Enzymatic Ring-opening Copolymerization Research Articles

Controlling the biodegradation rates of poly(globalide-co-ε-caprolactone) copolymers by post polymerization modification

Controlling the degradation rates of polymers is crucial for their application in tissue engineering or to achieve degradation of the polymers in the wastewater purification. As hydrophobic polyesters often exhibit very slow degradation rates, we report here increased biodegradation rates of poly(globalide-co-ε-caprolactone) copolymers (PGlCL) produced by enzymatic ring-opening copolymerization and post-functionalized with N-acetylcysteine by thiol-ene reaction. The degradation rates of the PGlCL and post-modified PGlCL-NAC films were determined by weight-loss experiments. The polymer films were immersed in phosphate-buffered saline (PBS) solution, and PBS containing lipase from Pseudomonas cepacia. The degree of functionalization affected the degradation behavior, and samples with a higher degree of functionalization presented higher weight loss. Finally, a degradation assay was performed in activated sludge, and PGlCL-NAC presented high degradability, having a degradation behavior similar to starch. Density Functional Theory (DFT) calculations were used to assess the changes in chemical properties and electronic charge distribution of PGlCL after its functionalization with NAC, helping to understand its influence in their degradability. The results obtained confirm the possibility to increase the degradation rates of copolyesters based on caprolactone and globalide by thiol-ene post-functionalization, being a promising alternative for applications in biomedicine or the packaging sector.

Copolymacrolactones Grafted with l-Glutamic Acid: Synthesis, Structure, and Nanocarrier Properties.

The enzymatic ring-opening copolymerization (eROP) of globalide (Gl) and pentadecalactone (PDL) was performed in solution from mixtures of the two macrolactones at ratios covering the whole range of comonomeric compositions. The resulting P(Glx-r-PDLy) random copolyesters were aminofunctionalized by thiol-ene reaction with aminoethanethiol. ROP of γ-benzyl-l-glutamate N-carboxyanhydride initiated by P(Glx-r-PDLy)-NH2 provided neutral poly(γ-benzyl-l-glutamate)-grafted copolyesters, which were converted by hydrolysis into negatively charged hybrid copolymers. Both water-soluble and nonsoluble copolymers were produced depending on copolymer charge and their grafting degree, and their capacity for self-assembling in nano-objects were comparatively examined. The emulsion solvent-evaporation technique applied to the chloroform-soluble copolymers grafted with benzyl glutamate rendered well-delineated spherical nanoparticles with an average diameter of 200–300 nm. Conversely, micellar solutions in water were produced from copolyesters bearing grafted chains composed of at least 10 units of glutamic acid in the free form. The copolymer micelles were shown to be able to load doxorubicin (DOX) efficiently through electrostatic interactions and also to release the drug at a rate that was markedly pH dependent.

One-Pot Synthesis of Poly(glycerol- co-succinic acid) Nanogels for Dermal Delivery.

Polyglycerol nanogels are three-dimensional polymeric networks with a few hundred nanometer sizes and the ability to encapsulate and deliver cargos for a wide range of biomedical applications. However, time-consuming and multistep synthetic routes as well as milligram-scale production have hindered further development of these nanomaterials. In this work, we report on a straightforward synthetic method for the production of polyglycerol nanoarchitectures. Enzymatic ring-opening copolymerization of a mixture of glycidol and succinic anhydride resulted in polyglycerol nanogels with succinic acid segments in their backbone. Novozyme 435 was used as a dual catalytic agent to support ring-opening polymerization of the above-mentioned cyclic monomers as well as esterification of the produced oligomers to obtain nanogels. While succinic acid segments improved the biodegradability and loading capacity of nanogels, polyglycerol caused water solubility, high functionality, and biocompatibility. Nanogels were loaded with tacrolimus and photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (mTHPP)-a close congener of the approved photosensitizer temoporfin (mTHPC)-and their ability to improve the skin penetration of these therapeutic agents was investigated. mTHPP delivery experiments on human skin, which were quantified by fluorescence microscopy, showed that these nanogels deposit in the stratum corneum and release the loaded drug to viable epidermis of skin efficiently in comparison with commercially available base cream. Taking advantage of the straightforward synthesis as well as biodegradability, biocompatibility, high loading capacity, and efficient skin penetration, the synthesized nanogels could be used as future topical delivery systems.

