Novel synthesis of biodegradable poly(lactide-co-ethylene glycol) block copolymers

Biodegradable and amphiphilic diblock copolymers [polylactide-block-poly(ethylene glycol)] and triblock copolymers [polylactide-block-poly(ethylene glycol)-block-polylactide] were synthesized by the anionic ring-opening polymerization of lactides in the presence of poly(ethylene glycol) methyl ether or poly(ethylene glycol) and potassium hexamethyldisilazide as a catalyst. The polymerization in toluene at room temperature was very fast, yielding copolymers of controlled molecular weights and tailored molecular architectures. The chemical structure of the copolymers was investigated with ¹H and ¹³C NMR. The formation of block copolymers was confirmed by ¹³C NMR and differential scanning calorimetry investigations. The monomodal profile of the molecular weight distribution by gel permeation chromatography provided further evidence of block copolymer formation as well as the absence of cyclic species. Additional confirmation of the block copolymers was obtained by the substitution of 2-butanol for poly(ethylene glycol); butyl groups were clearly identified by ¹H NMR as polymer chain end groups. The effects of the copolymer composition and lactide stereochemistry on the copolymer properties were examined. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2235–2245, 2007     

Phase transitions in aqueous triblock copolymers: NMR relaxation studies

Longitudinal NMR relaxation times were used to investigate the thermal transitions occurring in an aqueous triblock copolymer of the poly(oxyethylene)–poly(oxypropylene)–poly(oxyethylene) family. In such a system molecule–micelle and micelle–liquid crystal transitions are observed, depending on temperature and composition. The longitudinal relaxation time, R ₁, significantly changes when the aforementioned phase transitions take place. In the case of molecule–micelle equilibrium, changes in R ₁ values of the methyl (and methynic) group signal, located in the lipophilic portion of block copolymers, are observed. The effect is ascribed to a significant dehydration of the poly(oxypropylene) chains, as a consequence of micelle formation. Conversely, the thermal transitions from micelles to liquid-crystalline phases are associated with significant changes in the relaxation time of poly(oxyethylene) units. The latter effect is tentatively ascribed to a partial dehydration and/or interdigitation of the poly(oxyethylene) moieties in the block copolymer.     

Free-Radical Synthesis of Block Copolymers via Dixanthogen-Linked Polymer Sequences

Abstract

Due to high chain transfer and the subsequent terminator properties of the dixanthogen moiety, (AB)_n multiblock copolymers of poly(oxyethylene-block-methyl methacrylate) and ABA triblock copolymers of poly(methyl methacrylate-block-2-ethylhexyl acrylate) could be synthesized from dixanthogen-linked poly(oxyethylene) and poly(methyl methacrylate) pre-polymer sequences, respectively, using free-radical chemistry. A simple and efficient method was developed for the synthesis of dixanthogen-linked polymers: Hydroxyl-functionalized pre-polymers were reduced using NaH to form alkoxide; CS₂ was then added to the alkoxide to form xanthate; and finally the xanthate was oxidized either in an aqueous or organic medium to form the dixanthogen. The synthesis techniques provided in this paper are general and thus, in principle, can be applied to many other block copolymer systems.     

The Synthesis of Special Block Copolymers Using a Reaction Calorimeter

Summary : The paper provides experimental results about an easy and versatile method to produce amphiphilic block copolymers, block copolymer particles, and even inorganic – polymeric nano-composites via aqueous heterophase polymerization. Special emphasis is placed on the morphology and colloidal properties of some non-ionic di- and triblock copolymer particles with poly(ethylene glycol) of 10⁶ g/mol molecular weight as hydrophilic block as well as di-stimuli-responsive block copolymers containing both a poly(N-isopropyl acrylamide) and a poly(ionic liquid) block.     

