Effects of soft segments and hydrolysis on the crystallization behavior of degradable poly(oxyethylene)/poly(L-lactide) block copolymers

The crystallization behavior of poly(oxyethylene) (PEG)/poly(L -lactide) (PLLA) block copolymers with PEG (number-average molecular weights M _n = 1000–6000) contents ≦ 18,3 wt.-% has been studied under different isothermal temperature and linear cooling conditions. A differential scanning calorimeter was used to monitor the energetics of the crystallization process from the melt state. The influence of copolymer composition and hydrolysis on radial growth rates of spherulites, G, in PEG/PLLA copolymer was investigated using polarized light video-microscopy. The data were analyzed in terms of a model describing two processes, namely crystal nucleation and growth which were observed experimentally in a typical Avrami plot for the isothermal data. At a given crystallization temperature, G's are increased with increasing PEG content and with decreasing PEG segment length in PEG/PLLA copolymer spherulites. The Avrami exponent n and rate coefficient k of PEG/PLLA copolymers decrease with increasing hydrolysis time up to 200 h. The spherulite morphology appeared to be a complex function of copolymer composition, hydrolysis time and crystallization temperature.     

The crystal structure and drawing-induced polymorphism in poly(aryl ether ketone)s, 2. Poly(ether ether ketone ketone), PEEKK

The crystal structure, morphology and polymorphism induced by uniaxial drawing of poly(ether ether ketone ketone) [PEEKK] have been studied by transmission electron microscopy (TEM), electron diffraction (ED) and wide angle X-ray diffraction (WAXD). On the basis of WAXD and ED patterns, the crystal structure of unoriented PEEKK is determined to have two-chain orthorhombic packing with unit cell parameters of a = 0.772 nm, b = 0.600 nm, c = 1.004 nm (form I). A stress-induced crystal modification (form II) is identified and found to possess a two-chain orthorhombic lattice with unit cell dimensions of a = 0.461 nm, b = 1.074 nm, c = 1.080 nm. The 7.5% increase in c-axis dimension for form II is attributed to an overextended chain conformation, arising from extensional deformation during uniaxial drawing and fixed “in-situ” through strain-induced crystallization. The average ether-ketone bridge bond angles in form II crystal are determined to be 148.9° by using standard bond lengths. The crystal morphology of PEEKK bears a great similarity to that of PEEK. The crystals grow in the form of spherulites and have the b-axis of unit cell radial. The effects of draw rate on strain-induced crystallization and induction of form II structure are also discussed.     

Deformation of Hierarchical Lamellar Structure Formed by a Liquid Crystalline Block Copolymer

The deformation of a structure of alternating liquid crystal (LC)/viscous layers upon being stretched along the normal layer is investigated using highly ordered, near‐single‐crystal lamellar fibers of an LC block copolymer. The block copolymer consists of poly(ethyl methacrylate) (PEMA) segments attached to a main‐chain LC polyester at both ends. The LC block segregates from the PEMA block and forms a smectic LC, laying the layers parallel to the interface with PEMA block lamellae to form a hierarchical layered structure. Deformations on stretching the fiber sample are observed by X‐ray scattering measurements. The fiber deformation causes lamellae to dilate and undulate at elongation ratio (λ) < 1.6, wherein PEMA block lamellae are preferentially dilated to tilt lamellar boundaries. In the dilated LC block lamellae, the smectic layers undulate without changing the layer spacing. With further fiber elongation, the lamellae are folded into a chevron rather than dilated, recovering the lamellar spacing.     

Formation of spherulites during polymerization of lactams

The mechanism of the crystal growth of nylon in the course of alkaline polymerization of lactams was studied in terms of kinetics and morphologies of the resultant crystals. It was found that in the bulk polymerization of α-pyrrolidone, the resultant polymer precipitated in the form of spherulites. Spherulites formed in the early stage of polymerization were swollen, soft balls in which thin lamellar crystallites were radiating along the spherulitic radius. It is considered that the growing chain molecules, when they attained a critical length beyond which they lost the solubility in the system, will precipitate into the form of lamellae in which molecules are aligned perpendicularly to the lamellar surface. Such spherulites matured as the polymerization proceeded. In the early stage of the polymerization, the mutual coupling of the swollen spherulites occurred. In the subsequent stage, the vacant space was occupied by the product of further polymerization, so that the coupled spherulites grew into a sphere again. On the other hand, the propagation of the chains in the individual spherulites made the spherulites compact. It is postulated that the chains grown from the surface of the lamellar nuclei, precipitate in the interstices between the lamellae and a part of these chains will form molecular ties between the lamellae giving rise to compact spherulites. The decrease in the rate of polymerization observed may be attributable to the occlusion of the growing chain ends into the precipitates. The impurity in the system, i.e., water, seems to affect the rate of the monomer addition, but does not the morphology. Spherulites were also grown in the case of nylon 6, the polymerization of ?-caprolactam.     