Enzymatic ring opening copolymerization of globalide and ε-caprolactone under supercritical conditions

The enzymatic ring opening copolymerization of globalide and ε-caprolactone under supercritical conditions was investigated. Samples were evaluated in terms of molecular weight, thermal properties, ratio between repeating units, and production of cyclic oligomers. For the first time, poly(globalide-co-ε-caprolactone) (PGlCL) was synthesized by e-ROP using supercritical carbon dioxide (scCO2) and the mixture scCO2+dichloromethane (DCM) as solvents. The feed ratio between globalide and ε-caprolactone was evaluated. PGlCL synthesized in scCO2 showed the highest molecular weights, while the use of cosolvent caused a decrease on molecular weight values. For both scCO2 and scCO2+DCM, the increase on globalide content (relative to total monomers amount) increased molecular weight values. Thermal analysis indicated a non-isomorphic behavior, characteristic of random semi-crystalline copolymers, which is the case of the PGlCL produced. PGlCL synthesized on scCO2+DCM presented double melting point, which is related to a greater presence of cyclic oligomers, in comparison to PGlCL synthesized using only scCO2, being confirmed by MALDI-TOF analysis.

Enzymatic synthesis of poly(ε-caprolactone-co-ε-thiocaprolactone)

This study presents the successful enzymatic ring opening copolymerization of ε-caprolactone (ε-CL) and ε-thiocaprolactone (ε-TCL) catalyzed by Novozyme 435, immobilized lipase B from Candida antarctica. Various monomers feed ratio (from 0 to 100% in TCL content) were tested using two polymerization strategies. The first one is a direct one-step strategy, starting with both monomers mixed in the feed, while the two-steps strategy consists in a first step of ε-CL homopolymerization followed by a second step with ε-TCL addition in the medium and its polymerization from the previously formed PCL chains. The obtained copolymers have been fully characterized by NMR, DSC, SEC and MALDI-ToF MS spectroscopy. Main results of the one-step strategy showed a decrease in the final copolymer molar mass with the increase in ε-TCL content as well as minimum values of crystallinity and melting temperature for the 50:50 feed composition. An in-depth analysis of the MALDI-TOF mass spectra of the copolymers showed interesting patterns that suggest a micro-structuration of polymers from the one step strategy resulting from an uncommon multistep chain growth mechanism of trimers addition. The two-steps strategy produced copolymers showing a more blocky structure, as confirmed by their two distinct melting temperatures.

Lipase-Catalyzed Ring-Opening Copolymerization of ε-Caprolactone and β-Lactam

The enzymatic ring-opening copolymerization of ε-caprolactone (ε-CL) and β-lactam by using Candida antarctica lipase B (CAL-B) as catalyst was studied. Variation of the feed ratios of 25:75, 50:50, and 75:25 of ε-CL/β-lactam was performed. The products contain poly(ε-CL-co-β-lactam) and the homopolymers of poly(ε-CL) and poly(β-lactam). The structure of the copolymers was determined by MALDI-ToF MS. Poly(ε-CL-co-β-lactam) has an alternating and random structure consisting of alternating repeating units with oligo(ε-CL) or oligo(β-lactam). The highest fraction of the alternating copolymers resulted from the reaction with a feed ratio 50:50. The copolymer is a semicrystalline polymer with a Tm at 124 °C and Tgs at -15 and 50 °C. Interestingly, the copolymer also demonstrated cold crystallization at 29 and 74 °C, after quenching the sample from the melt in liquid nitrogen.

SYNTHESIS AND CHARACTERIZATION OF PNIPAM-b-POLYCARBONATE COPOLYMERS AS SELF-ASSEMBLED THERMOSENSITIVE MICELLES FOR DRUG DELIVERY

以多孔硅球固定化猪胰脂肪酶(IPPL)为催化剂,温敏性HO-PNIPAM为大分子引发剂,5-甲基-5-烯丙氧羰基-三亚甲基碳酸酯(MAC)和5,5-二甲基三亚甲基碳酸酯(DTC)为共聚单体,通过开环聚合合成了不同结构比例的两亲性嵌段型共聚物P(MAC-co-DTC)-b-PNIPAM.该嵌段型共聚物在水中可自组装形成稳定的胶束,其CMC值为20~60 mg/L,干态粒径20~70 nm,LCST值为38~43℃,细胞毒性实验显示其具有良好的生物相容性.以疏水性药物醋酸泼尼松为模型药物,研究了嵌段型共聚物胶束对药物的负载及释放行为,结果表明载药胶束具有良好的温敏性药物释放性能.