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     

Characterization of amphiphilic hydrocarbon modified Poly(ethylene glycol) synthesized through ring-opening reaction of 2-(1-octadecenyl)succinic anhydride

Poly(ethylene glycol) (PEG) triblock and diblock amphiphilic block copolymers were synthesized from poly(ethylene glycol) and poly(ethylene glycol) monomethyl ether, respectively. The hydroxyl groups of PEG readily react with 2-(1-octadecenyl) succinic anhydride (OSA) at 140 °C through ring-opening reaction of the succinic anhydride. Both the PEG-OSA diblock and triblock copolymers are produced without use of any solvent or catalyst. The molecular structure of the copolymers was characterized by ¹H NMR and FTIR spectroscopy, and the thermal properties by DSC. The behavior of the copolymers in selective and nonselective solvents was studied by ¹H NMR spectroscopy in deuterium oxide and d-chloroform. The aggregation of the polymers in water was studied with a particle size analyzer and a transmission electron microscope (TEM) in bright field mode. The results show that the hydrophobic C₁₈ chain with intramolecular succinic anhydride linker can be attached to the hydrophilic PEG chain, an ester bond forming between the blocks. The copolymers exhibit flexible, liquid-like hydrophobic blocks even in water, which is a nonsolvent for OSA. PEG-OSA block copolymers self-organize in water, forming micellar polymer aggregates in nanoscale.     

The effects of polyelectrolytes on the inhibition and aggregation of calcium oxalate crystallization

The influence of polyelectrolytes with different architecture on spontaneous batch crystallization of calcium oxalate was investigated. A series of acidic acrylate block copolymers were been made, by radical polymerization, with defined molecular weight and structure. Radical polymerization of acrylic acid (AA) was carried out in the presence of α‐thiopolyethylene glycol monomethylether as a chain transfer agent to produce poly(ethylene glycolblockacrylic acid) copolymers. Poly(ethylene glycol) (PEG) block length in the copolymers was controlled by using three different molecular weight chain transfer agents (M_n = 350, 750 and 2000 g/mol). The presence of copolymers inhibited the crystal growth of calcium oxalate possibly through adsorption onto the active growth sites for crystal growth due to the charge and hydrophilic effects. Copyright © 2006 John Wiley & Sons, Ltd.     

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     

PDEGMA-b-PDIPAEMA copolymers via RAFT polymerization and their pH and thermoresponsive schizophrenic self-assembly in aqueous media

We report on a new doubly responsive polymeric system of amphiphilic diblock copolymers, namely poly(di-[ethylene glycol] methyl ether methacrylate)-b-poly(2-[diisopropylamino] ethyl methacrylate), PDEGMA-b-PDIPAEMA, obtained by the reversible addition-fragmentation chain transfer (RAFT) polymerization technique. Molecular characterization by size exclusion chromatography (SEC), nuclearmagnetic resonance (¹H-NMR) and infrared spectroscopy (FT-IR) confirms the successful synthesis of these novel block copolymers. The PDEGMA-b-PDIPAEMA block copolymers formed aggregates in aqueous media in response to solution pH and temperature changes, as evidenced by dynamic and static light scattering techniques, as well as fluorescence spectroscopy. Aggregates with PDEGMA core and PDIPAEMA corona domains are formed at elevated temperatures and low pH, whereas aggregates with PDIPAEMA cores and PDEGMA coronas are formed at neutral and high pH. Overall structural characteristics and solution behavior of the copolymers are affected by the copolymer composition. The obtained results provide valuable new information on the behavior and design guidelines for the construction of stimuli responsive, “schizophrenic” polymeric nanostructures with potential application in the biomedical field.     

Melting behavior of ethylene oxide–propylene oxide (sym-PEP) block copolymers

Melting points and lamellar thicknesses have been measured for ethylene oxide–propylene oxide block copolymers (sym-PEP) with central poly(ethylene oxide) block lengths of 70–100 chain units and end poly(propylene oxide) block lengths of 0–30 chain units. Melting points of the block copolymers are lower than those of the corresponding poly(ethylene oxide) homopolymer by an amount (up to 15°C) which increases as the poly(propylene oxide) block length increases. Most samples have more than one melting transition, which can be assigned to variously folded chain crystals. End interfacial free energies σ_e for the various crystals have been estimated by use of Flory's theory of melting of block copolymers. For a given crystal type (e.g., once-folded-chain) σ_e is higher the longer the chain length of the end poly(propylene oxide) blocks. For a given copolymer σ_e is lower, the more highly folded the poly(ethylene oxide) chain.     

