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.     

Synthesis of thermoresponsive poly(N-isopropylmethacrylamide) and poly(acrylic acid) block copolymers via post-functionalization of poly(N-methacryloxysuccinimide)

Polymers exhibiting a thermoresponsive, lower critical solution temperature (LCST) phase transition have proven to be useful for many applications as “smart” or “intelligent” materials. A series of poly(N-isopropylmethacrylamide) (PNIPMAM) polymer, poly(N-isopropylmethacrylamide)-b-poly(acrylic acid) (PNIPMAM-b-PAA) diblock, and poly(acrylic acid)-b-poly(N-isopropylmethacrylamide)-b-poly(acrylic acid) (PAA-b-PNIPMAM-b-AA) triblock copolymer samples were synthesized via ATRP. A facile post-functionalization route was developed that uses an activated ester functionality to convert poly(N-methacryloxysuccinimide) (PMASI) blocks to LCST capable polyacrylamide, while poly(t-butyl acrylate) (PtBA) blocks were converted to water-soluble poly(acrylic acid) (PAA). The post-functionalization was monitored via ¹H NMR and ATR-FTIR. The aqueous solution properties were explored and the PNIPMAM polymers were shown to have a LCST phase transition varying from 35 to 60 °C. The ability to synthesize block copolymers that are thermoresponsive and water-soluble will be of great benefit for broader applications in drug delivery, bioengineering, and nanotechnology.     

Synthesis and characterization of poly(ethylene glycol)-b-poly (l-lactide)-b-poly(l-glutamic acid) triblock copolymer

A biodegradable amphiphilic triblock copolymer of poly(ethylene glycol)-b-poly(l-lactide)-b-poly(l-glutamic acid) (PEG-b-PLLA-b-PLGA) was obtained by catalytic hydrogenation of poly(ethylene glycol)-b-poly(l-lactide)-b-poly(γ-benzyl-l-glutamic acid) (PEG-b-PLLA-b-PBLGA) synthesized by the ring-opening polymerization (ROP) of N-carboxyanhydride of γ-benzyl-l-glutamate (BLG-NCA) with amino-terminated MPEG-b-PLLA-NH₂ as a macroinitiator. MPEG-b-PLLA-NH₂ converted from MPEG-b-PLLA-OH first reacted with tert-Butoxycarbonyl-l-phenylalanine (Phe-^NBOC) and dicyclohexylcarbodiimide (DCC) and then deprotected the tert-butoxycarbonyl group. MPEG-b-PLLA-OH was prepared by ROP of l-lactide with monomethoxy poly(ethylene glycol) in the presence of stannous octoate. The triblock copolymer and its diblock precursors were characterized by ¹H NMR, FTIR, GPC and DSA (drop shape analysis) measurements. The lengths of each block polymers could be tailored by molecular design and the ratios of feeding monomers. The triblock polymer PEG-b-PLLA-b-PLGA containing carboxyl groups showed obviously improved hydrophilic properties and could be a good potential candidate as a drug delivery carrier.     

Advances in drug delivery systems based on synthetic poly(hydroxybutyrate) (co)polymers

Within the general context of nanomedicine, drug delivery systems based on polymers have sparked a rapidly growing interest and raised many efforts to tackle various diseases, among which cancer. Polyester-based nanoparticulate drug delivery systems, including polymer-drug conjugates and amphiphilic block copolymers, represent a major class with promising outcomes, especially for those derived from poly(3-hydroxybutyrate) (PHB). This review describes recent advances in drug delivery systems designed from the self-assembly of synthetic (co)polymers derived from PHB. The various strategies for the synthesis of PHB-conjugates, PHB/poly(ethylene glycol) (PEG) and other PHB-based copolymers are first summarized. Nanoparticles, micelles, microparticles, and hydrogels elaborated from these (co)polymers following various preparation methods, along with their exploitation in the encapsulation and release of various therapeutic agents, are next detailed. Finally, we discuss the synthetic challenges, drug delivery outlooks, and perspectives of PHB-based drug delivery systems. Engineered nano-scaled materials based on PHB self-assembled systems are thus anticipated to emerge as a valuable platform for original drug delivery systems.     