Ring‐Banded Spherulitic Crystals of Poly(3‐butylthiophene) via Controlled Solvent Evaporation

The preparation of ring‐banded spherulites in poly(3‐butylthiophene) via controlled solvent evaporation of solution‐cast films is reported. The spherulites display unusual concentric ring‐banded structures under both polarized and unpolarized lights. The size of the ring‐banded spherulites is 300 ± 100 µm in diameter and the periodicity of the bands is 15 ± 2 µm. The periodic bands of the spherulite consist of alternating ridge and valley surface patterns and the crystalline lamellae in the bands are more or less parallel to the radial growth direction of the spherulites. Local lamellar bending and branching are observed analogous to that of classical non‐conjugated polymers. A possible diffusion‐induced rhythmic growth mechanism is proposed to interpret the formation of periodic banding of the spherulite.     

Lamellar Morphology of an ABA Triblock Copolymer with a Main‐Chain Nematic Polyester Central Block

A liquid crystal (LC) ABA triblock copolymer with poly(styrene) (PS) A blocks and a main‐chain nematic LC polyester B block is synthesized by atom‐transfer radical polymerization of styrene with an LC polyester macro‐initiator. The nematic LC and PS amorphous phases are segregated from each other to form lamellae with a spacing of 27 nm. The 16 nm‐thick nematic LC lamellae are significantly smaller than the contour length of the LC segment (63 nm), and the nematic director is parallel to the lamellae. The central LC segment is primarily more extended in the lamellar direction, but folds so as to meander through the LC lamella and bridges adjacent PS domains. The lamellar microstructure exhibits a reversible spacing increase of up to 31 nm with increasing temperature, suggesting a corresponding increase in the probability of the chain folding.

     

Targeted gene delivery by polyplex micelles with crowded PEG palisade and cRGD moiety for systemic treatment of pancreatic tumors

Adequate retention in systemic circulation is the preliminary requirement for systemic gene delivery to afford high bioavailability into the targeted site. Polyplex micelle formulated through self-assembly of oppositely-charged poly(ethylene glycol) (PEG)-polycation block copolymer and plasmid DNA has gained tempting perspective upon its advantageous core–shell architecture, where outer hydrophilic PEG shell offers superior stealth behaviors. Aiming to promote these potential characters toward systemic applications, we strategically introduced hydrophobic cholesteryl moiety at the ω-terminus of block copolymer, anticipating to promote not only the stability of polyplex structure but also the tethered PEG crowdedness. Moreover, M_w of PEG in the PEGylated polyplex micelle was elongated up to 20 kDa for expecting further enhancement in PEG crowdedness. Furthermore, cyclic RGD peptide as ligand molecule to integrin receptors was installed at the distal end of PEG in order for facilitating targeted delivery to the tumor site as well as promoting cellular uptake and intracellular trafficking behaviors. Thus constructed cRGD conjugated polyplex micelle with the elevated PEG shielding was challenged to a modeled intractable pancreatic cancer in mice, achieving potent tumor growth suppression by efficient gene expression of antiangiogenic protein (sFlt-1) at the tumor site.     

Synthesis,Structure and Crystal Morphology of Nylon 2/16

The alternating copolyamide poly(glycine‐co‐16‐aminohexadecanoic acid) (nylon 2/16) was synthesized by polycondensation of the “dimer” glycyl‐16‐aminohexadecanoic acid pentachlorophenyl ester hydrobromide in a N,N‐dimethylformamide solution. Both X‐ray diffraction and electron microscopy studies showed that this new 2/n copolyamide crystallized in a hexagonal lattice of a = 0.479 nm with a residue height of about 2.4 nm. The crystal structure was modeled for a 6‐fold helix with a period of 14.4 nm that is linked to its six neighbors by a three‐dimensional network of hydrogen bonds. The structure had the overall features of the so‐called Form II typical of nylons 2/n and was able to reproduce satisfactorily the experimental diffraction data. 4.5 nm‐thick lamellar single crystals accommodating only two nylon 2/16 chemical residues in height were obtained by crystallization from solution. Variations in the crystallization temperature produced changes in the lamellar crystal morphology consistent with the occurrence of preferential hydrogen bonding directions. Compared with all other members of the 2/n family studied already by us, no trace of crystal form with chains in fully extended conformation (Form I) was found for nylon 2/16.     