Synthesis and self‐association behavior of poly[bis(2‐(2‐methoxyethoxy)ethoxy)phosphazene]‐b‐poly(propyleneglycol) triblock copolymers

Amphilic triblock copolymers with varying ratios of hydrophilic poly[bis (methoxyethoxyethoxy)phosphazene] (MEEP) and relatively hydrophobic poly(propylene glycol) (PPG) blocks were synthesized via the controlled cationic‐induced living polymerization of a phosphoranimine (Cl₃P?NSiMe₃) at ambient temperature. A PPG block can function as either a classical hydrophobic block or a less hydrophobic component by varying the nature of a phosphazene block. The aqueous phase behavior of MEEP‐PPG‐MEEP block copolymers was investigated using fluorescence techniques, TEM, and dynamic light scattering (DLS). The critical micelle concentrations (cmcs) of MEEP‐PPG‐MEEP block copolymers were determined to be in the range of 3.7–16.8 mg/L. The mean diameters of MEEP‐PPG‐MEEP polymeric micelles, measured by DLS, were between 31 and 44 nm. The equilibrium constants of pyrene in these micelles ranged from 4.7 × 10⁴ to 9.6 × 10⁴. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 692–699, 2009     

pH/enzyme/light triple-responsive vesicles from lysine-based amphiphilic diblock copolymers

We report the synthesis of pH- and enzyme-responsive amphiphilic diblock copolymers through reversible addition-fragmentation chain transfer polymerization of a lysine-derived methacrylate monomer comprising p-nitrobenzyl carbamate (pNBC) functionality using a poly(ethylene glycol)-modified macro-chain transfer agent. Depending on the hydrophobic block length, the diblock copolymers self-assemble to form spherical micelles, wormlike micelles, and bilayered vesicles in the aqueous solution. The responsive behaviors of the polymeric vesicles to pH, enzyme, and light are investigated in detail. As the pH lowers to pH 5.0, the polymeric vesicles undergo a morphological transition from vesicles to spherical micelles. In the presence of nitroreductase and a cofactor NADH, the decomposition of pNBC releases the ε-NH₂ of the lysine moiety and hence induces the generation of the vesicles with crosslinked membranes at pH 7.4. Moreover, owing to the degradation of pNBC moiety under UV irradiation, the polymeric vesicles also demonstrate a photo-responsive feature. As the irradiation time prolongs, it is observed a light-triggered morphological transition from vesicles to wormlike micelles with network-like structures.     

Design of water-soluble block copolymers containing poly(4-vinylpyridine) by atom transfer radical polymerization

The preparation of block copolymers consisting of poly(4-vinylpyridine) (P4VP) by atom transfer radical polymerization (ATRP) was investigated. The goal was to synthesize water-soluble block copolymers with poly(ethylene oxide) (PEO) as first block, a water-soluble polymer at any pH. First, a PEO macroinitiator was prepared for the ATRP block copolymerization of 4-vinylpyridine. In the second stage, the kinetic behaviour of this block copolymerization was investigated for two different types of PEO-macroinitiators and catalyst systems, based on CuCl or CuCl₂/Cu(0), with tris[2-(dimethylamino)ethyl]amine (Me₆-TREN) as the ligand. Various combinations of initiator and catalyst led to a controlled block copolymerization with optimized results obtained for chlorinated poly(ethylene glycol) monomethyl ether as macroinitiator, together with CuCl₂/Cu(0)/Me₆-TREN as catalyst system. With the latter system, narrow polydispersities (1.25) could be reached for PEO-P4VP block copolymers.     

Well defined polymer structures by ionic ring-opening polymerization of cyclic monomers comprising the respective structure

Ring-opening polymerization of cyclic monomers is the method of choice when tailor-made polymers and copolymers with heteroatoms in the main chain are to be prepared. Triblock copolymers comprising a poly(ethylene oxide) block [poly(EO)] and two poly(2,2-dimethyltrimethylene carbonate) blocks [poly(DTC)] were prepared using a telechelic poly(EO) as initiator for the DTC polymerization. These block copolymers dissolve suitable salts leading to solid polymeric electrolytes. The thermal properties and the ionic conductivity of these materials are presented. Block copolymers comprising a poly(tetrahydrofuran) block [poly(THF)] and a poly(trimethylene urethane) block [poly(TU)] were obtained by sequential cationic polymerization of THF and TU with methyl trifluoromethane-sulfonate as initiator. Mechanistic and kinetic aspects of the TU polymerization are discussed. To achieve the synthesis of block copolymers with a poly(L-lactide) block [poly(LLA)] and a poly(α-amino acid) block [poly(AA)] amino-terminated poly(LLA) was prepared which served as initiator for the polymerization of α-amino acid N-carboxyanhydrides.     

