Combination Of Ring-opening Polymerization Research Articles

Combination of ring-opening polymerization and “click” chemistry towards functionalization of polycaprolactone with sulfobetaine groups

A novel polycaprolactone (PCL) bearing sulfobetaine (SB) and N,N-dimethylamine (DMA) pendent groups distributed randomly along the biodegradable PCL backbone, P(SBCL-co-DMACL-co-CL), PSDCC was synthesized by combination of ring-opening polymerization and ‘‘click’’ chemistry. The chemical composition and the structure of PSDCC were confirmed by 1H nuclear magnetic resonance (1H NMR) spectroscopy, fourier transform infrared (FT-IR) spectroscopy and gel permeation chromatography (GPC). Studies on the self-assembly in water show that the PSDCC nanoparticles have a narrow size distribution with the diameter about 140 nm. Besides, the nanoparticles possess enhanced stability, pH-sensitive doxorubicin (DOX) release behavior, excellent biocompatibility and cellular uptake to MCF-7 cells. Therefore, the copolymer of PSDCC synthesized by this simple method is a highly promising material as a new drug delivery carrier for cancer therapy.

Visible light and pH-responsive star copolymer and doxorubicin-polymer conjugate micelles for combination drug delivery and bioimaging

Amphiphilic 3-arm star copolymer containing visible light-cleavable BODIPY group and pH-responsive imine bonds at the junction of hydrophilic poly(ethylene glycol) (PEG) and two poly(ε-caprolactone) (PCL) arms was synthesized by the combination of ring-opening polymerization (ROP) and click chemistry. The formation and stimuli-responsive disruption of micelles were analyzed using dynamic light scattering and transmission electron microscopy. Dual stimuli-responsive release of anticancer drugs Doxorubicin (Dox) and Camptothecin (CPT) from the micelles was studied. Micellar assemblies containing Dox conjugated to PEG-BODIPY through imine bonds were prepared and controlled release of Dox in response to visible light and pH was shown. CPT and Dox-loaded star copolymer micelles as well as CPT loaded Dox-conjugated micelles were used in cellular uptake studies on MDA-MB 231 cells, and the synergistic effect of the two stimuli on the release of the two drugs was demonstrated inside the cells. Micellar assemblies also showed excellent bioimaging properties in the cellular uptake studies.

Synthesis and self-assembly of H-shaped amphiphilic block copolymer based on polyoxyethylene, polyoxybutylene, and poly(ε-caprolactone) units

In this research, a new amphiphilic copolymer with an H-shaped macromolecular structure consisting of three hydrophobic blocks and two hydrophilic blocks were synthesized by a combination of ring-opening polymerization and click chemistry. The central chain and two of the side arms of the H-shaped structure were made of oxybutylene and hexanoate repeating units, respectively (hydrophobic segments). The remaining two side arms are made of oxyethylene repeating units (hydrophilic segments) that are connected to the rest of the structure through disulfide bonds. The prepared H-shaped macromolecules were characterized by elemental analysis (CHNS), FT-IR, and 1H-NMR techniques. Based on transmission electron microscopy (TEM) images, the amphiphilic nature of the H-shaped polymer allowed it to form spherical molecular assemblies with a mean diameter of about 80 nm. The critical micelle concentration (CMC) in an aqueous solution was determined using the fluorometric method (CMC = 4.76 × 10−3 mg/mL). According to the profiles obtained from dynamic light scattering (DLS), the resulting spherical micelles had a mean hydrodynamic diameter ( H ) of ∼95 nm with a low polydispersity index (PDI = 0.26).

Phosphonate-Functionalized Polycarbonates Synthesis through Ring-Opening Polymerization and Alternative Approaches

Well-defined phosphonate-functionalized polycarbonate with low dispersity (Ð = 1.22) was synthesized using organocatalyzed ring-opening polymerization (ROP) of novel phosphonate-based cyclic monomers. Copolymerization was also performed to access different structures of phosphonate-containing polycarbonates (PC). Furthermore, phosphonate-functionalized PC was successfully synthesized using a combination of ROP and post-modification reaction.

