- Two-Dimensional Supramolecular Assemblies from pH-Responsive Poly(ethyl glycol)-b-poly(l -glutamic acid)-b-poly(N-octylglycine) Triblock Copolymer
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Amphiphilic block copolymers containing polypeptides can self-assemble into a variety of nonspherical structures arising from strong interactions between peptide units. Here, we report the synthesis of a pH-responsive poly(ethyl glycol)-block-poly(l-glutamic acid)-block-poly(N-octylglycine) (PEG-b-PGA-b-PNOG) triblock copolymers by sequential ring-opening polymerization using amine-terminated poly(ethyl glycol) as the macroinitiator followed by selective deprotection of the benzyl protecting group. The obtained triblock copolymer can be directly dispersed in aqueous solution with hydrophilic PEG, pH-responsive PGA block, and hydrophobic PNOG. We present a systematic study of the influence of pH, molar fraction, and molecular weight on the self-assemblies. It was found that the PEG-b-PGA-b-PNOG triblock tends to form two-dimensional nanodisks and nanosheet-like assemblies. The nanodisk-to-nanosheet transition is highly dependent on the pH and molar fraction despite the different molecular weights. We demonstrate that the dominant driving force of the nanodisks and nanosheets is the hydrophobicity of the PNOG blocks. The obtained bioinspired 2D nanostructures are potential candidates for applications in nanoscience and biomedicine.
- Ni, Yunxia,Sun, Jing,Wei, Yuhan,Fu, Xiaohui,Zhu, Chenhui,Li, Zhibo
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- Unimolecular Polypeptide Micelles via Ultrafast Polymerization of N-Carboxyanhydrides
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Polypeptide micelles are widely used as biocompatible nanoplatforms but often suffer from their poor structural stability. Unimolecular polypeptide micelles can effectively address the structure instability issue, but their synthesis with uniform structure and well-controlled and desired sizes remains challenging. Herein we report the convenient preparation of spherical unimolecular micelles through dendritic polyamine-initiated ultrafast ring-opening polymerization of N-carboxyanhydrides (NCAs). Synthetic polypeptides with exceptionally high molecular weights (up to 85 MDa) and low dispersity (? 1.05) can be readily obtained, which are the biggest synthetic polypeptides ever reported. The degree of polymerization was controlled in a vast range (25-3200), giving access to nearly monodisperse unimolecular micelles with predictable sizes. Many NCA monomers can be polymerized using this ultrafast polymerization method, which enables the incorporation of various structural and functional moieties into the unimolecular micelles. Because of the simplicity of the synthesis and superior control over the structure, the unimolecular polypeptide micelles may find applications in nanomedicine, supermolecular chemistry, and bionanotechnology.
- Lv, Shixian,Kim, Hojun,Song, Ziyuan,Feng, Lin,Yang, Yingfeng,Baumgartner, Ryan,Tseng, Kuan-Ying,Dillon, Shen J.,Leal, Cecilia,Yin, Lichen,Cheng, Jianjun
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- Post-polymerization modification of poly(L-glutamic acid) with D -(+)-glucosamine
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Carboxyl functional groups of poly(L-glutamic acid) (PGlu) were modified with a D-(+)-glucosamine (GlcN) by amidation using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as a coupling reagent. The coupling reaction was performed in aqueous medium without protection of hydroxyl functional groups of D-(+)-glucosamine. Poly(L-glutamic acid) and GlcN functionalized polyglutamates (P(Glu-GlcN)) were thoroughly characterized by 1D and 2D NMR spectroscopy and SEC-MALS to gain detailed information on their structure, composition and molar mass characteristics. The results reveal successful functionalization with GlcN through the amide bond and also to a minor extent through ester bond formation in position 1 of GlcN. In addition, a ratio between the α- and β-form of glucosamine substituent coupled to polyglutamate repeating units as well as the content of residual dimethoxy triazinyl active ester moiety in the samples were evaluated.
- Perdih, Peter,ebaek, Sao,Moir, Alenka,agar, Ema
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- Arborescent polypeptides from γ-benzyl l -glutamic acid
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The synthesis of arborescent polymers with poly(γ-benzyl L-glutamate) (PBG) side chains was achieved through successive grafting reactions. The linear PBG building blocks were produced by the ring-opening polymerization of γ-benzyl L-glutamic acid N-carboxyanhydride initiated with n-hexylamine. The polymerization conditions were optimized to minimize the loss of amino chain termini in the reaction. Acidolysis of a fraction of the benzyl groups on a linear PBG substrate and coupling with linear PBG using a carbodiimide/ hydroxybenzotriazole promoter system yielded a comb-branched or generation zero (G0) arborescent PBG. Further partial deprotection and grafting cycles led to arborescent PBG of generations G1 to G3. The solvent used in the coupling reaction had a dramatic influence on the yield of graft polymers of generations G1 and above, dimethylsulfoxide being preferable to N,N-dimethylformamide. This grafting onto scheme yielded well-defined (Mw/Mn ≤ 1.06), high molecular weight arborescent PBG in a few reaction cycles, with number-average molecular weights and branching functionalities reaching over 106 and 290, respectively, for the G3 polymer. α-Helix to coiled conformation transitions were observed from N,N-dimethylformamide to dimethyl sulfoxide solutions, even for the highly branched polymers.
- Whitton, Greg,Gauthier, Mario
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- Thermo-responsive peptide-based triblock copolymer hydrogels
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A series of novel thermo-responsive peptide-based triblock copolymers, poly(l-glutamic acid)-b-poly(N-isopropylacrylamide)-b-poly(l-glutamic acid) (PLGA-b-PNIPAM-b-PLGA), were successfully synthesized via ring opening polymerization (ROP) of the γ-benzyl l-glutamate derivative (BLG-NCA) using a diamino-terminated PNIPAM as a macroinitiator, followed by de-protection of the benzyl groups. These triblock copolymers form physically crosslinked networks after complexation with a diamino-terminated poly(ethylene oxide) (PEO) in an organic solvent through acid-base proton transfer and successive ionic-bonding confirmed by Fourier transform infrared (FTIR) spectroscopy. The secondary structure of the peptide block, before and after complexation, was confirmed by circular dichroism (CD) experiments, showing an α-helix conformation of the PLGA segments. Swelling experiments on the ionic-bonded networks showed that the water uptake process strongly depends on the temperature and relative humidity conditions. Thus, higher humidity and temperatures below the lower critical solubility temperature (LCST) of the PNIPAM block increase the amount of water absorbed into the network. These swollen ionic complexes contract and reject water when these thermo-responsive peptide-based hydrogels are heated up above their LCST, making them promising for biomedical applications and drug delivery systems.