ATP hydrolysis-dependent asymmetry of the conformation of CFTR channel pore

Despite substantial efforts, the entire cystic fibrosis transmembrane conductance regulator (CFTR) protein proved to be difficult for structural analysis at high resolution, and little is still known about the actual dimensions of the anion-transporting pathway of CFTR channel. In the present study, we therefore gauged geometrical features of the CFTR Cl⁻ channel pore by a nonelectrolyte exclusion technique. Polyethylene glycols with a hydrodynamic radius (R _h) smaller than 0.95 nm (PEG 300–1,000) added from the intracellular side greatly suppressed the inward unitary anionic conductance, whereas only molecules with R _h ≤ 0.62 nm (PEG 200–400) applied extracellularly were able to affect the outward unitary anionic currents. Larger molecules with R _h = 1.16–1.84 nm (PEG 1,540–3,400) added from either side were completely excluded from the pore and had no significant effect on the single-channel conductance. The cut-off radius of the inner entrance of CFTR channel pore was assessed to be 1.19 ± 0.02 nm. The outer entrance was narrower with its cut-off radius of 0.70 ± 0.16 nm and was dilated to 0.93 ± 0.23 nm when a non-hydrolyzable ATP analog, 5′-adenylylimidodiphosphate (AMP-PNP), was added to the intracellular solution. Thus, it is concluded that the structure of CFTR channel pore is highly asymmetric with a narrower extracellular entrance and that a dilating conformational change of the extracellular entrance is associated with the channel transition to a non-hydrolytic, locked-open state.     

Structure of tropomyosin-troponin T cocrystals

Summary Crystals formed from a mixture of tropomyosin and troponin T have an open double-stranded lattice structure with a diamond-shaped repeat. In some regions the appearance in electron micrographs of negatively stained specimens changes from this double-diamond lattice to a more condensed banded crystal form. The double-diamond lattice has plane group symmetrycmm with unit cell 76.3 by 21.7nm. The molecules form continuous chains along the diagonal of the unit cell and the diagonal length (79.4 nm) is that expected for two tropomyosin molecules joined end-to-end. Computer filtering of the micrographs shows that the strands of the lattice are thicker from the acute vertex of the large diamond to a point about half-way along the side of the diamond, where there is a small blob of density. At the acute vertex of the diamond is a large blob of density which is accentuated, however, by being at the lattice node where strands cross each other, and which is much weaker in regions of the micrographs where the crystals have condensed laterally. The results indicate that troponin T is a long thin molecule running in contact with the tropomyosin strands over 40–50% of the tropomyosin molecular length. The small globular region may represent the end-to-end overlap of tropomyosin but is more likely to be a globular region at the C-terminal region of troponin T.     

Structure and mechanical properties of Saxidomus purpuratus biological shells

The strength and fracture behavior of Saxidomus purpuratus shells were investigated and correlated with the structure. The shells show a crossed lamellar structure in the inner and middle layers and a fibrous/blocky and porous structure composed of nanoscaled particulates (∼100 nm diameter) in the outer layer. It was found that the flexure strength and fracture mode are a function of lamellar organization and orientation. The crossed lamellar structure of this shell is composed of domains of parallel lamellae with approximate thickness of 200–600 nm. These domains have approximate lateral dimensions of 10–70 μm with a minimum of two orientations of lamellae in the inner and middle layers. Neighboring domains are oriented at specific angles and thus the structure forms a crossed lamellar pattern. The microhardness across the thickness was lower in the outer layer because of the porosity and the absence of lamellae. The tensile (from flexure tests) and compressive strengths were analyzed by means of Weibull statistics. The mean tensile (flexure) strength at probability of 50%, 80–105 MPa, is on the same order as the compressive strength (∼50–150 MPa) and the Weibull moduli vary from 3.0 to 7.6. These values are significantly lower than abalone nacre, in spite of having the same aragonite structure. The lower strength can be attributed to a smaller fraction of the organic interlayer. The fracture path in the specimens is dominated by the orientation of the domains and proceeds preferentially along lamella boundaries. It also correlates with the color changes in the cross section of the shell. The cracks tend to undergo a considerable change in orientation when the color changes abruptly. The distributions of strengths, cracking paths, and fracture surfaces indicate that the mechanical properties of the shell are anisotropic with a hierarchical nature.     