Elastomeric copolyesters of ω-pentadecalactone and cyclohexylenedimethylene succinate obtained by enzymatic polymerization

The use of renewable monomers and green polymerization processes for preparing new synthetic polymers is a hot topic today. In this work we have obtained high molecular weight copolyesters derived from ω-pentadecalactone (PDL), dimethyl succinate (DMS) and 1,4-cyclohexanedimethanol (1,4-CHDM) by a combination of ring opening polymerization (ROP) and two step melt polycondensation processes. The reaction has been carried in bulk under mild conditions (80–120 °C) and catalyzed by immobilized Candida artarctica lipase B (N435 biocatalyst). These reactions were followed by 1H NMR and it was observed that although PDL reacted faster, at the end copolyesters displayed a random microstructure due to transesterification reactions taking place during polymerization. These copolyesters were thermally stable up to around 350 °C and semicrystalline for all compositions with melting temperatures decreasing with the increased content of the counterpart comonomer up to a pseudo-eutectic point located at 40 mol-% of PDL composition. The crystalline structure and transitions taken place by heating have been studied by WAXS and SAXS synchrotron X-ray diffraction. Copolyesters with elastomeric properties could be obtained at intermediate compositions.

Functional Poly(ε-caprolactone)/Poly(ethylene glycol) Copolymers with Complex Topologies for Doxorubicin Delivery to a Proteinase-Rich Tumor Environment

Doxorubicin (DOX)-loaded polymer nanoparticles based on poly(ethylene glycol)-poly(ε-caprolactone) copolymers with a complex macromolecular topology are proposed to tackle the matrix metalloproteinase (MMP)-rich tumor environment. Linear, 4-arm comb-like copolymers and 4-arm brush block copolymers were synthesized through a combination of ring opening polymerization and atom transfer radical polymerization, in order to control the molar mass distribution, the arm/brush architecture, as well as the final size and DOX loading of self-assembled nanoparticles obtained by nanoprecipitation. The optimized nanocarriers were conjugated with penetrating low molecular weight protamine peptides coupled to a polyanionic inhibitory domain cleavable by matrix metalloproteinase-2 (MMP2). DOX-loaded, MMP2-activable nanocarriers were evaluated in the context of glioblastoma (GBM), a brain tumor characterized by remarkable and relevant MMP2 expression. Uptake and cytotoxicity in patient-derived GBM cells correlated with the level of MMP2 enzymatic activity in a dose- and time-dependent manner. No effects were observed in nontumoral endothelial cells that do not express MMP2. Results demonstrated that, by tuning polymer topology and peptide sequence, nanoparticle self-assembly, DOX encapsulation, and delivery can be optimized for the development of an advanced treatment for MMP2-overexpressing tumors.

Peptide-guided self-assembly of polyethylene glycol-b-poly(ε-caprolactone-g-peptide) block copolymers

Biodegradable poly(ethylene glycol)-b-poly(ε-caprolactone-g-peptide) (PEG-b-PCL-g-peptide) copolymers were synthesized using a combination of ring opening polymerization and thiol-yne photoaddition of peptides on the alkyne functional PCL block. The peptides Phe-Phe, Tyr-Tyr and Arg-Gly-Asp were selected based on the expected interactions (Pi-stacking, H-bonding, electrostatic). The self-assembly of these copolymers was studied via testing the effect of various parameters such as the nature of the solvent and non-solvant as well as their ratio, mixing method, temperature and concentration. Structures obtained by varying these parameters were characterised using transmission electron microscopy (TEM) and dynamic light scattering (DLS). Spherical and lamellar structures (oval leaf-shaped) of different sizes were identified as a function of the conditions. The role of the crystallisation and of the peptides was highlighted with more defined and stable structures obtained for Tyr-Tyr functional copolymers.

Synthesis of an amphiphilic copolymer using biopolymer-dextran via a combination of ROP and RAFT techniques

Ring-opening polymerization (ROP) and reversible addition–fragmentation chain-transfer (RAFT) polymerization are efficient synthetic approaches to develop self-assembled copolymers with narrow dispersity (Đ).

