drug release rate of PCEC micelles were influenced by the feed weight ratio of FA and copolymer, and polymer composition. In addition, in vitro release experiments of the drug-loaded PCEC micelles exhibited sustained release behavior without any burst effects and the release behavior was also affected by the pH of release media.     

Formation of nanostructures in thermosets containing block copolymers: From self-assembly to reaction-induced microphase separation mechanism

In this work, we investigated the effect of formation mechanisms of nanophases on the morphologies and thermomechanical properties of the nanostructured thermosets containing block copolymers. Toward this end, the nanostructured thermosets involving epoxy and block copolymers were prepared via self-assembly and reaction-induced microphase separation approaches, respectively. Two structurally similar triblock copolymers, poly(ε-caprolactone)-block-poly(butadiene-co-styrene)-block-poly(ε-caprolactone) (PCL-b-PBS-b-PCL) and poly(ε-caprolactone)-block-poly(ethylene-co-ethylethylene-co-styrene)-block-poly(ε-caprolactone) (PCL-b-PEEES-b-PCL) were synthesized via the ring-opening polymerization of ε-caprolactone (CL) with α,ω-dihydroxyl-terminated poly(butadiene-co-styrene) (HO-PBS-OH) and α,ω-dihydroxyl-terminated poly(ethylene-co-ethylethylene-co-styrene) (i.e., HO-PEEES-OH) as the macromolecular initiators, respectively; the latter was obtained via the hydrogenation reduction of the former. Both the triblock copolymers had the same architecture, the identical composition and close molecular weights. In spite of the structural resemblance of both the triblock copolymers, the formation mechanisms of the nanophases in the thermosets were quite different. It was found that the formation of nanophases in the thermosets containing PCL-b-PBS-b-PCL followed a reaction-induced microphase separation mechanism whereas that in the thermosets containing PCL-b-PEEES-b-PCL was in a self-assembly manner. The different formation mechanisms of nanophases resulted in the quite different morphologies, glass transition temperatures (T_g's) and fracture toughness of the nanostructured thermosets.     

Synthesis of ε-caprolactone-b-l-lactide block copolymers by mean sequential polymerization,using diphenylzinc as initiator

Block copolymers of ε-caprolactone (CL) and l-lactide (l-LA) were synthesized by sequential polymerization using diphenylzinc as initiator. The composition of the copolymers was adjusted changing the comonomers in ratio. Copolymers were characterized by ¹H-NMR, ¹³C-NMR, DSC, and GPC. Results indicate that poly(ε-caprolactone)-b-poly(l-lactide) (PCL-b-PLA) block copolymers had a narrow molecular weight distribution and well-controlled sequences without random placement.     

PCL及PCL-PEG-PCL共聚物的合成与表征

以辛酸亚锡[Sn(Oct)2]作为引发剂,采用ε-己内酯(ε-CL)开环均聚合制备聚ε-己内酯(PCL),考察了n(ε-CL)/n[Sn(Oct)2]、反应温度和反应时间等因素对聚合产物特性黏数的影响。以Sn(Oct)2为催化剂,聚乙二醇(PEG)为引发剂,合成了不同相对分子质量的PCL-PEG-PCL三嵌段共聚物,研究了ε-CL均聚物及共聚物的结构、热性能和结晶形态。PCL最佳合成工艺为:n(ε-CL)/n[Sn(Oct)2]为400,温度130℃,反应时间4 h。随着PEG相对分子质量从2×103增加到8×103,三嵌段共聚物的熔融温度、熔融焓和结晶温度逐渐升高;结晶温度及PEG相对分子质量对PCL-PEG-PCL三嵌段共聚物球晶的形态和尺寸影响很大。     

星形嵌段共聚物PCL-b-PNVCL的合成

用季戊四醇引发ε-己内酯(ε-CL)开环聚合得到四臂星形PCL,将其末端羟基转变为O-乙基黄原酸酯,以此为大分子链转移剂调控N-乙烯基己内酰胺(NVCL)的RAFT聚合,合成了以季戊四醇为核、以PCL为内臂、PNVCL为外臂的两亲性星形嵌段共聚物,用1H NMR谱证明了所得聚合物的结构。     