Folate-conjugated amphiphilic hyperbranched block copolymers based on Boltorn® H40, poly(l-lactide) and poly(ethylene glycol) for tumor-targeted drug delivery

Folate-conjugated amphiphilic hyperbranched block copolymer (H40–PLA-b-MPEG/PEG–FA) with a dendritic Boltorn^® H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell and a hydrophilic methoxy poly(ethylene glycol) (MPEG) and folate-conjugated poly(ethylene glycol) (PEG–FA) outer shell was synthesized as a carrier for tumor-targeted drug delivery. The block copolymer was characterized using ¹H NMR and gel permeation chromatography (GPC) analysis. Due to its core–shell structure, this block polymer forms unimolecular micelles in aqueous solutions. The micellar properties of H40–PLA-b-MPEG/PEG–FA block copolymer were extensively studied by dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). An anticancer drug, doxorubicin in the free base form (DOX) was encapsulated into H40–PLA-b-MPEG/PEG–FA micelles. The DOX-loaded micelles provided an initial burst release (up to 4 h) followed by a sustained release of the entrapped DOX over a period of about 40 h. Cellular uptake of the DOX-loaded H40–PLA-b-MPEG/PEG–FA micelles was found to be higher than that of the DOX-loaded H40–PLA-b-MPEG micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. In vitro degradation studies revealed that the H40–PLA-b-MPEG/PEG–FA block copolymer hydrolytically degraded into polymer fragments within six weeks. These results indicated that the micelles prepared from the H40–PLA-b-MPEG/PEG–FA block copolymer have great potential as tumor-targeted drug delivery nanocarriers.     

Enhancement of the Photoalignment Stability of Block Copolymer Brushes by Anchor Segments

It is known that the use of a homopolymer derived from a relatively high‐surface‐energy block moiety in a diblock copolymer as a substrate can facilitate phase separation of the block copolymer in the form of a layered structure parallel to the substrate. This is an effective approach for preparing a photoresponsive surface molecular brush for liquid‐crystal alignment. However, the alignment of the polymer brushes soon diminishes during elastic deformation of the polymeric substrate due to the weak interaction between the copolymer and polymeric substrate in the interfacial blend layer. In this study, rigid segments composed of N‐p‐anisylmaleimide were controllably introduced via copolymerization into a series of well‐defined diblock copolymers as “anchors” to resist the “drift” of the copolymer from a polymethyl methacrylate substrate at above its glass transition temperature. The anchoring mechanism and the stability of the aligned azobenzene polymeric brushes were systematically studied and compared.     

Structural study of polybutadiene-poly(ethylene oxide) block copolymers. Influence of the nature of the amorphous block on the refolding of the poly(ethylene oxide) chains

Our earlier studies on block copolymers polystyrene-poly(ethylene oxide) has allowed to state the influence of the molecular weight of the copolymer and of its composition on the refolding of the crystallized poly(ethylene oxide) chains. To precise the effect of the nature of the amorphous block, we have studied by X-ray diffraction and differential scanning calorimetry, the lamellar crystalline structures exhibited by block copolymers polybutadiene-poly(ethylene oxide) (BEO) in the presence of a preferential solvent of one block: xylene for polybutadiene (PB), acetic acid or acrylic acid for poly(ethylene oxide) (PEO). In systems BEO copolymer/preferential solvent of PEO, the lamellar structure with crystallized PEO chains (LCC) exists at temperatures below about 45°C and for solvent concentrations ranging from 0 to a value characteristic of the copolymer. In the LCC structure, the chains of PEO crystallize in two layers; the solvent forms a third layer located between the PEO layers. We have studied the influence of the nature of the amorphous block on the variation of the structural parameters with the solvent concentration. In systems BEO copolymer/preferential solvent of PB, the lamellar structure with crystallized PEO chains (LC) appears at temperatures below about 50°C and for all solvent concentrations where the mesophase exists. In the LC structure, the chains of PEO crystallize folding in two superposed layers. We have established the influence of the solvent concentration and the nature of the amorphous block on the number of folds and the crystallinity of the PEO chains.     

Microstructural characterization of polypropene surfaces using grazing incidence X-ray diffraction

The grazing incidence X-ray diffraction was applied for characterizing the crystalline structure of the outermost layer of polypropene sheets. Even in the outermost surface layer within about 5 nm, the crystalline structure of the a form was confirmed by the X-ray diffraction patterns. The values of a and c for the crystal lattice dimension were almost constant in spite of the variation of surface layer crystallinity, whereas the value of b for the surface layer decreased with increasing crystallinity or decreasing comonomer content of polypropene. This suggests that the density of the crystal increased as a function of crystallinity. Additionally, the value of b for the surface layer was smaller than that of the bulk. It was concluded that the lattice distortion can be ascribed to the residual stress caused by the molding pressure under the higher super-cooling rate.     