Y‐shaped poly(ethylene glycol) and poly(trimethylene carbonate) amphiphilic copolymer: Synthesis and for drug delivery

New Y‐shaped (AB₂‐type) amphiphilic copolymers of poly(ethylene glycol) (PEG) with poly(trimethylene carbonate) (PTMC), PEG‐b‐(PTMC)₂, were successfully synthesized by the ring‐opening polymerization (ROP) of TMC with bishydroxy‐modified monomethoxy‐PEG (mPEG). First, a bishydroxy functional ROP initiator was synthesized by esterification of acryloyl bromide with mPEG, followed by Michael addition using excess diethanolamine. A series of Y‐shaped amphiphilic PEG‐(PTMC)₂ block copolymers were obtained via ROP of TMC using this PEG with bishydroxyl end groups as macroinitiator and ZnEt₂ as catalyst. The amphiphilic block copolymers with different compositions were characterized by gel permeation chromatography (GPC) and ¹H NMR, and their molecular weight was measured by GPC. The results showed that the molecular weight of Y‐shaped copolymers increased with the increase of the molar ratio of TMC to mPEG‐(OH)₂ initiator in feed while the PEG chain length was kept constant. The Y‐shaped copolymer mPEG‐(PTMC)₂ could self‐assemble into micelles in aqueous medium and the critical micelle concentration values of the micelles decrease with increase in hydrophobic PTMC block length of mPEG‐(PTMC)₂. The in vitro cytotoxicity and controlled drug release properties of the Y‐shaped amphiphilic block copolymers were also investigated. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 8131–8140, 2008     

One‐Step Synthesis of Multiphase Block Copolymers via Simultaneus Free Radical and Ring Opening Polymerization Using Poly(ethylene oxide) Possessing Azo Group

Multiphase block copolymers having the structure of poly(?‐caprolacton‐b‐etyhlene glycol‐b‐styrene‐b‐ethylene glycol‐b‐?‐caprolacton) were synthesized from poly(ethylene oxide) possesing azo group in the main chain by the combination of free radical polymerization (FRP) of styrene (S) and ring opening polymerization (ROP) of ?‐caprolacton (?‐CL) in one‐step. The block copolymers were characterized ¹H‐NMR and FT‐IR spectroscopy and gel permeation chromatography (GPC). ¹H‐NMR and FT‐IR spectroscopy and GPC studies of the obtained polymers indicate that multiphase block copolymers easily formed as a result of combination FRP and ROP in one‐step.     

The effect of cationic groups on the stability of 19F MRI contrast agents in nanoparticles

Fluorine‐19 (¹⁹F)‐based contrast agents are increasingly used for magnetic resonance imaging. Conjugated to polymers, they provide an excellent quantitative imaging tool to detect the movement of the polymeric nanoparticles in vivo as there is no background signal in tissue. One of the challenges is the decline in signal intensity when the conjugated hydrophobic fluorinated functionalities aggregate. Therefore, a new fluorinated monomer was prepared from l ‐arginine that carries a 2,2,2‐trifluoroethyl functional group for imaging. The resulting monomer, 2,2,2‐trifluoroethylamide l ‐arginine methacrylamide (3FArgMA), was copolymerized with poly(ethylene glycol) methyl ether methacrylate (PEGMEMA), [2‐(2,3,4,6‐tetra‐O‐acetyl‐α‐d ‐mannopyranosyloxy)ethyl methacrylate or 1‐O‐methacryloyl‐2,3:4,5‐di‐O‐isopropylidene‐β‐d ‐fructopyranose, respectively, using poly(methyl methacrylate) macro‐reversible addition–fragmentation chain transfer polymerization agent. The resulting block copolymers, which varied in 3FArgMA content, were self‐assembled into micelles of hydrodynamic diameters from 25 to 60 nm. The permanently positively charged arginine functionality on the 3FArgMA displayed repulsive forces against aggregation enabling high spin–spin relaxation times (T₂) in acidic as well as alkaline solutions. However, the longer poly(ethylene glycol) side functionality in PEGMEMA enabled better steric stabilization (T₂~30 ms) while the short fructose side chain was not enough to maintain high T₂ values, in particular when a higher 3FArgMA content was used. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1994–2001     