- Sanchez-Ferrer, Antoni,Kotharangannagari, Venkata Krishna,Ruokolainen, Janne,Mezzenga, Raffaele
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- Photoresponsive supramolecular architectures based on polypeptide hybrids
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Self-aggregation has recently emerged as an efficient tool for the production of well-ordered supramolecular structures at the nanometric scale. In this framework, peptides offer important advantages as building blocks because of their biocompatibility and 3D-structural/functional diversities. The chemical diversity of peptides may be further expanded by use of noncoded amino acids. In the present work, we focused our attention on two known photoswitchable azobenzene-containing α-amino acids and used them as initiators for the reversible modulation of the cis/trans conformational states of two poly(γ-benzyl-l-glutamate)-based hybrid molecules with either C2 or C3 symmetry. The microscopic photoresponsive self-assembly of these compounds was examined in detail. Moreover, these hybrids were exploited in the construction of macroscopic supramolecular architectures via the electrospinning technique. Finally, after appropriate thiol functionalization, we fabricated and characterized dimeric and trimeric gold nanoparticle/polypeptide hybrid systems.
- Mazzier, Daniela,Maran, Marco,Polo Perucchin, Omar,Crisma, Marco,Zerbetto, Mirco,Causin, Valerio,Toniolo, Claudio,Moretto, Alessandro
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- Synthesis of luminescent 3D microstructures formed by carbon quantum dots and their self-assembly properties
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We report in this communication the synthesis of star-shaped carbon quantum dots-(poly-γ-benzyl-l-glutamate) conjugates that self-assemble into microstructures and retain the characteristic emission properties of the native dots. Dots were used either as an initiator to give a daisy-like peptide-polymer structure or as capping agents towards more elaborated hybrid nanostructures. This journal is the Partner Organisations 2014.
- Mazzier,Favaro,Agnoli,Silvestrini,Granozzi,Maggini,Moretto
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- The effect of insulin-loaded linear poly(Ethylene glycol)-brush-like poly(L-lysine) block copolymer on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor
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The aim of this study was to observe the therapeutic effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(l-lysine)) (PEG-b-(PELG-g-PLL) on renal ischemia/ reperfusion-induced lung injury through downregulating hypoxia-inducible factor (HIF) as compared to free insulin. Sprague Dawley rats were pretreated with 30 U/kg insulin or insulin/ PEG-b-(PELG-g-PLL) complex, and then subjected to 45 minutes of ischemia and 24 hours of reperfusion. The blood and lungs were collected, the level of serum creatinine and blood urea nitrogen were measured, and the dry/wet lung ratios, the activity of superoxide dismutase and myeloperoxidase, the content of methane dicarboxylic aldehyde and tumor necrosis factor-α, and the expression of HIF-1α and vascular endothelial growth factor (VEGF) were measured in pulmonary tissues. Both insulin and insulin/PEG-b-(PELG-g-PLL) preconditioning improved the recovery of renal function, reduced pulmonary oxidative stress injury, restrained inflammatory damage, and downregulated the expression of HIF-1α and VEGF as compared to ischemia/ reperfusion group, while insulin/PEG-b-(PELG-g-PLL) significantly improved this effect.
- Tong, Fei,Tang, Xiangyuan,Li, Xin,Xia, Wenquan,Liu, Daojun
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- PH-sensitive polymeric micelles based on amphiphilic polypeptide as smart drug carriers
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A series of amphiphilic diblock copolymers having poly(ethylene glycol) (PEG) as one block and a polypeptide as the other block were synthesized by ring-opening polymerization using PEG-amine as a macroinitiator. These polymers were characterized by 1H-NMR and gel permeation chromatography. The influence of the substitution ratio of tertiary amine-containing groups on the pH sensitivity of the polymers was investigated in detail. Core/shell-structured micelles were fabricated from these polymers using an organic solvent-free method. pH- and concentration-dependent micellization behaviors were investigated by dynamic light scattering and fluorescence microscopy. Micelles loaded with doxorubicin, selected as a model drug, showed restricted drug release at physiological pH but accelerated drug release at tumor extracellular pH. Collectively, our findings suggest that these pH-sensitive micelles might have great potential for cancer therapy applications.
- Li, Yi,Gao, Guang Hui,Lee, Doo Sung
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- An unconventional method for purifying the N-carboxyanhydride derivatives of γ-alkyl-L-glutamates
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Common impurities in the phosgenation of α-amino acids to produce their N-carboxyanhydride (NCA) derivatives include hydrogen chloride and the hydrochloride salt of the starting amino acid. These impurities can be effectively removed by washing the reaction mixture with water and aqueous bicarbonate at 0 °C prior to isolation of the NCA., despite the well known sensitivity of the NCA to water. The method should be particularly useful for NCA derivatives which are isolated as oils since purifying them by recrystallization or solvent washes is not feasible. This study involved specifically the purification of NCA derivatives from a variety of γ-alkyl- L-glutamates and γ-benzyl-L-glutamate.
- Poche, Drew S.,Moore, Michael J.,Bowles, Jennifer L.
