Polymer vectors via controlled/living radical polymerization for gene delivery

The design of efficient gene delivery vectors is a challenging task in gene therapy. Recent progress in living/controlled radical polymerizations (LRPs), in particular atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization providing a means for the design and synthesis of new polymeric gene vectors with well-defined compositions, architectures and functionalities is reviewed here. Polymeric gene vectors with different architectures, including homopolymers, block copolymers, graft copolymers, and star-shaped polymers, are conveniently prepared via ATRP and RAFT polymerization. The corresponding synthesis strategies are described in detail. The recent research activities indicate that ATRP and RAFT polymerization have become essential tools for the design and synthesis of advanced, noble and novel gene carriers.     

Telechelic polymers by living and controlled/living polymerization methods

Telechelic polymers, defined as macromolecules that contain two reactive end groups, are used as cross-linkers, chain extenders, and important building blocks for various macromolecular structures, including block and graft copolymers, star, hyperbranched or dendritic polymers. This review article describes the general techniques for the preparation of telechelic polymers by living and controlled/living polymerization methods; namely atom transfer radical polymerization, nitroxide mediated radical polymerization, reversible addition-fragmentation chain transfer polymerization, iniferters, iodine transfer polymerization, cobalt mediated radical polymerization, organotellurium-, organostibine-, organobismuthine-mediated living radical polymerization, living anionic polymerization, living cationic polymerization, and ring opening metathesis polymerization. The efficient click reactions for the synthesis of telechelic polymers are also presented.     

Complex macromolecular architecture design via cyclodextrin host/guest complexes

The design of complex macromolecular architectures has driven macromolecular engineering over the past decades. The introduction of supramolecular chemistry into polymer chemistry provides novel opportunities for the generation of macromolecular architecture with specific functions. Cyclodextrins are attractive design elements as they form supramolecular inclusion complexes with hydrophobic guest molecules in aqueous solution affording the possibility to combine a large variety of building blocks to form novel macromolecular architectures. In the present critical review, the design of a broad range of macromolecular architectures driven by cyclodextrin host/guest chemistry is discussed, including supramolecular block copolymers, polymer brushes, star and branched polymers.     

Functionalized micelles from new ABC polyglycidol-poly(ethylene oxide)-poly(d,l-lactide) terpolymers

New ABC type terpolymers of poly(ethoxyethyl glycidyl ether)/poly(ethylene oxide)/poly(d,l-lactide) were obtained by multi-mode anionic polymerization. After successive deprotection of the ethoxyethyl groups from the first block, highly hydroxyl functionalized copolymers of polyglycidol/poly(ethylene oxide)/poly(d,l-lactide) were obtained. These copolymers form elongated ellipsoidal micelles by direct dissolution in water. The micelles consist of a poly(d,l-lactide) core and stabilizing shell of polyglycidol/poly(ethylene oxide). The hydroxyl groups of polyglycidol blocks situated at the micelle surface provide high functionality, which could be engaged in further chemical modification resulting in a potential drug targeting agents. The micellization process of the copolymers in aqueous media was studied by hydrophobic dye solubilization, static and dynamic light scattering, and transmission electron microscopy.     

Biodegradable synthetic polymers: Preparation, functionalization and biomedical application

Biodegradable polymers have been widely used and have greatly promoted the development of biomedical fields because of their biocompatibility and biodegradability. The development of biotechnology and medical technology has set higher requirements for biomedical materials. Novel biodegradable polymers with specific properties are in great demand. Biodegradable polymers can be classified as natural or synthetic polymers according to the source. Synthetic biodegradable polymers have found more versatile and diverse biomedical applications owing to their tailorable designs or modifications. This review presents a comprehensive introduction to various types of synthetic biodegradable polymers with reactive groups and bioactive groups, and further describes their structure, preparation procedures and properties. The focus is on advances in the past decade in functionalization and responsive strategies of biodegradable polymers and their biomedical applications. The possible future developments of the materials are also discussed.     

Atom transfer radical polymerization (ATRP): A versatile and forceful tool for functional membranes

The progress in atom transfer radical polymerization (ATRP) provides an effective means for the design and preparation of functional membranes. Polymeric membranes with different macromolecular architectures applied in fuel cells, including block and graft copolymers are conveniently prepared via ATRP. Moreover, ATRP has also been widely used to introduce functionality onto the membrane surface to enhance its use in specific applications, such as antifouling, stimuli-responsive, adsorption function and pervaporation. In this review, the recent design and synthesis of advanced functional membranes via the ATRP technique are discussed in detail and their especial advantages are highlighted by selected examples extract the principles for preparation or modification of membranes using the ATRP methodology.     