Preparation of ABCBA-type block copolymers by use of macro-initiators containing peroxy and azo groups

Some new macroinitiators ( 5 ) containing azo and peroxy groups were synthesized by transformation of esters of poly(ethylene glycol) ( 1 ) (PEG) of different molecular weight with hydroxyl end groups and an azo group in the middle into the corresponding polymers with tert-butylperoxycarbonyl end groups by reaction with terephthaloyl chloride and subsequently with tert-butyl hydroporoxide. Decomposition in the presence of styrene at 60°C or with 3,6,9-triazaun-decane-1,11-diamine in presence of methyl methacrylate gave the corresponding ABA block copolymer 6 and the ABBA block copolymer 7 , respectively. Both block copolymers were used as polymeric initiators. The ABCBA block copolymer 8 was synthesized from 6 and methyl methacrylate or from 7 and styrene by thermally induced polymerization at 80°C. The resulting block copolymers were separated from the homopolymers by selective solvent extraction and characterized by spectroscopic and fractional precipitation methods.     

Effect of PP-g-LCP compatibilizer on the structure and crystallization of blends of isotactic polypropylene (PP) with a semiflexible liquid crystalline polymer (LCP)

Blends of i-polypropylene and a semiflexible liquid crystalline polymer (iPP/LCP 90/10 and 80/20 w/w) were compatibilized with 2.5, 5 or 10 wt.-% PP-g-LCP copolymers. The crystal structure, crystallization behaviour and morphology of the compatibilized blends have been investigated by differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and optical microscopy. It is shown that the nucleation rate and crystallization rate of iPP strongly increased in the compatibilized blends in comparison to the uncompatibilized ones. In compatibilized blends, while iPP spherulites get smaller and crystallinity degree increases, the crystal growth mechanism of iPP remains unchanged. An assumption has been made about the mechanism of the compatibilization, using graft copolymers constructed of segments identical to the blended polymers: the PP segments of PP-g-LCP copolymers, if long enough, cocrystallize with bulk iPP, compatibilizing partially the two components; the LCP grafts of the copolymers cocrystallize with the bulk LCP or enter the amorphous phase of the blends. The miscibility of each part of the copolymer compatibilizers with the corresponding bulk component of the blend leads to a reduction of the interfacial tension and to a strong reduction of the dimensions of dispersed LCP phase. The compatibilized iPP/LCP blends display improved crystallization kinetics, enhanced degree of crystallinity and improved interphase adhesion. Consequently, an improvement of the mechanical properties and rheological characteristics should be expected for these blends.     

Poly(ethylene glycol) analogs grafted with low molecular weight poly(ethylene imine) as non-viral gene vectors

A novel class of non-viral gene vectors consisting of low molecular weight poly(ethylene imine) (PEI) (molecular weight 800 Da) grafted onto degradable linear poly(ethylene glycol) (PEG) analogs was synthesized. First, a Michael addition reaction between poly(ethylene glycol) diacrylates (PEGDA) (molecular weight 258 Da) and d,l-dithiothreitol (DTT) was carried out to generate a linear polymer (PEG–DTT) having a terminal thiol, methacrylate and pendant hydroxyl functional groups. Five PEG–DTT analogs were synthesized by varying the molar ratio of diacrylates to thiols from 1.2:1 to 1:1.2. Then PEI (800 Da) was grafted onto the main chain of the PEG–DTTs using 1,1′-carbonyldiimidazole as the linker. The above reaction gave rise to a new class of non-viral gene vectors, (PEG–DTT)–g-PEI copolymers, which can effectively complex DNA to form nanoparticles. The molecular weights and structures of the copolymers were characterized by gel permeation chromatography, ¹H nuclear magnetic resonance and Fourier transform infrared spectroscopy. The size of the nanoparticles was <200 nm and the surface charge of the nanoparticles, expressed as the zeta potential, was between +20 and +40 mV. Cytotoxicity assays showed that the copolymers exhibited much lower cytotoxicities than high molecular weight PEI (25 kDa). Transfection was performed in cultured HeLa, HepG2, MCF-7 and COS-7 cells. The copolymers showed higher transfection efficiencies than PEI (25 kDa) tested in four cell lines. The presence of serum (up to 30%) had no inhibitory effect on the transfection efficiency. These results indicate that this new class of non-viral gene vectors may be a promising gene carrier that is worth further investigation.     

A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors

Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20–120 nm) depending on the PPT-to-PEG molar ratio (2–20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ∼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (∼2.5%/day and ∼1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.