Enzymatic Synthesis and Characterization of Novel Biodegradable Copolymers of 5-Benzyloxy-trimethylene Carbonate with 1,4-Dioxan-2-one

Enzymatic ring-opening copolymerization of 5-benzyloxy-trimethylene carbonate (BTMC) and 1,4-dioxan-2-one (DON) was investigated for the first time. Immobilized porcine pancreas lipase (IPPL) on silica particles was selected to perform the copolymerization. A series of novel biodegradable copolymers with different compositions were characterized by (1)H NMR, (13)C NMR, and GPC. The influences of reaction conditions such as polymerization time and catalyst concentration on the yield and molecular weight of the copolymers were also studied. The copolymerizations of different monomer feed ratios were carried out in bulk at 150 degrees C with 4.5 wt per thousand IPPL as a catalyst for 24 h. With the increase of the BTMC molar feed ratio from 20% to 79%, the M(n) of the resulting copolymers increased from 5600 to 63400. Water uptake and static contact angle experiments showed that the hydrophilicity of copolymers could be improved with increasing DON content in the copolymers. Moreover, the in vitro drug release rate (ibuprofen as the model drug) of the resulting copolymers also increased along with the DON content in the copolymers.

Enzymatic ring-opening copolymerization of trimethylene carbonate and ethylene ethyl phosphate

Enzymatic ring-opening copolymerization of trimethylene carbonate (TMC) and ethylene ethyl phosphate (EEP) are performed in bulk at 100°C using porcine pancreas lipase (PPL) or candida rugosa lipase (CL) as catalyst. The factors affecting the yield and molecular weights such as catalyst concentration, polymerization time and monomer feed ratio are investigated. The random copolymers obtained have molecular weight ranging from 3200 to 10200. The glass transition temperature (T g) of the copolymers decreases from −28 to −41.7°C, with the increase of the EEP content in the feed from zero to 5:10. Degradation tests show that the degradability of the copolymers is improved by introduction of the EEP unit into the copolymer chain.

Enzyme-catalyzed ring-opening copolymerization of 5-methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one (MBC) with trimethylene carbonate (TMC): synthesis and characterization.

Enzymatic ring-opening copolymerization of 5-methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one (MBC) with trimethylene carbonate (TMC) was investigated. A route to aliphatic polycarbonates decorated with pendent carboxylic acid groups is demonstrated. Lipase from Pseudomonas fluorescens (AK) was selected to perform the copolymerization at various monomers feed ratios. Copolymers with different composition were prepared by varying the monomer feed ratio from 10% to 80% MBC. 1H, 13C, and 1H-13C HETCOR NMR spectra were used to analyze the microstructure of the copolymers. The 1H NMR spectra indicated lower incorporation of TMC in the copolymer than was expected from the monomer feed ratio. Analysis of the 13C spectra did not indicate an ordered structure but instead suggested the formation of random polymers. This was further confirmed by the thermal data obtained for representative samples. The thermal properties at different feed ratios of poly[MBC-co-TMC] copolymers were investigated by differential scanning calorimetry (DSC). No melting temperature (Tm) for either homopolymers or copolymers was observed. A plot of 1/Tg(K) vs the weight composition of MBC in the copolymers was constructed and was consistent with copolymers that tend toward random distribution; this was confirmed from the NMR data.

Synthesis of Polyesters by Enzymatic Ring-Opening Copolymerization Using Lipase Catalyst.

Enzymatic ring-opening copolymerization of lactones was carried out by using Pseudomonas fluorescens lipase in bulk. In the copolymerizaton of e-caprolactone (e-CL) and δ-valerolactone at 60°C for 10 days a copolymer with molecular weight of 3.7×103 was obtained and its structure was found to be of random structure having both units from 13C NMR anlaysis. Effects of the feed ratio, the reaction time and temperature on the copolymerization have been examined. The enzymatic copolymerization of e-CL with other lactones and D-lactide also gave corresponding copolymers.