Crystallization behavior of linear 1-arm and 2-arm poly(l-lactide)s: Effects of coinitiators

Linear 1-arm and 2-arm poly(l-lactide) [i.e., poly(l-lactic acid) (PLLA)] polymers having relatively low number-average molecular weights (M_n) (≤5 × 10⁴ g mol⁻¹) were synthesized by ring-opening polymerization of l-lactide initiated with tin(II) 2-ethylhexanoate (i.e., stannous octoate) and coinitiators of l-lactic acid, 1-dodecanol (i.e., lauryl alcohol), and ethylene glycol (these PLLA polymers are abbreviated as LA, DN, and EG, respectively). For M_n below 1.5 × 10⁴ g mol⁻¹, non-isothermal crystallization during heating and isothermal spherulite growth were disturbed in linear 2-arm PLLA (EG) compared to those in linear 1-arm PLLA (LA and DN). This finding indicates that the chain directional change, the incorporation of the coinitiator moiety as an impurity in the middle of the molecule, and their mixed effect disturbed the crystallization of linear 2-arm PLLA compared to that of linear 1-arm PLLA, in which the chain direction is unvaried and the coinitiator moiety is incorporated in the chain terminal. Also, the finding strongly suggests that the reported low crystallizability of multi-arm PLLA (arm number ≥ 3) compared to that of linear 1-arm PLLA is caused not only by the presence of branching points but also by the chain directional change, the incorporation of the coinitiator moiety in the middle of the molecule, and their mixed effect. The effects of the chain directional change and the position of the incorporated coinitiator moiety on the crystallization and physical properties of linear 1-arm and 2-arm PLLA decreased with an increase in M_n.     

Hydrolytic degradation of poly(d,l-lactide) as a function of end group: Carboxylic acid vs. hydroxyl

d,l-Lactide was initiated with 1,4-butanediol in the presence of stannous octoate catalyst to provide hydroxyl-terminated poly(d,l-lactide) at 5000 and 20,000 g/mol. Portions of these materials were reacted with succinic anhydride in the presence of 1-methylimidazole to convert the hydroxyl functionality to succinic acid-terminated polymers in relatively high yield. The four materials were placed in a 7.4 pH buffered saline solution at 37 °C and monitored up to 180 days for their relative moisture uptake and weight loss behaviors. Carboxylic acid functionality displayed a dramatic effect on the moisture uptake behaviors for the 5000 and 20,000 g/mol polymers when compared to their respective hydroxyl functional materials. Carboxylic acid functionality significantly increased the hydrolytic degradation rate and mass loss behavior for the 5000 g/mol material, but did not affect the hydrolytic degradation rate for the higher molecular weight sample. These results suggest that moisture uptake is not the rate limiting step for the hydrolytic degradation high molecular weight poly(d,l-lactide).     

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.     

Ring-opening polymerization of six-membered cyclic esters catalyzed by tetrahydroborate complexes of rare earth metals

Catalytic behavior of tetrahydroborate complexes of rare earth metals, Ln(BH₄)₃(THF)_x (1: Ln = La, x = 3; 2: Ln = Pr, x = 2; 3: Ln = Nd, x = 3; 4: Ln = Sm, x = 3; 5: Ln = Y, x = 2.5; 6: Ln = Yb, x = 3), for ring-opening polymerization (ROP) of six-membered cyclic esters, δ-valerolactone (VL) and d,l-lactide (d,l-LA), was studied. The controlled polymerization of VL with 1-6 proceeded in THF at 60 °C. The catalytic activities of these complexes for the ROP of VL were observed to be in order of the ionic radii of the metals: 1(La) ≥ 2(Pr) ≥ 3(Nd) > 4(Sm) > 5(Y) > 6(Yb). The obtained polymers were demonstrated to be hydroxy-telechelic by ¹H NMR and MALDI-TOF MS spectroscopy. The controlled ROP of d,l-LA also proceeded by these complexes. The activities of these complexes for the d,l-LA ROP were also in order of the ionic radii of the metals.     

Glass transition behavior and dynamic fragility in polylactides containing mobile and rigid amorphous fractions

The segmental dynamics of polylactide chains covering the T_g − 30 °C to T_g + 30 °C range was studied in absence and presence of a crystalline phase by dynamic mechanical analysis (DMA) using the framework provided by the WLF theory and the Angell's dynamic fragility concept. An appropriate selection of stereoisomers combined with a thermal conditioning strategy to promote crystallization (above T_g) or relaxation of chains (below T_g) was revealed as an efficient method to tune the ratio of the rigid and mobile amorphous phases in polylactides. A single bulklike mobile amorphous phase was taken for poly(d,l-lactide) (PDLLA). In turn three phases, comprising a mobile amorphous fraction (MAF, X_MA), a rigid amorphous fraction (RAF, X_RA) and a crystalline fraction (X_c) were determined in poly(l-lactide) (PLLA) by modulated differential scanning calorimetry (MDSC) according to a three-phase model. The analysis of results confirms that crystallinity and RAF not only elevate the T_g and the breadth of the glass transition region but also yields an increase in dynamic fragility parameter (m) which entails the existence of a smaller length-scale of cooperativity of polylactide chains in confined environments. Consequently it is proposed that crystallinity is acting in polymeric systems as a topological constraint that, preventing longer range dynamics, provides a faster segmental dynamics by the temperature dependence of relaxation times according to the strong-fragile scheme.     