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- The behavior of poly(amino acids) containing l -cysteine and their block copolymers with poly(ethylene glycol) on gold surfaces
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Poly(ethylene glycol) (PEG) is often used to biocompatibilize surfaces of implantable biomedical devices. Here, block copolymers consisting of PEG and l-cysteine-containing poly(amino acid)s (PAA's) were synthesized as polymeric multianchor systems for the covalent attachment to gold surfaces or surfaces decorated with gold nanoparticles. Amino-terminated PEG was used as macroinitiator in the ring-opening polymerization, (ROP), of respective amino acid N-carboxyanhydrides (NCA's) of l-cysteine (l-Cys), l-glutamate (l-Glu), and l-lysine (l-Lys). The resulting block copolymers formed either diblock copolymers, PEG-b-p(l-Glux-co-l-Cysy) or triblock copolymers, PEG-b-p(l-Glu)x-b-p(l-Cys)y. The monomer feed ratio matches the actual copolymer composition, which, together with high yields and a low polydispersity, indicates that the NCA ROP follows a living mechanism. The l-Cys repeat units act as anchors to the gold surface or the gold nanoparticles and the l-Glu repeat units act as spacers for the reactive l-Cys units. Surface analysis by atomic force microscopy revealed that all block copolymers formed homogenous and pin-hole free surface coatings and the phase separation of mutually immiscible PEG and PAA blocks was observed. A different concept for the biocompatibilization of surfaces was followed when thiol-terminated p(l-Lys) homopolymer was first grafted to the surface and then covalently decorated with HOOC-CH2-PEG-b-p(Bz-l-Glu) polymeric micelles. Copyright
- Obeid, Rodolphe,Armstrong, Tracy,Peng, Xiaoju,Busse, Karsten,Kressler, Joerg,Scholz, Carmen
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- Synthesis and self-assembly of well-defined poly(amino acid) end-capped poly(ethylene glycol) and poly(2-methyl-2-oxazoline)
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Poly(ethylene glycol) (PEG) and poly(2-methyl-2-oxazoline) (PMOx) are water-soluble, biocompatible polymers with stealth hemolytic activities. Poly(amino acid) (PAA) end-capped PEG and PMOx were prepared using amino-terminated derivatives of PEG and PMOx as macroinitiators for the ring-opening polymerization of γ-benzyl protected l-glutamate N-carboxyanhydride and S-benzyloxycarbonyl protected l-cysteine N-carboxyanhydride, respectively, in the presence of urea, at room temperature. The molecular weight of the PAA moiety was kept between Mn = 2200 and 3000 g mol-1. PMOx was polymerized by cationic ring-opening polymerization resulting in molecular weights of Mn = 5000 and 10 000 g mol-1, and PEG was a commercial product with Mn = 5000 g mol-1. Here, we investigate the self-assembly of the resulting amphiphilic block copolymers in water and the effect of the chemical structure of the block copolymers on the solution properties of self-assembled nanostructures. The PEG-block-poly(amino acid), PEG-b-PAA, and PMOx-block-poly(amino acid), PMOx-b-PAA, block copolymers have a narrow and monomodal molecular weight distribution (PDI H) ranging in size from RH 70 to 130 nm, depending on the block copolymer architecture and the polymer molecular weight. Larger RH and critical association concentration values were obtained for copolymers containing poly(S-benzyloxycarbonyl-l-cysteine) compared to their poly(γ-benzyl-l-glutamate) analogue. FTIR investigations revealed that the poly(γ-benzyl-l-glutamate) block adopts a helical conformation, while the poly(S-benzyloxycarbonyl-l-cysteine) block exists as β-sheet.
- Obeid, Rodolphe,Scholz, Carmen
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- Surface-grafting of polyglutamate on Si wafer using micro contact printing
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Surface-grafting of poly(-benzyl-, L-glutamate) (PBLG) on the 3-aminopropyl triethoxysilane (APS) pretreated silicone substrates was conducted by the monomer, -benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) which was synthesized through the phosgenation procedure. PBLG, one of liquid crystalline polymers, micro-patterns were fabricated by micro-contact printing (CP) and surface-grafting method. Then, PBLG patterns were characterized with electron microscopy (SEM), atomic force microscopy (AFM), infrared spectroscopy (FT-IR), Raman spectroscopy and polarized optical microscopy. -helix conformation of PBLG was dominated on the patterned surface which was confirmed by FT-IR spectroscopy. From the polarizing microscope images, lyotropic liquid crystalline properties of the patterned surfaces were observed. The SEM and AFM images show that the height of PBLG patterns was 300nm and line width was 15m. The interval between lines was about 5m.
- Kim, Jonghyub,Park, Jaehyun,Lee, Seongyeol,Sohn, Daewon
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- Proximity-Induced Cooperative Polymerization in "hinged" Helical Polypeptides
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Cooperative interactions and transitions are among the most important strategies utilized by biological systems to regulate a variety of physical and chemical processes. We report herein an auto-accelerated, rapid cooperative polymerization of N-carboxyanhydrides (NCAs) with initiators structurally as simple as linear aliphatic diamines for the synthesis of polypeptides. The polymerization initiated by diamines proceeds via the formation of "hinged" polypeptides, which are two blocks of helical chains connected head-to-head by the diamine molecules in the polymerization solution. The reactions follow a two-stage, cooperative polymerization kinetic; the cooperative interactions between the macrodipoles of the two hinged helical polypeptides dramatically accelerate the polymerization. Compared to the NCA polymerization initiated by the hexylamine (CH3(CH2)5NH2), the chain propagation rate of the NCA polymerization is increased by more than 600 times when initiated by its diamine analogue (1,6-diaminohexane, NH2(CH2)6NH2). This proximity-induced cooperative polymerization showcases the single helix as a remarkable cooperativity-enabling motif in synthetic chemistry.
