Lipase-catalyzed synthesis of pH-responsive poly(β-thioether ester)-b-poly(ethylene glycol)-b-poly(β-thioether ester) amphiphilic triblock copolymers for drug delivery

Novel amphiphilic triblock copolymers poly(β-thioether ester)-b-poly(ethylene glycol)-b-poly(β-thioether ester) (PTE-b-PEG-b-PTE) were designed for the first time and used as carriers for the sustained release of the hydrophobic drug curcumin (Cur). These BAB-type triblock copolymers were synthesized via one-step enzymatic polycondensation with catalysis by immobilized lipase B from Candida antarctica (CALB). The copolymers could self-assemble to form flower-like nanosized micelles in aqueous solution. The pH-triggered disassembly behaviors of the micelles were evaluated from the changes of the micellar size and molecular weight due to the acid-degradable β-thiopropionate groups in the hydrophobic PTE core. Cur was encapsulated into the micelles and showed faster release at pH 5.0 than pH 7.4. In vitro experiments indicated that the copolymers were non-cytotoxic, while the Cur-loaded micelles effectively inhibited the proliferation of HeLa cells. All these findings demonstrated the potential of PTE-b-PEG-b-PTE triblock copolymers as a promising pH-responsive nanocarrier for controlled drug delivery.     

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.     

Biodegradable nanoparticles of methoxy poly(ethylene glycol)-b-poly( d, l-lactide)/methoxy poly(ethylene glycol)- b-poly(ϵ-caprolactone) blends for drug delivery

The effects of blend weight ratio and polyester block length of methoxy poly(ethylene glycol)-b-poly( d, l-lactide) (MPEG- b-PDLL)/methoxy poly(ethylene glycol)- b-poly(ϵ-caprolactone) (MPEG- b-PCL) blends on nanoparticle characteristics and drug release behaviors were evaluated. The blend nanoparticles were prepared by nanoprecipitation method for controlled release of a poorly water-soluble model drug, indomethacin. The drug-loaded nanoparticles were nearly spherical in shape. The particle size and drug loading efficiency slightly decreased with increasing MPEG- b-PCL blend weight ratio. Two distinct thermal decomposition steps from thermogravimetric analysis suggested different blend weight ratios. Thermal transition changes from differential scanning calorimetry revealed miscible blending between MPEG- b-PDLL and MPEG- b-PCL in an amorphous phase. An in vitro drug release study demonstrated that the drug release behaviors depended upon the PDLL block length and the blend weight ratios but not on PCL block length.     

Sintered electrospun poly(ɛ-caprolactone)–poly(ethylene terephthalate) for drug delivery

Electrospinning has the inherent advantage of being able to achieve molecular mixing of polymers having substantially different melting points. Electrospun poly(ɛ-caprolactone)–poly(ethylene terephthalate) (PCL:PET) capsules are densified by sintering to enable drug encapsulation. Proton and diffusive nuclear magnetic resonance, as well as a selective dissolution, suggest an absence of reaction between the two polymers. Sintering at 100 °C successfully densifies 88.89:11.11 and 75:25 PCL:PET blends. Following sintering, the otherwise dense 75:25 composition retains electrospun features and exhibits some “memory” of its previous state. Sintering increases UTS approximately eightfold versus as-spun values for 88.89:11.11 and 75:25. Elongation increases sixfold and twofold and modulus 44- and 69-fold for the 75:25 and 88.89:11.11 samples, respectively. Differential scanning calorimetry suggests a postsintering structure of nanoscale PET dispersed in PCL along the original fiber directions. Selective PCL removal from dense blends shows that fibrous characteristics remain. An internal shish–kebab-like structure is also present in as-spun 75:25 PCL:PET. Water absorption of hydrophobic oil-containing capsules is approximately zero after 49 days. In contrast, hydrophilic (HPI) oils allow substantial water uptake. Unsurprisingly, there is no release of a model drug from the hydrophobic carrier. HPI oil provides linear (zero-order) release inversely proportional to PET from the 88.89:11.11 and 75:25 ratios. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47731.     