Phase behaviour of l-lactic acid based polymers of low molecular weight in supercritical carbon dioxide at high pressures

The results of investigations of phase behaviour in the systems l-lactic acid based polymers + carbon dioxide at high pressures are presented. The measurements have been performed in wide temperature and composition ranges. Two samples of the polymer differing in molecular weight (M_n: 1080 and 3990 g/mol) have been investigated. Both samples of the polymer were characterized with the gel permeation chromatography and NMR spectroscopy. The influence of the structure of the polymer on the solubility in supercritical carbon dioxide has been discussed. The results obtained suggest that the solubility of low molecular weight l-lactic acid based polymers in supercritical carbon dioxide is not controlled by its size, but to a large extent by the character of its terminal groups. The phase behaviour in the system l-lactic acid + carbon dioxide has been also investigated and the results were compared with those for the systems composed of l-lactic acid based polymers and carbon dioxide.     

Conjugated-polymer grafting on inorganic and organic substrates: A new trend in organic electronic materials

This review highlights recent developments in the grafting of conjugated polymers onto various substrates for organic electronic devices. The rapid development of multi-layer architectures demands the preparation of well-defined interfaces between both compatible and incompatible materials. It is promising therefore that interface-engineering is now known to help passivate charge trap states, control energy level alignments, enhance charge extraction, guide active-layer morphologies, and improve material compatibility, adhesion and device stability. In organic electronic devices, conjugated polymers are in contact with a wide range of constituents, such as metals, metal oxides, organic materials, and inorganic particles. Covalent bonds between these materials and macromolecules are desired to yield intimate contacts and well-defined interfaces. Following an overview of the various synthetic methodologies of conjugated polymers, the chemistry of tethering macromolecular chains onto nanoparticles and flat surfaces is described. The creation of functional hybrid materials offers the potential to deliver efficient and low-cost devices.     

A poly(2-hydroxyethyl methacrylate)-based immobilized metal affinity chromatography adsorbent for protein purification

Poly(HEMA) microbeads were prepared by suspension polymerization of 2-hydorxyethylmethacrylate and ethyleneglycoldimethacrylate (EGDMA). The water content, ligand density, and selectivity for poly(His)-tagged d-hydantoinase of the poly(HEMA)-based adsorbents were affected by the concentration of EDGMA used during polymerization. The Ni(II)-loaded poly(HEMA) adsorbent exhibited an adsorption capacity of 1.0 mg/g for poly(His)-tagged d-hydantoinase under optimal conditions with buffer containing 100-300 mM NaCl at pH 6.0. One-step purification protocol with the adsorbent gave a purity of at least 92%. The adsorption capacity of adsorbent declined by 54% after 7 cycles, due to the leaching of Ni(II) from the adsorbent. However, upon regeneration the adsorption capacity can be restored. Given the ease of preparation and the chemical and microbial resistance, the poly(HEMA)-based IMAC adsorbent could be a promising substitute for the polysaccharide-based IMAC adsorbents.     

Aqueous RAFT polymerization: recent developments in synthesis of functional water-soluble (co)polymers with controlled structures

Reversible addition-fragmentation chain transfer (RAFT) polymerization has been the focus of intensive research over the past few years since this methodology allows the synthetic tailoring of macromolecules with complex architectures including block, graft, comb, and star structures with predetermined molecular weight, terminal functionality, and narrow molecular weight distribution. In this paper we recount significant milestones in achieving controlled free radical homopolymerization and block copolymerization of water-soluble and amphiphilic monomers including nonionic, cationic, anionic, and zwitterionic species. It is shown that under aqueous conditions, control of homopolymerization and further blocking to extend the molecular weight or to produce precisely structured block copolymers require not only careful selection of reagents (initiator, chain transfer agent, and monomer) but also regulation or elimination of hydrolysis of the omega-terminal thiocarbonylthio functionality. The technological potential of such systems is illustrated for the stimuli (pH) reversible micellization of amphiphilic block copolymers and for stabilization and stimuli responsive aggregation of gold nanoparticles bearing covalently tethered co(polymers). Given the advantages of RAFT over other controlled free radical techniques for preparation of water-soluble architectures, it may be anticipated that this technology will be at the forefront of nano- and microscale self-assembly in electronics and biotechnology.     