- Chen, Chongyi,Fu, Hailin,Baumgartner, Ryan,Song, Ziyuan,Lin, Yao,Cheng, Jianjun
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- Macroporous Biodegradable Cryogels of Synthetic Poly(α-amino acids)
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We present an investigation of the preparation of highly porous hydrogels based on biodegradable synthetic poly(α-amino acid) as potential tissue engineering scaffolds. Covalently cross-linked gels with permanent pores were formed under cryogenic conditions by free-radical copolymerization of poly[N5-(2-hydroxyethyl)-l-glutamine-stat-N5-(2-methacryloyl-oxy-ethyl)-l-glutamine] (PHEG-MA) with 2-hydrohyethyl methacrylate (HEMA) and, optionally, N-propargyl acrylamide (PrAAm) as minor comonomers. The morphology of the cryogels showed interconnected polyhedral or laminar pores. The volume content of communicating water-filled pores was >90%. The storage moduli of the swollen cryogels were in the range of 1-6 kPa, even when the water content was >95%. The enzymatic degradation of a cryogel corresponded to the decrease in its storage modulus during incubation with papain, a model enzyme with specificity analogous to wound-healing enzymes. It was shown that cryogels with incorporated alkyne groups can easily be modified with short synthetic peptides using azide-alkyne cycloaddition "click" chemistry, thus providing porous hydrogel scaffolds with biomimetic features.
- Sedla?ík, Tomá?,Proks, Vladimír,?louf, Miroslav,Du?ková-Smr?ková, Miroslava,Studenovská, Hana,Rypá?ek, Franti?ek
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- Quantitative single molecule measurements on the interaction forces of poly(L-glutamic acid) with calcite crystals
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The interaction between poly(L-glutamic acid) (PLE) and calcite crystals was studied with AFM-based single molecule force spectroscopy. Block copolymers of poly(ethylene oxide) (PEO) and PLE were synthesized and covalently attached to the tip of an AFM cantilever. In desorption measurements the molecules were allowed to adsorb on the calcite crystal faces and afterward successively desorbed. The corresponding desorption forces were detected with high precision, showing for example a force transition between the two blocks. Because of its importance in the crystallization process in biominerals, the PLE-calcite interaction was investigated as a function of the pH as well as the calcium concentration of the aqueous solution. The sensitivity of the technique was underlined by resolving different interaction forces for calcite (104) and calcite (100).
- Sonnenberg, Lars,Luo, Yufei,Schlaad, Helmut,Seitz, Markus,Coelfen, Helmut,Gaub, Hermann E.
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- Uniting polypeptides with sequence-designed peptides: Synthesis and assembly of poly(γ-benzyl L-glutamate)-b-coiled-coil peptide copolymers
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A new class of peptide has been created, polypeptide-b-designed peptides, which unites the useful qualities of the two constituent peptide types. We demonstrate the synthesis and self-assembly possibilities of this class of peptide chimera with a series of amphiphilic polypeptide-b-designed peptides in which the hydrophobic block is poly(γ-benzyl L-glutamate) (PBLG) and the hydrophilic block is a coiledcoil forming peptide (denoted E). The synthetic approach was to synthesize the coiled-coil forming peptide on the solid phase, followed by the ring-opening polymerization of γ-benzyl L-glutamate AAcarboxyanhydride, initiated from the N-terminal amine of the peptide E on the solid support. The polypeptide-b-peptide was then cleaved from the resin, requiring no further purification. Peptide E contains 22 amino acids, while the average length of the PBLG block ranged from 36 to 250 residues. This new class of peptide was applied to create a modular system, which relied on juxtaposing the properties of the component peptide types, namely the broad size range and structure-inducing characteristics of the polypeptide PBLG blocks, and the complex functionality of the sequence-designed peptide. Specifically, the different PBLG block lengths could be connected noncovalently with various hydrophilic blocks via the specific coiled-coil folding of E with K or K-poly(ethylene glycol), where K is a peptide of complementary amino acid sequence to E. In this way, nanostructures could be formed in water at neutral pH over the entire compositional range, which has not been demonstrated previously with such large PBLG blocks. It was found that the size, morphology (polymersomes or bicelles), and surface functionality could be specified by combining the appropriate modular building blocks. The self-assembled structures were characterized by dynamic light scattering, circular dichroism, scanning electron microscopy, cryogenic-transmission electron microscopy, fluorescence spectroscopy, and zeta-potential measurements. Finally, as the structures are able to encapsulate watersoluble compounds, and the surfaces are easily functionalized via the coiled-coil binding, it is expected that these peptide-based nanocapsules will be able to act as delivery vehicles to specific targets in the body.
- Robson Marsden, Hana,Handgraaf, Jan-Willem,Nudelman, Fabio,Sommerdijk, Nico A.J.M.,Kros, Alexander
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- Surface structure and composition of narrowly-distributed functional polystyrene particles prepared by dispersion polymerization with poly(l-glutamic acid) macromonomer as stabilizer
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A novel macromonomer composed of poly(α-l-glutamic acid) was used as a stabilizer for dispersion polymerization of styrene in DMF-water medium with AIBN initiator, giving narrowly-distributed functional polystyrene particles on which the poly(α-l-glutamic acid) was grafted. The resultant particles had 0.54-2.12 μm in size and 0.2-2.6 residue/nm2 in surface density and showed a pH-responsive colloidal behavior associated with a helix-coil transformation of the surface poly(α-l-glutamic acid). Not only the particle size but also the surface density were controlled with macromonomer concentration, macromonomer length, DMF composition, and styrene concentration, while no consistent trend for AIBN concentration was observed. A gel-permeation-chromatography curve of the particles was separated into three components. We tentatively identify the origin of each component and propose a possibility that unstable particles, which were generated even after the growing particles were stabilized, took an important role in particle growth and size distribution of the resultant particles.