Thermogelation properties of poly(N-isopropylacrylamide) – block – poly(ethylene glycol) – block – poly(N-isopropylacrylamide) triblock copolymer aqueous solutions

Low polydispersity PNIPAM–PEG–PNIPAM triblock copolymers with PEG blocks of 1–6 kDa and PNIPAM chains of 5–30 kDa were synthesized and their thermogelation behavior in aqueous solution as a function of their composition and block length was investigated for the first time. DSC, dynamic rheometry and the tube inverting method were employed to characterize the gelation process at various polymer concentrations, and their results were compared. The thermogelation process depended mainly on the length of both PNIPAM and PEG blocks. Both association and aggregation temperatures of the PNIPAM chains decreased with the MW of PNIPAM and increased with the length of the PEG block. The amplitude of these effects depended on the molecular weights of the blocks forming the copolymer as a consequence of the partial mixing of PNIPAM and PEG chains during the association/aggregation process, while the overall hydrophilicity of the entire copolymer played only a minor role. The length of the PEG block proved also to be the most important factor for the preparation of a stable gel in 20 wt.% solutions, while the hydrophilic groups/hydrophobic groups ratio had no importance.     

A single-step polymerization method for poly(β-amino ester) biodegradable hydrogels

A novel one-step method for the preparation of poly(β-amino ester) hydrogels has been developed. The one-step method utilizes a Michael type addition reaction between a difunctional diacrylate and a tetrafunctional primary diamine to create a crosslinked biodegradable hydrogel. It was shown that the molar ratio of the reactive acrylate to amine controlled the extent of polymerization and crosslinking density of the hydrogel system, which enabled for the end properties of the network (e.g., swelling, degradation, and mechanical) to be tuned.     

Stereocomplexed 8-armed poly(ethylene glycol)–poly(lactide) star block copolymer hydrogels: Gelation mechanism,mechanical properties and degradation behavior

Mixing aqueous poly(ethylene glycol)-poly(d-lactide) and poly(ethylene glycol)-poly(l-lactide) star block copolymer solutions resulted in the formation of stereocomplexed hydrogels within 1 min. A study towards the mechanism of the temperature dependent formation of stereocomplexes in the hydrogels using rheology and nuclear magnetic resonance experiments revealed that the formation of stereocomplexes is facilitated at higher temperatures, due to rearrangement in the micellar aggregates thereby exposing more PLA units available for stereocomplexation. The formed gels became temperature irreversible due to the presence of highly stable semi-crystalline stereocomplexed PLA domains. An enantiomeric mixture of 8-armed star block copolymers linked by an amide group between the poly(ethylene glycol) core and the poly(lactide) arms (PEG–(NHCO)–(PLA)₈) yielded hydrogels with improved mechanical properties and stability at 37 °C in PBS compared to 8-armed star block copolymers linked by an ester group. The possibility to be formed in situ in combination with their robustness make PEG–(NHCO)–(PLA)₈ hydrogels appealing materials for various biomedical applications.     

Non-enzymatic and enzymatic degradation of poly(ethylene glycol)-b-poly(?-caprolactone) diblock copolymer micelles in aqueous solution

The non-enzymatic and enzymatic degradation behaviors of the monomethoxy-poly(ethylene glycol)-b-poly(?-caprolactone) diblock copolymers (MPEG-PCL) micelles in aqueous solution were investigated by DLS, ¹H NMR, SEC and HPLC. It is found that the degradation mechanism of MPEG-PCL micelles in aqueous solution in non-enzymatic case is quite different from that in the presence of enzyme. In non-enzymatic case, the degradation induced by acidic catalysis was not found in low pH aqueous solution but the degradation of the micelles occurred under neutral and basic conditions. The degradation of MPEG-PCL micelles first happens near the interface region of the MPEG shell and PCL core, leading to the part detachment of PEG chains. With increasing degradation time, the degradation inside the PCL core with a random scission on PCL chains occurred. Compared with non-enzymatic degradation, the enzymatic degradation of MPEG-PCL micelles is much fast and the degradation rate of MPEG-PCL micelles is proportional to either the micelles or the enzyme concentration in a certain range. Based on the micelle degradation behaviors that we observed, a possible mechanism for the enzymatic degradation of the MPEG-b-PCL micelles including PCL core erosion which results in cavitization of micellar core and micellar dissociation is proposed.     