Synthesis and characterization of diblock copolymers based on crystallizable poly(ε-caprolactone) and mesogen-jacketed liquid crystalline polymer block

Diblock copolymers comprising crystallizable poly(ε-caprolactone) and poly{2,5-bis[(4-methoxyphenyl)oxycarbonyl]styrene} (PMPCS) were synthesized by ring-opening polymerization of ε-caprolactone and subsequent atom transfer radical polymerization (ATRP) of MPCS. The molecular structure of the copolymers was confirmed by ¹H NMR spectroscopy and GPC. Kinetic study of ATRP showed that the polymerization proceeded in a controlled way up to high conversions. Three series of diblock copolymers were obtained with relatively narrow polydispersity indices (PDI≤1.11) and PCL blocks of 8000, 12,900, and 22,800 molecular weights, respectively. The existence of microphase separation was identified by differential scanning calorimetry (DSC) and directly observed through transmission electron microscopy (TEM). The melting behavior of PCL block was significantly affected by the length of PCL block and composition of PMPCS. The thermotropic liquid crystalline behavior was examined by polarized optical microscopy (POM) and DSC. The result showed that the diblock copolymer exhibited liquid crystalline behavior when the degree of polymerization (DP) of PMPCS block was not less than 44.     

Novel micelle-forming block copolymer composed of poly (ε-caprolactone) and poly(vinyl pyrrolidone)

The well-defined poly (ε-caprolactone) (PCL)/poly(vinyl pyrrolidone) (PVP) diblock copolymers were synthesized through combining radical polymerization of VP and the controlled coordination-insertion ring-opening polymerization of CL using an aluminum alkoxide macroinitiator formed from the equimolar reaction of triethylaluminum with hydroxy-terminated PVP (PVP-OH). The molecular characterization of PCL/PVP diblock copolymers was confirmed through ¹H NMR spectroscopy and GPC analysis. Polymeric micelles composed of PCL as a hydrophobic core and PVP as a hydrophilic shell were prepared by a diafiltration method. The micellar properties such as sizes, shapes, and critical micelle concentrations (CMC) were investigated with a dynamic light scattering (DLS) spectrometer, transmission electron microscope (TEM) and spectrofluorimeter. The sizes of micelles ranged from 30 to 80 nm in average size. The novel micelles formed from the well-defined PCL/PVP diblock copolymers seem to be feasible as novel promising carriers in biomedical and pharmaceutical applications.     

Synthesis and characterization of fluorescein isothiocyanate (FITC)-labeled PEO-PCL-PEO triblock copolymers for topical delivery

We present the synthesis of fluorescein isothiocyanate (FITC)-labeled poly(ethylene oxide)-block-poly(?-caprolactone)-block-poly(ethylene oxide) (PEO-PCL-PEO) triblock copolymers and their applications for tracking the penetration behavior of FITC-labeled copolymers in the hairless mouse skin. In the first step, PEO-PCL diblock copolymers with different ratios of PCL to PEO (i.e., [CL]/[EO]) were prepared by ring opening polymerization of ?-caprolactone (CL), where monomethoxy poly(ethylene glycol) (mPEG, M_n = 2000 g mol⁻¹) was used as a macro-initiator. FITC was successively reacted with octadecylamine, isophorone diisocyanate (IPDI), and then used as a linker to obtain PEO-PCL-PEO triblock copolymers from the PEO-PCL diblock copolymers. In aqueous solution, both FITC-labeled triblock copolymers show two UV absorption peaks at 489 and 455 nm, attributed to the monomeric FITC and H-aggregated FITC moieties, respectively. Due to the strong H-aggregation of FITC in the copolymer of high [CL]/[EO], fluorescent emission intensities considerably decreased at high concentrations of the copolymer. FITC-labeled copolymers exhibited more sharper polarized optical and fluorescence microscopic images compared to the mixtures of FITC and unlabeled copolymer in both solid crystalline and multiple emulsion state. Furthermore, the Frantz diffusion cell test was carried out to demonstrate the penetration behavior of the FITC-labeled copolymers in the hairless mouse skin.     