Novel Synthesis of Reactive Poly(ethylene glycol) grafted Poly(L-lactide) via Two Step Polymerizations

Summary Novel poly(L-lactide)-graft-poly(ethylene glycol) having reactive group at the end of grafted chain was prepared by two step polymerizations: ring-opening polymerization of L-lactide and 1,2-epoxy-5-hexene followed by radical polymerization of the product of ring-opening reaction and poly(ethylene glycol) methacrylate. Al(Et)₃·0.5H₂O and AIBN were used as catalyst and initiator for the two step polymerizations respectively. The structure of the synthesized polymers was also characterized.     

Synthesis of pH-Responsive Multilayer Micelles for Sustained Release of Folic Acid

Two novel triblock copolymers poly(hydroxypropyl acrylate)-b-poly (methyl methacrylate)-b-poly(N,N-dimethylaminoethyl methacrylate) and poly(hydroxypropyl acrylate)-b-poly(methyl methacrylate)-b-poly(acrylic acid) were successfully synthesized. In acetone media, using the electrostatic interactions between N,N-dimethylaminoethyl methacrylate and acrylic acid units, they could form spherically shaped multilayer micelles with pH-responsive, and have a mean diameter around 110 nm. The critical micelle concentration of it was determined to be 2.42 mg/L. In vitro release experiments, the folic acid-loaded micelles exhibited sustained release behavior and the drug release rate was affected by the pH value of release media. These results indicate that the multilayer micelles may serve as a novel intelligent drug delivery system.     

Syntheses of well-defined poly(siloxane)-b-poly(styrene) and poly(norbornene)-b-poly(styrene) block copolymers using functional alkoxyamines

Functional alkoxyamines, 1-[4-(4-lithiobutoxy)phenyl]-1-(2,2,6,6-tetramethylpiperidinyl-N-oxyl)ethane (2) and 1-[4-(2-vinyloxyethoxy)phenyl]-1-(2,2,6,6-tetramethylpiperidinyl-N-oxyl)ethane (3) were prepared, and well-defined poly(hexamethylcyclotrisiloxane)-b-poly(styrene)[poly(D₃)-b-poly(St)] and poly(norbornene)-b-poly(St) [poly(NBE)-b-poly(St)] were prepared using the alkoxyamines. The first step was preparation of poly(D₃) and poly(NBE) macroinitiators, which were obtained by the ring-opening anionic polymerization of D₃ using 2 as an initiator and the ring-opening metathesis polymerization of NBE using 3 as a chain transfer. The radical polymerization of St by the poly(D₃) and poly(NBE) macroinitiators proceeded in the ‘living’ fashion to give well-defined poly(D₃)-b-poly(St) and poly(NBE)-b-poly(St) block copolymers.     

(S)-2-(ethyl propionate)-(O-ethyl xanthate)- and (S)-2-(Ethyl isobutyrate)-(O-ethyl xanthate)-mediated RAFT polymerization of vinyl acetate

(S)-2-(Ethyl propionate)-(O-ethyl xanthate) (X1) and (S)-2-(Ethyl isobutyrate)-(O-ethyl xanthate) (X2) were used as the reversible addition-fragmentation chain transfer (RAFT) agents for the radical polymerization of vinyl acetate (VAc). The former showed the better chain transfer ability in the polymerization at 60°C. Kinetic study with both RAFT agents showed pseudo-first order kinetics up to around 85% monomer conversion. Molecular weight of the resulting polymer increased linearly with increase in the monomer conversion up to around 85%. The observed molecular weights calculated from ¹H-NMR spectrum [M_n(NMR)] are close to the corresponding theoretical molecular weights [M_n(theor)]. The corresponding polydispersity index (PDI) of the resulting polymers remained almost constant at around 1.2 up to ∼ 65% monomer conversion and then increased gradually with the further increase in the monomer conversion. Chain-end analysis of the resulting polymers by ¹H-NMR showed clearly that polymerization started with the radical forming out of the xanthate mediator. The negligible homo-chain extension and the hetero-chain extension involving synthesis of poly(VAc)-b-poly(NVP) diblock copolymer were occurred. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