The crystallization behavior of poly(ethylene glycol)-poly(ε-caprolactone) diblock copolymers with asymmetric block compositions

Crystallization behavior, structural development and morphology evolution of a series of poly (ethylene glycol)-poly(ε-caprolactone) diblock copolymers (PEG-b-PCL) were investigated via differential scanning calorimetry (DSC), X-ray diffraction (XRD) and atomic force microscopy (AFM). In these copolymers, both blocks were crystallizable and biocompatible. The mutual effects between the PEG and PCL blocks were significant, leading to the obvious block composition dependence of the crystallization behavior and morphology of the PEG-b-PCL copolymers. The relative block length determined which block crystallized first. The temperature-dependent XRD measurements confirmed which block crystallized first from the copolymer during the cooling procedure. Single crystals of the PCL and PEG homopolymers and the PEG-b-PCL copolymers were obtained and observed by AFM. The block (PCL or PEG) crystallized first would determine the crystal morphology. The block crystallized later acted as a solvent, which was advantageous to forming perfect single crystals of the whole block copolymers.     

Gold nanoparticle conjugated poly(p-phenylene-β-cyclodextrin)-graft-poly(ethylene glycol) for theranostic applications

Fluorescent conjugated polymers gained interest in the last decades for both imaging and targeting tumor cells for the purpose of diagnosis and treatment of cancer. In the light of this objective conjugated poly(p-phenylene) possessing β-cyclodextrin (β-CD) units in the main chain and poly(ethylene glycol) side chains is used as an imaging and therapeutic agent to target U87 and Vero cells. Additionally, imaging quality and therapy efficiency of the bare graft copolymer and its gold nanoparticle (AuNP) conjugated form were investigated and compared. It is observed that β-CD is effective not only for the imaging of the tumor cells, but also as a radiotherapy agent. Conjugation of the polymer with the AuNPs provides significant improvement in the therapeutic efficiency. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47250.     

Biodegradable vesicular nanocarriers based on poly(?-caprolactone)-block-poly(ethyl ethylene phosphate) for drug delivery

Biodegradable polymer vesicle for drug delivery is reported. Poly(?-caprolactone)-block-poly(ethyl ethylene phosphate) with well-defined structure (PCL₁₅₀-b-PEEP₃₀) has been prepared by ring-opening polymerization. It forms vesicles in aqueous solution using the thin-film hydration method and further exclusion of the as-formed vesicles results in vesicles at nano-size, demonstrated by confocal laser scanning microscope (CLSM) and transmission electron microscopy observations. Doxorubicin (DOX) has been loaded into the vesicles with a loading content of 4.38% using an acid gradient method. The release of DOX from the vesicles is accelerated in the presence of an enzyme phosphodiesterase I that is known to catalyze the degradation of polyphosphoester, achieving 83.8% release of total loaded DOX in 140 h. The DOX-loaded vesicles can be successfully internalized by A549 cells, and it results in enhanced inhibition to A549 cell proliferation, likely owning to the sustained intracellular release of DOX as observed by CLSM. With these properties, the vesicles based on the block copolymer of PCL and PEEP are attractive as drug carriers for pharmaceutical application.     