Synthesis and characterization of poly(ε-caprolactone) tetra-arm star polymer using tetra terminal alkynyl-substituted phthalocyanine by the combination of ring-opening polymerization and “click” chemistry

Abstract The synthesis of poly(ε-caprolactone) (PCL) tetra-arm star polymer was carried out using “click” chemistry and ring-opening polymerization techniques. For this purpose, poly(ε-caprolactone) azido (PCL-N3) was acquired using ring-opening polymerization of ε-caprolactone and 2-[2-(2-azidoethoxy)ethoxy]ethanol (N3ol). N3ol was obtained using sodium azide and 2-[2-(2-chloroethoxy)ethoxy]ethanol. 4-(prop-2-ynyloxy)-phthalonitrile was obtained by using 4-nitrophthalonitrile and propargyl alcohol. 2(3),9(10),16(17),23(24) Tetrakis-[(prop-2-ynyloxy)-phthalocyaninato]zinc(II) (Pc-propargyl) was synthesized by using 4-(prop-2-ynyloxy)-phthalonitrile and a metal salt. By reacting Pc-propargyl and PCL-N3, PCL tetra-arm star polymer was obtained by “click” chemistry. The products were characterized via scanning electron microscopy, 1H-nuclear magnetic resonance spectroscopy, ultraviolet-visible spectrophotometry, Fourier-transform infrared spectroscopy, and gel permeation chromatography instruments. The spectroscopic analyses of PCL tetra-arm star polymer prove that the star polymer was built through the combination of ROP and “click” chemistry. We provided a protocol for PCL tetra-arm star polymer, and a statement of reproducibility with respect to the properties of this tetra-arm star polymer. This study is an example of a novel type of combination reaction, from ring-opening polymerization to “click” chemistry using phthalocyanine. This can open the door for diverse tetra-arm star polymer synthesis that could potentially cause major advances in synthetic macromolecular chemistry.

Synthesis of a Diapocynin Prodrug for Its Prolonged Release from Zwitterionic Biodegradable Nanoparticles

AbstractToday, neurodegenerative diseases are affecting more and more individuals. A typical therapeutic target to treat the progression of the symptoms related to these diseases is the proinflammatory microglia. Diapocynin, the dimeric version of apocynin, is often the drug of choice. However, suitable carriers for its controlled delivery are currently lacking in the clinics. In fact, its high hydrophilicity hampers the development of a formulation enabling its sustained release in a biological environment. In this work, the possibility of modifying diapocynin is explored in order to synthesize a prodrug that can be chemically incorporated into biodegradable zwitterionic polymer nanoparticles (NPs). These NPs are synthesized via combination of ring opening polymerization and reversible addition–fragmentation chain transfer (RAFT) polymerization, allowing the incorporation of the desired number of diapocynin units into the carrier and thus to set the drug dosage a priori. The chemical binding of diapocynin avoids its premature release compared to its physical loading inside similar nanovectors. With this strategy, sustained diapocynin release can be achieved for more than 9 days, thus paving the way to a therapy with low number of repeated administrations.

Synthesis of core-shell bottlebrush polymers of poly(polycaprolactone-b-polyethylene glycol) via ring-opening metathesis polymerization

This research was focused on the synthesis of core-shell bottlebrush polymer poly(PCL-b-PEG) (PCL: polycaprolactone; PEG: polyethylene glycol) through a combination of ring-opening polymerization (ROP) and ring-opening metathesis polymerization (ROMP). Three main steps were involved in this synthesis: firstly, the ROP of ε-caprolactone was conducted to form an amphiphilic linear polymer PEG-b-PCL in presence of methoxypolyethylene glycols and Sn(Oct)2; secondly, macromonomers with norbornenyl-functionalization were synthesized by the esterification of the hydroxyl-terminated PEG-b-PCL with 5-norbornene-2-carboxylic acid; thirdly, the synthesized macromonomers were further polymerized by ROMP in presence of Grubbs second-generation catalyst to form a core-shell bottlebrush structured polymer. The effects of the reaction time, concentrations of small-molecule monomers, amount of catalyst and the molecular weights of macromonomers on the performance of the ROMP of the macromonomers were investigated in detail. 1H NMR and GPC analyses confirmed the structures of the resulting polymers. DSC, XRD, TGA were used to characterize the properties of PEG-b-PCL and poly(PCL-b-PEG). Compared with the linear block polymers PEG-b-PCL, the resulting polymers with core-shell bottlebrush structures have a more regular chain arrangement and better thermal stability.