A biodegradable triblock copolymer poly(ethylene glycol)-b-poly(l-lactide)-b-poly(l-lysine): Synthesis,self-assembly,and RGD peptide modification

A novel biodegradable triblock copolymer poly(ethylene glycol)-b-poly(l-lactide)-b-poly(l-lysine) (PEG–PLA–PLL) was synthesized by acidolysis of poly(ethylene glycol)-b-poly(l-lactide)-b-poly(ɛ-benzyloxycarbonyl-l-lysine) (PEG–PLA–PZLL) obtained by the ring-opening polymerization (ROP) of ɛ-benzyloxycarbonyl-l-lysine N-carboxyanhydride (ZLys NCA) with amino-terminated PEG–PLA–NH₂ as a macroinitiator, and the pendant amino groups of the lysine residues were modified with a peptide known to modulate cellular functions, Gly-Arg-Gly-Asp-Ser-Tyr (GRGDSY, abbreviated as RGD) in the presence of 1,1′-carbonyldiimidazole (CDI). The structures of PEG–PLA–PLL/RGD and its precursors were confirmed by ¹H NMR, FT-IR, amino acid analysis and XPS analysis. The cell adhesion and cell spread on the PEG–PLA–PLL/RGD film were enhanced compared to those on pure PLA film. Therefore, the novel RGD-grafted triblock copolymer is promising for cell or tissue engineering applications. Both copolymers PEG–PLA–PZLL and PEG–PLA–PLL showed an amphiphilic nature and could self-assemble into micelles of homogeneous spherical morphology. The micelles were determined by fluorescence technique, dynamic light scattering (DLS), and field emission scanning electron microscopy (ESEM) and could be expected to find application in drug and gene delivery systems.     

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.     

Thermosensitive poly(N-isopropylacrylamide)-b-poly(ε-caprolactone) nanoparticles for efficient drug delivery system

To investigate thermosensitive polymeric nanoparticle, amphiphilic block copolymers of poly(N-isopropylacrylamice)-b-poly(ε-caprolactone) (PNPCL) with different PCL block lengths were synthesized by hydroxy-terminated poly(N-isopropyoacrylamide) (PNiPAAm) initiated ring opening polymerization of ε-caprolactone. Owing to their amphiphilic characteristics, the block copolymers formed self-assembled polymeric nanoparticles in aqueous milieus with thermosensitive PNiPAAm shell compartment. The characterizations of the nanoparticles revealed that the PNPCL nanoparticles showed PCL block length dependent physicochemical characters such as particle sizes, critical aggregation concentrations, and core hydrophobicities. Moreover, the thermosensitive PNiPAAm shells conferred unique temperature responsive properties such as phase transitions with temperature elevation over its lower critical solution temperature (LCST). The temperature induced phase transition resulted in the formation of PNiPAAm hydrogel layer on the PNPCL nanoparticle surface. The drug release tests revealed that the formation of thermosensitive hydrogel layer resulted in the enhanced sustained drug release patterns by acting as an additional diffusion barriers. Therefore, the introduction of thermosensitive polymers on polymeric nanoparticles might be a potential approaches to modulate drug release behaviors.     

Functionalization of amphiphilic coil-rod-coil triblock copolymer poly(2-vinylpyridine)-b-poly(n-hexyl isocyanate)-b-poly(2-vinylpyridine) with florescence moiety and C60

We recently achieved quantitative synthesis of an amphiphilic coil-rod-coil triblock copolymer, poly(2-vinylpyridine)-b-poly(n-hexyl isocyanate)-b-poly(2-vinylpyridine), by coupling in situ living diblock copolymer poly(2-vinylpyridine)-b-poly(n-hexyl isocyanate) (P2VP-b-PHIC) using malonyl chloride in the presence of pyridine. This led to the introduction of an active methylene group that is a site for further functionalization in the rod block. The Michael addition reaction of the triblock copolymer with 7-(4-trifluoromethyl) coumarin acrylamide led to copolymer bearing a fluorescent pendent in the rod block. The fluorescent labeled copolymers were isolated in ∼94% yields. Similarly C₆₀ pendent was introduced to the rod block by the Bingel reaction. The yields of C₆₀ functionalized copolymers were ∼54%. The precursor and functionalized amphiphilic coil-rod-coil copolymer show diverse morphologies, such as micelles and vesicles by simply changing the solvent. For the C₆₀ functionalized block copolymer, structural constraints in micelles and vesicles prevented C₆₀ pendents to aggregate.     