Preparation of curcumin loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) nanofibers and their in vitro antitumor activity against Glioma 9L cells

The purpose of this work was to develop implantable curcumin-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) nanofibers, which might have potential application in cancer therapy. Curcumin was incorporated into biodegradable PCEC nanofibers by electrospinning method. The surface morphology of the composite nanofibers was characterized on Scanning Electron Microscope (SEM). The average diameter of the nanofibers was 2.3-4.5μm. In vitro release behavior of curcumin from the fiber mats was also studied in detail. The in vitro cytotoxicity assay showed that the PCEC fibers themselves did not affect the growth of rat Glioma 9L cells. Antitumor activity of the curcumin-loaded fibers against the cells was kept over the whole experiment process, while the antitumor activity of pure curcumin disappeared within 48 h. These results strongly suggested that the curcumin/PCEC composite nanofibers might have potential application for postoperative chemotherapy of brain cancers.     

Synthesis and characterization of a novel graft copolymer with poly(n-octylallene-co-styrene) backbone and poly(?-caprolactone) side chain

A novel graft copolymer consisting of poly(n-octylallene-co-styrene) (PALST) as backbone and poly(?-caprolactone) (PCL) as side chains was synthesized with the combination of coordination copolymerization of n-octylallene and styrene and the ring-opening polymerization (ROP) of ?-caprolactone. Poly(n-octylallene-co-styrene) (PALST) backbone was prepared from the copolymerization of n-octylallene and styrene with high yield by using the coordination catalyst system composed of bis[N,N-(3,5-di-tert-butylsalicylidene)anilinato]titanium(IV) dichloride (Ti(Salen)₂Cl₂) and tri-isobutyl aluminum(Al(i-Bu)₃). The molar ratio of each segment in the copolymer, and the molecular weight of the copolymer as well as the microstructure of the copolymer could be adjusted by varying the feeding ratio of both styrene and n-octylallene. The hydroxyl functionalized copolymer PALST-OH was prepared by the reaction of mercaptoethanol with the pendant double bond of PALST in the presence of radical initiator azobisisbutyronitrile (AIBN). The target graft copolymer [poly(n-octylallene-co-styrene)-g-polycaprolactone] (PALST-g-PCL) was synthesized through a grafting-from strategy via the ring-opening polymerization using PALST-OH as macroinitiator and Sn(Oct)₂ as catalyst. Structures of resulting copolymer were characterized by means of gel permeation chromatography (GPC) with multi-angle laser light scattering (MALLS), ¹³C NMR, ¹H NMR, DSC, polarized optical microscope (POM) and contact angle measurements.     

Helix-helix transition of poly(β-phenylpropyl l-aspartate) embedded in stable helical poly(γ-phenylethyl glutamate) matrix

We studied the helix-helix transition of poly(β-phenylpropyl l-aspartate) (3PLA) embedded in a right-handed α-helical (α_R) poly(γ-phenylethyl l-glutamate) (2PLG) or left-handed α-helical poly(γ-phenylethyl d-glutamate) (2PDG) matrix. Binary mixtures were prepared with 3PLA:2PLG (2PDG) mole fractions of 9:1 to 1:9. In all these mixtures, the 3PLA molecule exhibited helical sense inversion even if dispersed or isolated into the hard-rod matrix, and the inversion rate of the embedded 3PLA molecule was relatively higher than that of the pure system. Thus, it was concluded that the transition occurs in only a limited space and more easily for the isolated molecule. Further, the 3PLA molecule recognized the chiral environment produced by the surrounding polymers. For 3PLA surrounded by a 2PDG matrix, the helix-helix transition temperature was lower and the transition rate on cooling was slower than those for 3PLA surrounded by a 2PLG matrix. This is reasonable since the left-handed matrix helps right-handed to left-handed helical inversion.     