High Antibacterial Activity and Selectivity of the Versatile Polysulfoniums that Combat Drug Resistance.

Sulfonium-ion-containing polymers exhibit significant potential benefits for various applications. An efficient strategy to synthesize a type of antibacterial sulfonium-ion-bearing polypeptoids via a combination of ring-opening polymerization and a post-polymerization functionalization with various functional epoxides is presented. A systematic investigation is further performed in order to explore the influence of the overall hydrophobic/hydrophilic balance on the antimicrobial activity and selectivity of the prepared polysulfoniums. Notably, those chlorepoxypropane-modified polysulfoniums with an optimized amphiphilic balance show higher selectivity toward both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, than to red blood cells. The polymers also show great efficiency in inhibiting S. aureus biofilm formations, as well as in further eradicating the mature biofilms. Remarkably, negligible antibacterial resistance and cross-resistance to commercial antibiotics is shown in these polymers. The polysulfoniums further show their potent in vivo antimicrobial efficacy in a multidrug-resistant S. aureus infection model that is developed on mouse skin. Similar to the antimicrobial peptides, the polysulfoniums are demonstrated to kill bacteria through membrane disruption. The obtained polypeptoid sulfoniums, with high selectivity and potent antibacterial property, are excellent candidates for antibacterial treatment and open up new possibilities for the preparation of a class of innovative antimicrobials.

Nanocarriers based on block copolymers of l-proline and lactide: The effect of core crosslinking versus its pH-sensitivity on their cellular uptake

Although doxorubicin (DOX) is an effective drug with cytotoxicity against a variety of different tumors, it also induces undesired side-effects to the healthy tissues. Therefore, the smart nanocarrier-based systems are the solution for this problem due to the entrapment of the drug in the stimuli-responsive, polymeric core. This allows to decrease the toxicity of the DOX and allows for the delivery of DOX precisely to the tumor sites. Herein, we present such a smart nanoparticle platform composed of stimuli-responsive copolymers of l,l-lactide/d,d-lactide with l-proline, which were successfully synthesized through the combination of ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. These copolymers were used for the preparation of enantiomeric and stereocomplexed nanoparticles (NPs) with a mean diameter of about 160–210 nm that were used as a reservoir of the anticancer drug. The drug release results showed that (co)polymeric NPs possess an excellent pH-sensitive behavior under the acidic tumor microenvironment, however, it was less pronounced for NPs cross-linked by stereocomplexation between poly(l-lactide) (PLLA) and poly(d-lactide) PDLA chains. Additionally, the DOX-loaded NPs were effective against AGS, HeLa, and Lovo cells, nevertheless, their cytotoxicity strongly depends on the building blocks of the nanocarrier. Interestingly, the l-proline functionality enhances the cellular uptake of enantiomeric NPs, nonetheless, the high stability of NPs due to the supramolecular crosslinking of PLA macromolecules prevails over this effect and stereocomplexed NPs were better internalized by the cancer cells. These advantageous features indicate that stereocomplexed (sc), (co)polymeric NPs are promising candidates as a smart and versatile nanocarrier platform for the treatment of different types of tumors.

Reduction and temperature dually-triggered size-shrinkage and drug release of micelles for synergistic photothermal-chemotherapy of cancer

Reduction and temperature dually responsive poly(2-(2-methoxyethoxy)ethylmethacrylate-co-oligo(ethylene glycol) methacrylate)-b-poly(ε-caprolactone)-SS-poly(ε-caprolactone)-b-poly(2-(2-methoxyethoxy)ethylmethacrylat-co-oligo(ethylene glycol) methacrylate) (P(MEO2MA-co-OEGMA)-b-PCL-SS-PCL-b-P(MEO2MA-co-OEGMA)) was synthesized by the combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The copolymer can self-assemble into spherical micelles. After loading doxorubicin (DOX) and photothermal agent Indocyanine green (ICG), the micelles were endowed with synergistic effect of chemotherapy and photothermal therapy to cancer through reduction and temperature dually triggered size-shrinkage and drug release. The micelles showed good reduction and temperature responsiveness due to the presence of disulfide bond and thermoresponsive segments in copolymer. Under reducing conditions, the disulfide bond broke and the micelles were converted into micelles with half the original size, which was conducive to drug release. Near Infrared light (NIR) promoted the photothermal conversion of ICG, so that the micelle underwent a temperature response transition and further promoted the release of drugs. The micelles showed drug release rate, high photothermal conversion efficiency, highly cytotoxic to cancer cells and excellent synergistic photothermal-chemotherapy effect.