Aqueous lubricating properties of charged (ABC) and neutral (ABA) triblock copolymer chains

Application of charged polymer chains as additives for lubricating neutral surfaces in aqueous environment, especially via polymer physisorption, is generally impeded by the electrostatic repulsion between adjacent polymers on the surface. In this study, we have investigated the adsorption and aqueous lubricating properties of an amphiphilic triblock copolymer, comprised of a neutral poly(ethylene glycol) (PEG) block, a hydrophobic poly(2-methoxyethyl acrylate) (PMEA) block, and a charged poly(methacrylic acid) (PMAA) block, namely PEG-b-PMEA-b-PMAA. After adsorption onto a nonpolar hydrophobic surface from aqueous solution, an equal and homogeneous mixture of neutral PEG and charged PMAA chains is formed on the surface, with an adsorbed polymer mass comparable to its fully neutral counterpart, PEG-b-PMEA-b-PEG. The lubricity of PEG-b-PMEA-b-PMAA showed significant improvement compared to fully charged polymer chains, e.g. poly(acrylic acid)-block-poly(2-methoxyethyl acrylate) (PAA-b-PMEA), which is attributed to dilution of charged moieties on the surface and subsequent improvement of the lubricating film stability.     

Synthesis and characterization of poly(l-glutamic acid)-block-poly(l-phenylalanine)

Poly(γ-benzyl l-glutamate)-block-poly(l-phenylalanine) was prepared via the ring opening polymerization of γ-benzyl l-glutamate N-carboxyanhydride and l-phenylalanine N-carboxyanhydride using n-butylamine·HCl as an initiator for the living polymerization. Polymerization was confirmed by ¹H-nuclear magnetic resonance spectroscopy and matrix assisted laser desorption ionization time of flight mass spectroscopy. After deprotection, the vesicular nanostructure of poly(l-glutamic acid)-block-poly(l-phenylalanine) particles was examined by transmission electron microscopy and dynamic light scattering. The pH-dependent properties of the nanoparticles were evaluated by means of ζ-potential and transmittance measurements. The results showed that the block copolypeptide could be prepared using simple techniques. Moreover, the easily prepared PGA-PPA block copolypeptide showed pH-dependent properties due to changes in the PGA ionization state as a function of pH; this characteristic could potentially be exploited for drug delivery applications.     

Design of novel poly(methyl vinyl ether) containing AB and ABC block copolymers by the dual initiator strategy

A new set of block copolymers containing poly(methyl vinyl ether) (PMVE) on one hand and poly(tert-butyl acrylate), poly(acrylic acid), poly(methyl acrylate) or polystyrene on the other hand, have been prepared by the use of a novel dual initiator 2-bromo-(3,3-diethoxy-propyl)-2-methylpropanoate. The dual initiator has been applied in a sequential process to prepare well-defined block copolymers of poly(methyl vinyl ether) (PMVE) and hydrolizable poly(tert-butyl acrylate) (PtBA), poly(methyl acrylate) (PMA) or polystyrene (PS) by living cationic polymerization and atom transfer radical polymerization (ATRP), respectively. In a first step, the Br and acetal end groups of the dual initiator have been used to generate well-defined homopolymers by ATRP (resulting in polymers with remaining acetal function) and living cationic polymerization (PMVE with pendant Br end group), respectively. In a second step, those acetal functionalized polymers and PMVE-Br homopolymers have been used as macroinitiators for the preparation of PMVE-containing block copolymers. After hydrolysis of the tert-butyl groups in the PMVE-b-ptBA block copolymer, PMVE-b-poly(acrylic acid) (PMVE-b-PAA) is obtained. Chain extension of the AB diblock copolymers by ATRP gives rise to ABC triblock copolymers. The polymers have been characterized by MALDI-TOF, GPC and ¹H NMR.     