Synthesis of well-defined star-branched polymers by stepwise iterative methodology using living anionic polymerization

This article reviews the synthesis of regular and asymmetric star-branched polymers with well-defined structures by methodologies using living anionic polymerization, especially focusing on the synthetic approaches accessible for precisely controlled architectures of star-branched polymers concerning molecular weight, molecular weight distribution, arm number, and composition. The reason for selecting living anionic polymerization from many living/controlled polymerization systems so far developed is that this living polymerization system is still the best to meet the strict requirements for the precise structures of star-branched polymers. Furthermore, we herein mainly introduce a novel and quite versatile stepwise iterative methodology recently developed by our group for the successive synthesis of many-armed and multi-compositional asymmetric star-branched polymers. The methodology basically involves only two sets of the reaction conditions for the entire iterative synthetic sequence. The reaction sequence can be, in principle, limitlessly iterated to introduce a definite number of the same or different polymer segments at each stage of the iteration. As a result, a wide variety of many-armed and multi-compositional asymmetric star-branched polymers can be synthesized.     

Properties of l-tyrosine based polyphosphates pertinent to potential biomaterial applications

Since their introduction by Kohn and Langer et al. in 1984, l-tyrosine based ‘pseudo’ poly(amino acids) have undergone extensive research in the area of polymeric biomaterials. Starting from l-tyrosine based diphenolic monomers, polyiminocarbonates, polycarbonates and polyarylates have been developed by Kohn and co-workers and are being investigated for potential orthopedic biomaterial applications. Mao et al. have reported development of l-tyrosine based polyphosphates and polyphosphonates in a patent, however, detailed structural and physico-chemical characterization studies on such polymers have not been reported yet. For the purpose of the current paper, using a novel solid phase process for synthesis of l-tyrosine based diphenolic monomers and adapting the polymerization process described by Mao et al., l-tyrosine based polyphosphates were developed and investigated for their pertinent bioengineering properties. The properties investigated consist of chemical solubility, hydrophilicity and hydrolytic degradation. The results of this investigation are crucial to validate further investigation of biomaterial applications of these polymers.     

Effect of copolymer ratio on hydrolytic degradation of poly(lactide-co-glycolide) from drug eluting coronary stents

The in vitro hydrolytic degradation behavior of poly(d,l-lactide-co-glycolide) (PLGA) has been systematically investigated from the drug eluting coronary stents with respect to different copolymer compositions. The drug-polymer coated stents were incubated in phosphate buffer saline (pH 7.4) at 37 °C and 120 rpm up to 12 months to facilitate hydrolytic degradation. Gel permeable chromatography, differential scanning calorimetry and scanning electron microscopy were employed to characterize their degradation profiles. The study supports the bulk degradation behavior for PLGA from coated stents. Molecular weight of polymer decreased immediately after immersion in PBS but mass loss was not observed during first few days. The rate of hydrolytic degradation was influenced by copolymer ratio, i.e., degradation of 50:50 PLGA was fastest followed by 65:35 PLGA and 75:25 PLGA. The drug release from PLGA coated stent followed biphasic pattern which was governed by surface dissolution and diffusion of drug rather than polymer degradation.     

Fabrication and characterization of aligned nanofibrous PLGA/Collagen blends as bone tissue scaffolds

Aligned nanofibrous blends of poly (d, l-lactide-co-glycolide) (PLGA) and collagen with various PLGA/collagen compositions (80/20, 65/35 and 50/50) were fabricated by electrospinning and characterized for bone tissue engineering. Morphological characterization showed that the addition of collagen to PLGA resulted in narrowing of the diameter distribution and a reduction in average diameter. Differential scanning calorimetric (DSC) studies showed that the triple helix structure of the native collagen was not destroyed during the fabrication process. However, the blending had a marked effect on the overall enthalpy of the blends, whereby the total enthalpy decreased as the collagen content decreased. Thermogravimetric analysis showed the addition of collagen increased the hydrophilicity of the scaffolds. The crosslinking of collagen to increase the biostability was done using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) in ethanol and an overall ∼25% degree of crosslinking was achieved. The EDC crosslinking had little effect on the nanofibrous morphology of the 80/20 blend system; however, the nanofibrous features were compromised to some extent at higher collagen concentrations. The mechanical characterization under dry and wet conditions showed that increasing collagen content resulted in a tremendous decrease in the mechanical properties. However, crosslinking resulted in the increase in elastic modulus from 47 MPa to 83 MPa for the wet PLGA/Collagen 80/20 blend system, with little effect on the tensile strength. In conclusion, the aligned nanofibrous scaffold used in this study constitutes a promising material for bone tissue engineering.