Suprarmolecular hydrogels driven by the dual host–guest interactions between α-cyclodextrin and ferrocene-modified poly(ethylene glycol) with low-molecular-weight

In general, α-cyclodextrin (α-CD) and low-molecular weight poly(ethylene glycol) (low-MW PEG) (M_w = 400–10,000) cannot construct supramolecular hydrogels but easily form crystalline precipitates. In this study, low-MW PEG (M_n = 2000, PEG-2000) was functionalized by ferrocene as mono-end-group. The obtained ferrocene-modified PEG-2000 (FcPEG-2000) further self-assembled into supramolecular hydrogel with α-CD even at low concentration (C_FcPEG-2000 = 17 mg/ml), driven by dual host–guest interaction between α-CD and FcPEG-2000. Interestingly, the hydrogel was still observed even when hydrophobic Fc group was oxidized to hydrophilic ferrocenium (Fc⁺) or included into the cavity of β-CD. In the former case, the existence of Fc⁺ end groups is considered to decrease the probability of PEG de-penetration from α-CD cavity, so that α-CDs have more location and opportunities to aggregate into more channel-type crystalline domains as physical cross-linking points. While in the later case, the synergistic effect of host–guest interaction between β-CD and ferrocenyl groups and host–guest interaction between α-CD and PEG chains are considered to be the main reason. The resultant FcPEG-2000 based hydrogels showed the property of shear-thinning.     

Nanoparticle formulation of poly(?-caprolactone-co-lactide)-d-α-tocopheryl polyethylene glycol 1000 succinate random copolymer for cervical cancer treatment

Cervical cancer remains a critical problem that is second only to breast cancer affecting women worldwide. The objective of this study was to develop formulation of docetaxel-loaded biodegradable poly(?-caprolactone-co-lactide)-d-α-tocopheryl polyethylene glycol 1000 succinate (PCL-PLA-TPGS) nanoparticles for cervical cancer chemotherapy. A novel random copolymer, PCL-PLA-TPGS, was synthesized from ?-caprolactone, lactide and d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) by ring-opening polymerization. The obtained polymers were characterized by ¹H NMR, FTIR, GPC and TGA. The docetaxel-loaded PCL-PLA-TPGS nanoparticles were prepared by a modified solvent extraction/evaporation technique and characterized in terms of size and size distribution, morphology, surface charge and physical state of encapsulated docetaxel. Cellular uptake and in vitro cytotoxicity of nanoparticle formulations were done in comparison with commercial formulation Taxotere^® to investigate the efficacy of PCL-PLA-TPGS nanoparticles. In vitro cellular uptakes of such nanoparticles were investigated with CLSM, demonstrating the coumarin 6-loaded PCL-PLA-TPGS nanoparticles could be internalized by Hela cells. In vitro cancer cell viability experiment showed that judged by IC₅₀, the PCL-PLA-TPGS nanoparticle formulation was found to be more effective in cell number reduction than the Taxotere^® after 48 h (p < 0.05), 72 h (p < 0.05) treatment. In conclusion, the PCL-PLA-TPGS copolymer could be acted as a novel and promising biologically active polymeric matrix material for nanoparticle formulation in cervical cancer treatment.     

Preparation and characterization of poly(ethylene glycol)-block-poly[ε-(benzyloxycarbonyl)-l-lysine] thin films for biomedical applications

The nanoscale architectures evident in the thin films of self-assembling hybrid block copolymers—which are tailored to inherit the advantageous properties of their constituent synthetic (homo)polymer and polypeptide blocks—have continued to inspire a variety of new applications in different fields, including biomedicine. The thin films of symmetric hybrid block copolymer, α-methoxy-poly(ethylene glycol)-block-poly[ε-(benzyloxycarbonyl)-l-lysine], MPEG₁₁₂-b-PLL(Z)₁₇, were prepared by solvent casting in five different solvents and characterized using Attenuated Total Reflectance-Fourier Transform Infrared spectroscopy, Thermogravimetric analysis, Derivative Thermogravimetric analysis, Differential Scanning Calorimetry, Contact Angle goniometry, Wide-Angle X-ray Diffraction, and Scanning Electron Microscopy. Film thickness was estimated to be 51 ± 23 μm by the “step-height” method, using a thickness gauge. Although no significant change to the block copolymer’s microstructure was observed, its solvent-cast films displayed divergent physical and thermal properties. The resulting cast films proved more thermally stable than the bulk but indicated greater block miscibility. Additionally, the thin films of MPEG₁₁₂-b-PLL(Z)₁₇ preserved the microphase separation exhibited by the bulk copolymer albeit with appreciable loss of crystallinity. The surface properties of the polymer–air interface were diverse as were the effects of the casting solvents. Oriented equilibrium morphologies are also evident in some of the as-cast thin films.     