Poly(ε-caprolactone)-block-poly(N-vinyl pyrrolidone) diblock copolymers grafted from macrocyclic oligomeric silsesquioxane

Poly(ε-caprolactone)-block-poly(N-vinyl pyrrolidone) diblock copolymers grafted from macrocyclic oligomeric silsesquioxane (MOSS) (denoted MOSS[PCL-b-PVPy]₁₂) were synthesized via the sequential polymerizations involving ring-opening polymerization (ROP) of ε-caprolactone (CL) and RAFT/MADIX polymerization of N-vinyl pyrrolidone (NVP). The organic-inorganic brush-like diblock copolymers were characterized by means of nuclear magnetic resonance spectroscopy (NMR) and gel permeation chromatography (GPC). Small angle X-ray scattering (SAXS) showed that all the MOSS[PCL-b-PVPy]₁₂ was microphase-separated in the amorphous state. The microphase-separated morphologies were quite dependent on the length of PVPy blocks and the crystallization behavior of PCL subchains was significantly affected by the lengths of PVPy subchains. In aqueous solutions, the MOSS[PCL-b-PVPy]₁₂ can be self-assembled into the polymeric micelles as evidenced by dynamic light scattering (DLS) and transmission election microscopy (TEM). The critical micelle concentrations of the brush-like diblock copolymers increased with increasing the lengths of PVPy blocks. It is proposed that the stability of the micellar cores was increased with the macrocyclic molecular brush structure of the diblock copolymers and the formation of the MOSS aggregates via MOSS–MOSS interactions.     

Triblock and star-block copolymers of N-(2-hydroxypropyl)methacrylamide or N-vinyl-2-pyrrolidone and D,L-lactide: synthesis and self-assembling properties in water

Novel A-B-A triblock and star-block amphiphilic copolymers, i.e. poly(N-(2-hydroxypropyl)methacrylamide)-block-poly(D,L-lactide)-block-poly(N-(2-hydroxypropyl)metha-crylamide), poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide)-block-poly(N-vinyl-2-pyrrolidone), star-poly(D,L-lactide)-block-poly(N-(2-hydroxypropyl)methacrylamide) and star-poly(D,L-lactide)-block-poly(N-vinylpyrrolidone), were synthesized and characterized. These polymers were prepared by free radical polymerization of N-(2-hydroxypropyl)methacrylamide and N-vinyl-2-pyrrolidone in the presence of either poly(D,L-lactide) dithiol or star-poly(D,L-lactide) tetrakis-thiol, both biodegradable macromolecular chain-transferring agents. All copolymers self-assembled in aqueous solution to form supramolecular aggregates of 20–180 nm in size. The critical aggregation concentration of the copolymers ranged from 5 to 24 mg/L, depending on their hydrophobicity. The partition equilibrium constant of pyrene in the hydrophobic core of micelles was between 0.71×10⁵ and 1.63×10⁵. The triblock copolymer micelles were loaded with two model poorly water-soluble drugs, namely, indomethacin (1.5–16.4% w/w) and paclitaxel (0.4–1.5% w/w), by a dialysis procedure. These triblock and star-block copolymers could prove useful as nanocarriers for the solubilization and delivery of hydrophobic drugs.     

Enzyme-catalyzed polymerization and degradation of copolymers prepared from ?-caprolactone and poly(ethylene glycol)

Copolymerizations of ?-caprolactone (CL) with monohydroxyl or dihydroxyl poly(ethylene glycol) (PEG) were successfully performed using Novozyme-435 (immobilized lipase B from Candida antartica) as catalyst. Diblock and triblock copolymers with different compositions were characterized by ¹H NMR, GPC, DSC and X-ray diffraction. The enzymatic copolymerization carried out in toluene presented higher reaction rate and yield than that in bulk. Increasing the [CL]/[EO] feed ratio resulted in increases of molecular weight (M_n) of copolymers. Moreover, the compositions of triblock copolymers were closer to the monomer feed ratios than those of diblock copolymers. The resulting copolymers were all semicrystalline, the crystalline structure being of the PCL type. Solution cast films were allowed to degrade in a pH 7.0 phosphate buffer solution containing Pseudomonas lipase. Weight loss data showed that the introduction of PEG segments to the PCL main chain did not alter the enzymatic degradation of PCL significantly.