- Itoh, Tomomichi,Tamamitsu, Tetsuo,Shimomoto, Hiroaki,Ihara, Eiji
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- Endolytic, pH-responsive HPMA-b-(l-Glu) copolymers synthesized via sequential aqueous RAFT and ring-opening polymerizations
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A facile synthetic pathway for preparing block copolymers with pH-responsive l-glutamic acid segments for membrane disruption is reported. Aqueous reversible addition-fragmentation chain transfer (aRAFT) polymerization was first used to prepare biocompatible, nonimmunogenic poly[N-(2-hydroxypropyl) methacrylamide]. This macro chain transfer agent (CTA) was then converted into a macroinitiator via simultaneous aminolysis and thiol-ene Michael addition using the primary amine substituted N-(3-aminopropyl)methacrylamide. This macroinitiator was subsequently utilized in the ring-opening polymerization of the N-carboxyanhydride monomer of γ-benzyl-l-glutamate. After deprotection, the pH-dependent coil-to-helix transformations of the resulting HPMA-b-(l-Glu) copolymers were monitored via circular dichroism spectroscopy. HPMA segments confer water solubility and biocompatibility while the l-glutamic acid repeats provide reversible coil-to-helix transitions at endosomal pH values (~5-6). The endolytic properties of these novel [HPMA-b-(l-Glu)] copolymers and their potential as modular components in drug carrier constructs was demonstrated utilizing red blood cell hemolysis and fluorescein release from POPC vesicles.
- Holley, Andrew C.,Ray, Jacob G.,Wan, Wenming,Savin, Daniel A.,McCormick, Charles L.
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- Self-assembled micelles composed of doxorubicin conjugated Y-shaped PEG-poly(glutamic acid)2 copolymers via hydrazone linkers
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In this work, micelles composed of doxorubicin-conjugated Y-shaped copolymers (YMs) linked via an acid-labile linker were constructed. Y-shaped copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin)2 and linear copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin) were synthesized and characterized. Particle size, size distribution, morphology, drug loading content (DLC) and drug release of the micelles were determined. Alterations in size and DLC of the micelles could be achieved by varying the hydrophobic block lengths. Moreover, at fixed DLCs, YMs showed a smaller diameter than micelles composed of linear copolymers (LMs). Also, all prepared micelles showed sustained release behaviors under physiological conditions over 72 h. DOX loaded in YMs was released more completely, with 30% more drug released in acid. The anti-tumor efficacy of the micelles against HeLa cells was evaluated by MTT assays, and YMs exhibited stronger cytotoxic effects than LMs in a dose- and time-dependent manner. Cellular uptake studied by CLSM indicated that YMs and LMs were readily taken up by HeLa cells. According to the results of this study, doxorubicin-conjugated Y-shaped PEG-(polypeptide)2 copolymers showed advantages over linear copolymers, like assembling into smaller nanoparticles, faster drug release in acid, which may correspond to higher cellular uptake and enhanced extracellular/intracellular drug release, indicating their potential in constructing nano-sized drug delivery systems.
- Sui, Bowen,Xu, Hui,Jin, Jian,Gou, Jingxin,Liu, Jingshuo,Tang, Xing,Zhang, Yu,Xu, Jinghua,Zhang, Hongfeng,Jin, Xiangqun
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- Hexamethyldisilazane-mediated controlled polymerization of α-amino acid N-carboxyanhydrides
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Ring-opening polymerizations of α-amino acid N-carboxyanhydrides (NCAs) initiated with amines typically form polypeptides with uncontrolled molecular weights and broad molecular weight distributions. However, we found that hexamethyldisilazane (HMDS)-mediated controlled NCA polymerizations gave polypeptides with predictable molecular weights and narrow molecular weight distributions. Using MS, NMR, and FT-IR, we demonstrated that the initiation step involved the cleavage of the N-Si bond of HMDS and the formation of a trimethylsilyl carbamate (TMS-CBM) terminal group. Polypeptide chains were propagated through the migration of TMS of the TMS-CBM end group to the incoming monomer and formed a new TMS-CBM terminal group. This organosilicon reagent mediated NCA polymerization offers a metal-free strategy for the convenient synthesis of homo- or block polypeptides with predictable molecular weights and narrow molecular weight distributions. Copyright
- Lu, Hua,Cheng, Jianjun
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- Effect of molecular weight of PGG-paclitaxel conjugates on in vitro and in vivo efficacy
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Polymeric prodrugs are one of the most promising chemotherapeutic agent delivery approaches, displaying unique drug release profiles, serum stability, formulation flexibility, and reduced drug resistance. One of the most important aspects of a polymeric prodrug, albeit a less-extensively studied one, is the polymer's molecular weight, which affects particle formation, drug release and PK/PD profiles, drug stability, and cell uptake; these factors in turn affect the prodrug's maximum tolerated dose and anticancer efficacy. Poly(l-γ-glutamylglutamine) (PGG) is a linear polymer designed to improve the therapeutic index of attached drugs. In this study we selected poly(l-γ-glutamylglutamine)-paclitaxel (PGG-PTX), as a model system for the methodical investigation into the effects of the poly(l-γ- glutamylglutamine) backbone molecular weight on its pharmacological performance. The polymeric prodrug was characterized by NMR, DLS and GPC-MALS, and its anticancer activity in vitro and in vivo was assessed. Herein we present data which provide valuable insight into improving anticancer polymer-based prodrug design and development.
- Yang, Danbo,Liu, Xiaoqing,Jiang, Xinguo,Liu, Yun,Ying, Wenbin,Wang, Hai,Bai, Hao,Taylor, Wendy D.,Wang, Yuwei,Clamme, Jean-Pierre,Co, Erick,Chivukula, Padmanabh,Tsang, Kwok Yin,Jin, Yi,Yu, Lei
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- Bioactive polypeptide hydrogels modified with RGD and N-cadherin mimetic peptide promote chondrogenic differentiation of bone marrow mesenchymal stem cells
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Cell-material and cell-cell interactions represent two crucial aspects of the regulation of cell behavior. In the present study, poly (L-glutamic acid) (PLG) hydrogels were prepared by catalyst-free click crosslinking via a strain-promoted azide-alkyne cycloaddition (SPAAC) reaction between azido-grafted PLG (PLG-N3) and azadibenzocyclooctyne-grafted PLG (PLG-ADIBO). The bioactive peptides c(RGDfK) and N-cadherin mimetic peptide (N-Cad) were both conjugated to the PLG hydrogel (denoted PLG+RGD/N-Cad) in order to regulate cell-material and cell-cell interactions. Gelation time and storage modulus of the hydrogels were tunable through variations in the concentration of polypeptide precursors. The hydrogels degraded gradually in the presence of proteinases. The viability of bone marrow mesenchymal stem cells (BMSCs) was maintained when cultured with extracts of the hydrogels or encapsulated within the hydrogels. Degradation was observed within 10 weeks following the subcutaneous injection of hydrogel solution in rats, displaying excellent histocompatibility in vivo. The introduction of RGD into the PLG hydrogel promoted the adhesion of BMSCs onto the hydrogels. Moreover, when encapsulated within the PLG+RGD/N-Cad hydrogel, BMSCs secreted cartilage-specific matrix, in addition to chondrogenic gene and protein expression being significantly enhanced in comparison with BMSCs encapsulated in hydrogels without N-Cad modification. These findings suggest that these biodegradable, bioactive polypeptide hydrogels have great potential for use in 3D cell culture and in cartilage tissue engineering.