Hollow organic/inorganic hybrid nanoparticles from dextran-block-polypeptide copolymer: Double click reaction synthesis and properties

To increase the drug loading and prolong the drug release time, novel hollow organic/inorganic hybrid nanoparticles based on dextran-b-poly(L-glutamate-graft-3-mercaptopropyltrimethoxysilane) (Dex-b-P(ALG-g-MTPMS)) were prepared. First, a polysaccharide block polypeptide diblock copolymer, dextran-block-poly(γ-allyl-L-glutamate) (Dex-b-PALG) bearing allyl side-groups, has been synthesized by the combination of ring-opening polymerization and alkyne-azide [2 + 3] Huisgen's cycloaddition. Next, the allyl side-groups residing in the poly(γ-allyl-L-glutamate) block were further functionalized with 3-mercaptopropyltrimethoxysilane(MPTMS) by radical “thiol-ene” addition reactions. Finally, after a sol-gel process of the obtained copolymers, the novel organic/inorganic hybrid nanoparticles were prepared. The molecular structures, physicochemical, and self-assembly of these copolymers were characterized through FTIR, 1H NMR, dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The cross-linked hybrid nanoparticles have a higher drug loading ability and slower release rate as compared to the uncross-linked counterparts. The MTT evaluation demonstrated that the organic/inorganic hybrid nanoparticles with good biocompatibility.

Preparation and Self-Assembling of PLA-b-PNIPAM-b-PS Triblock Copolymer Thin Films.

Polylactide-b-poly(N-isopropylacrylamide)-b-polystyrene (PLA-b-PNIPAM-b-PS) triblock copolymers (tri-BCPs) with various chemical compositions (block ratio) were prepared from the combination of ring-opening polymerization and reversible addition-fragmentation chain transfer polymerization. Subsequently, the self-assembling behaviors of these tri-BCP films obtained from spin-coating were investigated by annealing them under different solvent atmosphere. We found that these films could self-assemble into various morphologies due to the microphase separation of incompatible copolymer blocks. Atomic force microscopy confirmed the perpendicular cylindrical morphology self-assembled from PLA4.5k-b-PNIPAM5.2k-b-PS22.4k tri-BCP film under mixed solvent atmosphere of toluene/acetone (7:3, v/v). Self-assembled PLA cylinders are evenly distributed among the PS matrix and perpendicular to the film surface, with PNIPAM component taking place at the PLA/PS interphase. Furthermore, by etching the degradable PLA component, porous PS film decorated with PNIPAM "brushes" hoisting channels were generated. This work provides a facile method and detailed protocol for fabricating stimuli-responsive porous films which are promising for thermoresponsive "smart" separation technologies.

Synthesis of Four-arms Star-shaped PCL-b-PEG as a Potential Amphiphilic Hydrogel

Hydrogel formulations have drawbacks in delivering hydrophobic drugs which can affect its efficiency. Introducing amphiphilic system into hydrogel can overcome this limitation and increase hydrogel effectiveness as a drug cargo. In this study, four arms star-shaped block copolymers with polyethylene glycol (PEG) as hydrophilic block and polycaprolactone (PCL) as hydrophobic block were synthesized via a combination of ring-opening polymerization (ROP) and Steglich esterification. The structures were confirmed by 1H-NMR and FTIR analysis. The polydispersity index (PDI) indices from gas permeation chromatography (GPC) were 1.3 to 1.6 suggesting controlled polymerisation reaction occurred. Average molecular weight analysis, Mn based on 1H-NMR are close to the theoretical value. However, there is a slight difference of Mn between GPC and proton analysis due to the ability of GPC determining Mn for the star-shaped polymer. Both star-shaped polymers possesses high thermal stability (>350 °C) based on thermal decomposition study using TGA analysis. The presence of PEG had increased the hydrophilicity and solubility of the PCL in the hydrogel since an opaque homogeneous formulation form when using the amphiphilic star-shaped polymer. The pH (7.25 ± 0.03) and viscosity (9330 cP) of the formulation are set within the compatibility and suitable for human skin and topical application.