Preparation and characterization of p-toluene sulfonyl ester and amino derivatives of tri- and poly(ethylene glycol)

Methods described in the literature are inadequate for the preparation of pure polyethylene glycol (PEG) tosylate. Therefore an improved method is presented. The hydroxyl groups on PEG can be quantitatively converted into the tosylate and isolated from the reaction medium free from impurities with no chain cleavage or reduction in molecular weight. 1,2-Di(N-phenyl 2-aminoethoxy) ethane, α,ω-di(N-phenyl 2-aminoethyl) poly(oxyethylene), and α,ω-di(N-phenyl, N-benzyl 2-aminoethyl) poly(oxyethylene) were prepared from the tosylates of tri- and poly(ethylene glycol)s and the corresponding primary and secondary aromatic amines.     

Novel Amphiphilic Block Copolymers for the Formation of Stimuli-Responsive Non-Lamellar Lipid Nanoparticles

Non-lamellar lyotropic liquid crystalline (LLC) lipid nanoparticles contain internal multidimensional nanostructures such as the inverse bicontinuous cubic and the inverse hexagonal mesophases, which can respond to external stimuli and have the potential of controlling drug release. To date, the internal LLC mesophase responsiveness of these lipid nanoparticles is largely achieved by adding ionizable small molecules to the parent lipid such as monoolein (MO), the mixture of which is then dispersed into nanoparticle suspensions by commercially available poly(ethylene oxide)–poly(propylene oxide) block copolymers. In this study, the Reversible Addition-Fragmentation chain Transfer (RAFT) technique was used to synthesize a series of novel amphiphilic block copolymers (ABCs) containing a hydrophilic poly(ethylene glycol) (PEG) block, a hydrophobic block and one or two responsive blocks, i.e., poly(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate) (PTBA) and/or poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA). High throughput small angle X-ray scattering studies demonstrated that the synthesized ABCs could simultaneously stabilize a range of LLC MO nanoparticles (vesicles, cubosomes, hexosomes, inverse micelles) and provide internal particle nanostructure responsiveness to changes of hydrogen peroxide (H₂O₂) concentrations, pH and temperature. It was found that the novel functional ABCs can substitute for the commercial polymer stabilizer and the ionizable additive in the formation of next generation non-lamellar lipid nanoparticles. These novel formulations have the potential to control drug release in the tumor microenvironment with endogenous H₂O₂ and acidic pH conditions.     

Synthesis and characterization of amphiphilic triblock polymers by copper mediated living radical polymerization

2-Dimethylaminoethyl methacrylate (DMAEMA) and 2-diethylaminoethyl methacrylate (DEAEMA) block copolymers have been synthesized by using poly(ethylene glycol), poly(tetrahydrofuran) (PTHF) and poly(ethylene butylenes) macroinitiators with copper mediated living radical polymerization. The use of difunctional macroinitiator gave ABA block copolymers with narrow polydispersities (PDI) and controlled number average molecular weights (M_n’s). By using DMAEMA, polymerizations proceed with excellent first order kinetics indicative of well-controlled living polymerization. Online ¹H NMR monitoring has been used to investigate the polymerization of DEAEMA. The first order kinetic plots for the polymerization of DEAMA showed two different rate regimes ascribed to an induction period which is not observed for DMAEMA. ABA triblock copolymers with DMAEMA as the A blocks and PTHF or PBD as B blocks leads to amphiphilic block copolymers with M_n’s between 22 and 24 K (PDI 1.24-1.32) which form aggregates/micelles in solution. The critical aggregation concentrations, as determined by pyrene fluorimetry, are 0.07 and 0.03 g dm⁻¹ for PTHF- and PBD-containing triblocks respectively.