Physical and mechanical properties of poly(methyl methacrylate) -functionalized graphene/poly(vinylidine fluoride) nanocomposites: Piezoelectric β polymorph formation

Poly(methyl methacrylate) -functionalized graphene (MG) is prepared from graphene oxide (GO), using atom transfer radical polymerization (ATRP) and reducing with hydrazine hydrate. PMMA causes an increase of height of MG sheet for polymerization of MMA at side and basal planes. MG layers become thinner for exfoliation during composite formation. Graphene sheets enhance piezoelectric β-polymorph PVDF formation. MG sheets nucleate PVDF crystals and a gradual decrease of α phase occurs with a concomitant rise of β phase. Thermal stability of nanocomposites increases significantly and the T_g increase is really large (21 °C). Storage modulus shows an increase of 124%, stress at break 157% and Young’s modulus 321% for 5% MG. Parallel orientation of graphene sheets changes to random orientation for high graphene content. It exhibits conducting percolation threshold at 3.8% MG and variable range hopping model suggests that conductivity is contributed from the intergrain tunnelling and hopping between the grains.     

Cross-linked degradable poly(β-thioester) networks via amine-catalyzed thiol-ene click polymerization

A set of binary and ternary biodegradable cross-linked poly(β-thioester) networks have been synthesized via thiol-ene Michael additions, by reacting combinations of dithiols, diacrylates and multifunctional cross-linkers. Insoluble binary thermoset networks and soluble ternary branched polymers with broad molar mass distributions are obtained in a facile manner after polymerization at room temperature for only few minutes. The networks display excellent thermal stability up to 250 °C and exhibit low glass transition temperatures. The soluble branched polymers show degradation of the polyester backbone upon chemical degradation by acidic and basic solutions. Finally, the (bio)degradability of ternary PBT polymer films is examined via quartz crystal microbalance measurements. Weight loss is measured as a function of time upon exposure to phosphate buffers at different pH. PBTs carrying apolar chain segments display surface degradation, while PBTs with more polar ethylene glycol segments allow for swelling in aqueous solution, which is reflected in concomitant surface and bulk degradation of the materials. Because of their biodegradability, these easy to synthesize poly(β-thioesters) networks are considered to be suitable candidates to use in future biomedical or ecological applications.     

Thermal properties of di- and triblock copolymers of poly(l-lactide) with poly(oxyethylene) or poly(ε-caprolactone)

High molecular weight di- and triblock copolymers of poly(l-lactide), PLLA, (80 wt%) with a crystallizable flexible second component such as poly(ε-caprolactone), PCL, or poly(oxyethylene), PEO, (20 wt%) were obtained in nearly quantitative yields by ring opening of l-lactide initiated by PCL or PEO hydroxy terminated macromers. The copolymers were characterized by ¹H NMR and FTIR spectroscopy and size exclusion chromatography and showed unimodal and narrow molecular weight distributions. X-ray diffraction measurements revealed high crystallinity (38-56%) of the PLLA blocks and gave no clear evidences of PCL or PEO crystallinity. DMTA and DSC techniques showed a melting behaviour of the copolymers (T_m=174-175 °C; ΔH_m=19-37 J/g) quite similar to that of PLLA. PCL and PLLA segments are immiscible, while PLLA and PEO segments are partially miscible in the amorphous phase. Stress-strain measurements indicated a ductile behaviour of the copolymers, characterized by lower tensile moduli (225-961 Pa) and higher elongations at break (25-134%) with respect to PLLA.