- Rong, Yan,Zhang, Zhen,He, Chaoliang,Chen, Xuesi
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- Establishment of a controlled insulin delivery system using a glucose-responsive double-layered nanogel
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Glucose-responsive insulin delivery systems have been proposed as a promising alternative to conventional intramuscular administration methods, which causes low patient compliance due to the requirement of multiple administration. In addition, protein-based glucose-responsive systems using glucose oxidase and lectin have not achieved success in clinical trials because of their low biostability and potential cytotoxicity. In order to overcome these issues, the phenylboronic acid (PBA)-derivatives converted to hydrophilic moieties with an elevated glucose level play a key role in controlled insulin delivery systems due to their better biostability and high biocompatibility. In order to endow glucose-responsiveness to insulin delivery carriers using PBA derivatives, a glycol chitosan (GC)/sodium alginate (SA)-poly(L-glutmate-co-N-3-L-glutamylphenylboronic acid) (PGGA) graft polymer double-layered nanogel is synthesized by N-carboxyanhydride (NCA) polymerization and carbodiimide coupling reactions. The GC/SA-PGGA double-layered nanogel controllably releases insulin at diabetic glucose levels in vitro, and shows high biocompatibility, determined by cell viability and a hemolysis assay. Moreover, controlled insulin release at high glucose levels can be accomplished using the GC/SA-PGGA double-layered nanogel in mouse studies. Therefore, the GC/SA-PGGA double-layered nanogel characterized by glucose-sensitivity and superior biocompatibility may act as a potential platform for advanced insulin delivery systems.
- Lee, DaeYong,Choe, Kibaek,Jeong, YongJun,Yoo, Jisang,Lee, Sung Mun,Park, Ji-Ho,Kim, Pilhan,Kim, Yeu-Chun
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Read Online
- Carboxylic Anhydride Synthesis from γ-Benzyl-L-glutamate and Dimethyl Carbonate
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A green, environmentally friendly, and nontoxic method was developed to synthesize carboxylic anhydrides (NCAs) from γ-benzyl-l-glutamate (BLG) and dimethyl carbonate (DMC) though two steps: synthesis of N-methoxycarbonyl-γ-benzyl-l-glutamate intermediate (NOM-BLG) and cyclization. The highest yields of NOM-BLG (up to 83.7%) and NCA-BLG (up to 66.7%) were obtained. Most importantly, the use of DMC will open an innovative door to synthesize NCAs.
- Zhang, Zhao,Su, Kunmei,Li, Zhenhuan
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Read Online
- One-Step Preparation of pH-Responsive Polymeric Nanogels as Intelligent Drug Delivery Systems for Tumor Therapy
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In this work, pH-responsive polypeptide-based nanogels are reported as potential drug delivery systems. By the formation of pH-sensitive benzoic imine bonds, pH-responsive nanogels are constructed using hydrophilic methoxy poly(ethylene glycol)-b-poly[N-[N-(2-aminoethyl)-2-aminoethyl]-l-glutamate] (MPEG-b-PNLG) and hydrophobic terephthalaldehyde (TPA) as a cross-linker. At pH 7.4, MPEG-b-PNLG nanogels exhibit high stabilities with hydrophobic inner cores, which allow encapsulation of hydrophobic therapeutic agents. Under tumoral acidic environments (pH ~6.4), the cleavage of benzoic imine bonds induces the destruction of MPEG-b-PNLG nanogels and leads to rapid release of their payloads. The formation and pH sensitivity of the nanogels are investigated by dynamic light scattering. These nanogels exhibit excellent stabilities in the presence of salt or against dilution. The globular morphologies of the nanogels are confirmed using transmission electron microscopy. Doxorubicin is used as a model drug to evaluate drug encapsulation and release. Finally, the anticancer activities of the drug-encapsulated nanogels are assessed in vitro.
- Li, Yi,Bui, Quang Nam,Duy, Le Thai Minh,Yang, Hong Yu,Lee, Doo Sung
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- Enzyme responsive supramolecular hydrogels assembled from nonionic peptide amphiphiles
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Smart peptide hydrogels are of great interest for their great potential applications. Here, we report a facile approach to prepare a class of enzyme-responsive hydrogels in a scalable manner. These hydrogels self-assemble from a family of nonionic peptide amphiphiles (PAs) synthesized by sequential ring-opening polymerization (ROP) of γ-benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) and L-tyrosine N-carboxyanhydride (Tyr-NCA), followed by subsequent aminolysis. These PA samples can readily form a clear hydrogel with a critical gelation concentration as low as 0.5 wt%. The incorporation of tyrosine residues offers hydrophobicity, hydrogen-bonding interaction and enzyme-responsive properties. The hydrogel-to-nanogel transition is observed under physiological conditions in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). The obtained PA hydrogels are ideal candidates for the new generation of smart scaffolds.