Amphiphilic well‐defined degradable star block copolymers by combination of ring‐opening polymerization and atom transfer radical polymerization: Synthesis and application as drug delivery carriers

AbstractAtom transfer radical polymerization (ATRP) is one of the most popular advanced polymerization techniques in macromolecular science, allowing the synthesis of tailor‐made polymers with controlled molecular weight, architecture, composition, and functionality. The combination of ATRP and ring‐opening polymerization (ROP) provides a straightforward route for the preparation of polymers exhibiting both targeted and well‐defined features and biodegradability, which is very interesting for the development of new materials for biomedical applications. Among the different types of polymer architectures, amphiphilic star block copolymers (BCPs) represent a very attractive one, due to their high degree of functionality at the molecular surface, low hydrodynamic volume and higher encapsulation ability, compared to molecular systems based on linear polymers. This review article highlights the research focused on the synthesis of amphiphilic well‐defined degradable star BCPs by combination of ROP and ATRP, with particular focus on the development of polymers for biomedical applications, such as anticancer drug delivery, diagnosis therapy, or photodynamic therapy, which is the most investigated field regarding these polymers.

Complex poly(ε-caprolactone)/poly(ethylene glycol) copolymer architectures and their effects on nanoparticle self-assembly and drug nanoencapsulation

Well-defined amphiphilic PCL-PEG copolymers with complex molecular architectures were synthesized through a combination of Ring Opening Polymerization (ROP) and Atom Transfer Radical Polymerization (ATRP) and used to produce self-assembled nanoparticles for drug nanoencapsulation. By varying the functionality of the initiator used for the ATRP (i.e. linear, 4-armed or multifunctional brush macroinitiators), a library of comb-like and brush block copolymers were obtained with different structure, molecular weight, and number of PEG and PCL blocks. We investigated how these parameters influenced nanoparticle self-assembly in aqueous environment, as well as the ability to encapsulate and release hydrophobic therapeutic molecules. In particular, the hydrophobic corticosteroid dexamethasone, known as a therapeutic drug with anti-inflammatory and immunosuppressive effects, was chosen as a model. The results indicate that self-assembly, final particle size and drug loading can be tuned by designing a specific macromolecular architecture, which therefore represents a key feature for the design of efficient polymer nanocarriers for drug delivery.

The Effects of Blending Ratio of Poly(lactic acid)/POSS Cored Star Poly(ε-caprolactone) Biopolymers

Abstract: A8-type eight-arm star-shaped poly(ε-caprolactone) (PCL) polymers with polyhedral oligomeric silsesquioxane (POSS) (SP) core having different molecular weight with different chain lengths (n=10, 20, 30, and 50 repeating units) were synthesized via arm-first approach by combination of ring-opening polymerization (ROP) and “click” chemistry reactions. The obtained polymers were then melt-blended with neat poly(lactic acid) (PLA) to improve some of the properties like toughness of PLA. These blends were prepared depending on the blend ratio (95/5 and 80/20 wt%) via utilizing laboratory scale twin-screw mini extruder to examine morphological, thermal and mechanical properties of PLA/SP composite as a function of SP and blending ratio. In addition, the PLA/SP composites containing a blend ratio of 90/10 wt% which were prepared in the previous study was used to compare with other composite having different blend ratio. The incorporation of SP polymers improved some of the mechanical properties of PLA. It was verified that SP20 (n=20) is the most proper SP-type for enhancing the mechanical behavior of PLA at a blending ratio of 90/10. Also, 1,4-phenylene diisocyanate (PDI) which was used as a commercial compatibilizer was incorporated to blends at fixed amount (%1). It is concluded that the incorporation of SP polymers into PLA matrix decreased the tensile modulus with increasing blending ratio and increased the elongation at break values in the presence of PDI.