Rheology modification of PVC plastisols with poly(butylene terephthalate)-b-poly(tetramethylene glycol)

A few percent of poly(butylene)-b-poly(tetramethylene glycol) was able to turn a liquid plasticizer into a gel, and thus imparted yield stresses to the fluid. When the plasticizer contained as little as 2.5 wt % of the block copolymer, sag free plastisols were obtained. A reduction in tensile strength was found for the modified plastisols, while the elongation was not affected. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 66: 749–753, 1997     

Development of a new azido-oxazoline monomer for the preparation of amphiphilic graft copolymers by combination of cationic ring-opening polymerization and click chemistry

A new monomer (2-(5-azidopentyl)-2-oxazoline) bearing an azido group was synthesized. The cationic ring-opening copolymerization of this monomer with 2-methyl-2-oxazoline resulted in a well-defined linear polymer backbone with pendant azido groups. Alkynyl-poly(d,l-lactide) was grafted onto the azido groups of poly(oxazoline) via a Huisgen 1,3-dipolar cycloaddition reaction to give a novel amphiphilic graft copolymer [poly(2-methyl-2-oxazoline-co-2-pentyl-2-oxazoline)-g-poly(d,l-lactide)] (P[(MeOx-co-PentOx)-g-LA]). Different graft copolymers were prepared with PLA of different lengths. Preliminary results of the self-association of this copolymer in water indicated the formation of nanoparticles, which suggests this copolymer may have applications as vehicles for drug delivery.     

Effect of vortex-induced physical stress on fluorescent properties of dye-containing poly(ethylene glycol)-block-poly(lactic acid) micelles

The effect of vortex-induced mechanical stresses on the fluorescent properties of dye-containing poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) block copolymer micelles has been investigated. PEG-b-PLA block copolymer micelles containing fluorescent dyes, 3,3′-dioctadecyloxacarbocyanine perchlorate (DiO) and/or 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI), are prepared by a simple one-step procedure that involves the self-assembly of block copolymers and spontaneous incorporation of hydrophobic dyes into the core of the micelles. Upon vortexing, the micelle dispersion samples showed a decrease in fluorescence intensity in a rotational speed- and time-dependent manner. The results demonstrated that the vortexing can alter the fluorescent properties of the dye-containing PEG-b-PLA block copolymer micelle dispersion samples, suggesting the potential utility of block copolymer micelles as a mechanical stress-responsive nanomaterial.     

Studies with gradient polymers of polystyrene and poly(methyl acrylate)

A series of [net-polystyrene]-ipn-[net-poly(methyl acrylate)] systems with gradients of poly(methyl acrylate) in a polystyrene matrix are prepared and tested mechanically. The results showed no distinct differences from that of corresponding interpenetrating polymer network (IPN) samples with similar compositions, in contrast to the substantially improved fracture strains obtained for [net-poly(methyl methacrylate)]-ipn-[-net poly(methyl acrylate)] gradient systems and their nongradient IPN's in our previous work. Hence, it is concluded that the toughening effect of gradient structure observed is not universally applicable for all gradient systems but it is unique for the acrylic system studied. Moduli-temperature responses and dynamic mechanical spectra of gradients and IPN's prepared in the current study are also presented. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 73: 1721–1725, 1999     

Physical properties of poly(cyclohexyl methacrylate)-b-poly(iso-butyl acrylate)-b-poly(cyclohexyl methacrylate) triblock copolymers synthesized by controlled radical polymerization

The microphase segregation of different poly(cyclohexyl methacrylate)-b-poly(iso-butyl acrylate)-b-poly(cyclohexyl methacrylate), PCH-b-PiBA-b-PCH, triblock copolymers obtained by atom transfer radical polymerization has been evaluated by dynamic mechanical thermal analysis through location of the two relaxations ascribed to cooperative motions of each block. Additionally, other secondary relaxations have been found, whose characteristics are also dependent on molecular weight of outer and rigid segments. The length of these hard blocks influences significantly the stiffness and microhardness found in these triblock copolymers. These two mechanical parameters increase as molecular weight of poly(cyclohexyl methacrylate) does. The morphological aspects have been examined by small angle X-ray scattering and atomic force microscopy.