- Liu, Rui,Shi, Zhekun,Sun, Jing,Li, Zhibo
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Read Online
- Superfast and Water-Insensitive Polymerization on α-Amino Acid N-Carboxyanhydrides to Prepare Polypeptides Using Tetraalkylammonium Carboxylate as the Initiator
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We design the tetraalkylammonium carboxylate-initiated superfast polymerization on α-amino acid N-carboxyanhydrides (NCA) for efficient synthesis of polypeptides. Carboxylates, as a new class of initiator for NCA polymerization, can initiate the superfast NCA polymerization without the need of extra catalysts and the polymerization can be operated in open vessels at ambient condition without the use of glove box. Tetraalkylammonium carboxylate-initiated polymerization on NCA easily affords block copolymers with at least 15 blocks. Moreover, this method avoids tedious purification steps and enables direct polymerization on crude NCAs in aqueous environments to prepare polypeptides and one-pot synthesis of polypeptide nanoparticles. These advantages and the mild polymerization condition of tetraalkylammonium carboxylate-initiated NCA polymerization imply its great potential in functional exploration and application of polypeptides.
- Chen, Jiacheng,Chen, Kang,Ding, Yun,Ji, Zhemin,Liu, Longqiang,Liu, Runhui,Liu, Shiqi,Shao, Ning,Wu, Xue,Wu, Yueming,Zhang, Weiwei,Zhou, Min,Zhu, Minghui
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supporting information
p. 26063 - 26071
(2021/11/12)
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- Synthesis of α-Amino Acid N-Carboxyanhydrides
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A simple phosgene- and halogen-free method for synthesizing α-amino acid N-carboxyanhydrides (NCAs) is described. The reaction between Boc-protected α-amino acids and T3P reagent gave the corresponding NCA derivatives in good yield and purity with no detectable epimerization. The process is safe, is easy-to-operate, and does not require any specific installation. It generates nontoxic, easy to remove byproducts. It can apply to the preparation of NCAs for the on-demand on-site production of either little or large quantities.
- Laconde, Guillaume,Amblard, Muriel,Martinez, Jean
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supporting information
p. 6412 - 6416
(2021/08/30)
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- Biodegradable supramolecular micellesviahost-guest interaction of cyclodextrin-terminated polypeptides and adamantane-terminated polycaprolactones
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Biodegradable supramolecular micelles were prepared exploiting the host-guest interaction of cyclodextrin and adamantane. Cyclodextrin-initiated polypeptides acted as the hydrophilic corona, whereas adamantane-terminated polycaprolactones served as the hydrophobic core.
- Pottanam Chali, Sharafudheen,Azhdari, Suna,Galstyan, Anzhela,Gr?schel, André H.,Ravoo, Bart Jan
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supporting information
p. 9446 - 9449
(2021/09/22)
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- METHOD FOR PREPARATION OF N-CARBOXYANHYDRIDES
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The invention discloses a method for the preparation off N-carboxyanhydrides (NCAs) by reaction of amino acids with phosgene.(II)
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Page/Page column 12; 13
(2020/05/12)
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- Facile and scalable synthesis of topologically nanoengineered polypeptides with excellent antimicrobial activities
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A facile and scalable strategy for the quick library synthesis of linear-, hinged-, star-, and cyclic-polypeptides with broad-spectrum antimicrobial activity has been reported. The topologically nanoengineered polypeptides show superior antimicrobial activity against Gram-positive and Gram-negative bacteria and low toxicity, allowing screening of architectural polypeptides as mimics of host defense peptides for antimicrobials.
- Zhang, Yu,Song, Wenliang,Li, Shuwei,Kim, Dae-Kyoung,Kim, Jae Ho,Kim, Jung Rae,Kim, Il
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p. 356 - 359
(2020/01/11)
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- Block copolymer [(l-GluA-5-BE)-: B -(l-AspA-4-BE)]-based nanoflower capsules with thermosensitive morphology and pH-responsive drug release for cancer therapy
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Herein, the synthesis of an amino-acid-based di-block copolymer (di-BCP) in-between an l-glutamic acid-5-benzyl ester and l-aspartic acid-4-benzyl ester [(l-GluA-5-BE)-b-(l-AspA-4-BE)] has been reported. However, the synthesis of di-BCP of [(l-GluA-5-BE)-b-(l-AspA-4-BE)] was carried out through the facile modified ring-opening polymerization (ROP) without using any surfactants and harmful chemicals. Interestingly, the synthesized [(l-GluA-5-BE)-b-(l-AspA-4-BE)] has been used to design nanoflower capsules (NFCs) with surface-functionalized nanoflakes and petals. Notably, the simple solvent propanol has been used as a dispersing medium for the di-BCP-based powder to observe morphology of NFCs. Moreover, these amino-acid-based NFCs are biocompatible, biodegradable, and bio-safe for mankind usage. Consequently, di-BCP-based NFCs show changes in morphology with different temperature conditions, i.e., at ~10 °C, ~25 °C (RT), and ~37 °C (body temperature). Furthermore, the average thickness of the surface-functionalized nanopetals has been calculated as ~324 nm (in diameter). Similarly, the average distance between petals is calculated as 3.6 μm and the pore depth is ~21 nm. Additionally, the porosity throughout the surface of capsules in-between nanopetals is an advantageous characteristic feature to improve the drug/paclitaxel (PTX) loading capacity. It is a unique and novel approach to design NFCs, which are a potential payload for nanomedicine and cancer therapy. Furthermore, NFCs were used to evaluate the loading efficacy of drugs and showed ~78% (wt/wt%) of the PTX loading. Moreover, NFCs showed ~74% drug release at physiological body temperature. Thus, NFCs showed remarkable release at acidic pH medium. However, PTX released from NFCs showed greater cell inhibition (i.e., ~79%) with an increase of the PTX concentration after 24 h incubation over HeLa (human epithelial cervical cancer) cells. Besides, PTX released from NFC showed significant (~34%) cell killing capacity. Such promising NFCs are recommended for breast, liver, and lung cancer therapeutics.
- Amgoth, Chander,Chen, Shuai,Malavath, Tirupathi,Tang, Guping
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supporting information
p. 9258 - 9268
(2020/11/03)
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- Nano-cluster for treating cancer and preparation method of nano-cluster
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The invention relates to the technical field of polymer drug carriers, and in particular relates to a nano-cluster for treating cancer and a preparation method of the nano-cluster. The preparation method includes the following steps: A) performing a reaction on a first mixed liquid and a second mixed liquid to obtain a product solution, wherein the first mixed liquid includes polyamino acid nanoparticles loaded with cisplatin, sodium phosphate, sodium chloride, N-(2-hydroxyethyl)piperazin-N'-2-ethanesulfonic acid and water, and the second mixed solution includes arsenic trioxide, calcium chloride and water; and B) performing dialysis on the product solution, and performing lyophilization to obtain the nano-cluster for treating the cancer. The nano-cluster for treating the cancer prepared by the method can be enriched in tumor tissue parts through the enhanced permeability and retention (EPR) effect, and release the cisplatin and the arsenic trioxide with anti-tumor properties under thepH condition in tumor cells to synergistically inhibit tumor growth, reduce the toxic and side effects on non-lesional sites, and improve the treatment coefficient of tumor sites.
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Paragraph 0093-0095
(2020/05/29)
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- Polyionic type micelle shielding system with electric charge turnover function and preparation method thereof
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The invention provides a polyionic type micelle shielding system with reversible charges. The polyionic type micelle shielding system is formed by a compound shown as formula (III) and cis-diamminedichloroplatinum through coordination. According to the polyionic type micelle shielding system with the reversible charges, cis-diamminedichloroplatinum is supported under a coordination action, a support material is good in biocompatibility and solubility, the nano-support is enriched at a tumor tissue part through an EPR (enhanced permeability and retention effect), a shell with a shielding capability is removed under the condition of pH at the tumor tissue part, a positively charged cis-diamminedichloroplatinum supported core is exposed, endocytosis is facilitated by the positively charged core, and after the cis-diamminedichloroplatinum supported core enters a cell, the drug cis-diamminedichloroplatinum with anti-tumor performance is released by the cis-diamminedichloroplatinum supportedcore.
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Paragraph 0101-0102
(2020/06/24)
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- Dual-Emissive Platinum(II) Metallacage with a Sensitive Oxygen Response for Imaging of Hypoxia and Imaging-Guided Chemotherapy
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Imaging of hypoxia in vivo helps with accurate cancer diagnosis and evaluation of therapeutic outcomes. A PtII metallacage with oxygen-responsive red phosphorescence and steady fluorescence for in vivo hypoxia imaging and chemotherapy is reported. The therapeutic agent and diagnostic probe were integrated into the metallacage through heteroligation-directed self-assembly. Nanoformulation by encapsulating the metallacage into nanoparticles greatly enhanced its stability the in physiological environment, rendering biomedical applications feasible. Apart from enhanced red phosphorescence upon hypoxia, the ratio between red and blue emissions, which only varies with intracellular oxygen level, provides a more precise standard for hypoxia imaging and detection. Moreover, in vivo explorations demonstrate the promising potential applications of the metallacage-loaded nanoparticles as theranostic agents for tumor hypoxia imaging and chemotherapy.
- Ge, Fujing,Huang, Feihe,Li, Qi,Liu, Yuezhou,Mao, Zhengwei,Shi, Bingbing,Stang, Peter J.,Wang, Sheng,Yu, Guocan,Zhu, Hong,Zhu, Huangtianzhi
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supporting information
p. 20208 - 20214
(2020/09/02)
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- Preparation method and application of folic acid-targeted dual-drug-loaded nanoparticles
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The invention relates to a preparation method and application of folic acid-targeted dual-drug-loaded nanoparticles, and can effectively solve problems that anti-tumor drugs are low in water solubility, serious in toxic and side effects, lack of targeting, etc. A technical solution is to prepare dendrimers PLD and polyglutamic acid (PGA), and paclitaxel, gemcitabine and folic acid are loaded on the PGA to obtain PGA-PTX, PGA-GEM and PGA-FA. The four materials in an aqueous solution are attracted to each other by positive and negative charges, and self-assembled to form the nanoparticles, and particle diameters of the nanoparticles are about (190 plus or minus 15) nm. The nanoparticles enter tumor cells and release the paclitaxel and the gemcitabine through combination of the folic acid andfolic acid receptors on surfaces of the tumor cells, thereby inhibiting proliferation of the tumor cells and promoting apoptosis. The drug-loaded nanoparticles can effectively inhibit growth of tumorcells 4T1 and have a better inhibitory effect on tumor models of the 4T1 cells in vivo.
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Paragraph 0016; 0059-0061
(2020/01/14)
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- A method for preparation of hybrid amphiphilic star copolymer nano micelles
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Hybrid amphiphilic star copolymer nano micelles are prepared in the invention. Cage shaped octa(γ-aminopropyl) silsesquioxanes is selected as the inorganic part, and L-glutamic benzyl ester-five membered ring anhydride is ring-opening polymerized by the initiation of amino groups on the surface of cage shaped octa(γ-aminopropyl) silsesquioxanes, producing copolymers with cage shaped octa(γ-aminopropyl) silsesquioxanes as nucleus and poly (L-glutamic-benzyl ester) as arms. The copolymers reacts with monomethoxy poly (ethylene glycol) carboxylic acid by condensation. Finally, the benzyl groups in the side chains of poly (L-glutamic acid-benzyl ester) are converted into hydrazine groups by acylhydrazination to obtain hybrid amphiphilic star copolymer nano micelles. The micelles can load doxorubicin, they are safe to human body and have good application prospects.
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Paragraph 0030
(2019/04/30)
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- Folic acid mediated dual-drug-loading targeting polymeric micelle and preparation method and application thereof
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The invention discloses a folic acid mediated dual-drug-loading targeting polymeric micelle and a preparation method and application thereof. The polymeric micelle is a nanoparticle formed by that polyglutamic acid grafted with paclitaxel, gemcitabine and folic acid is subjected to electrostatic self-assembly with polylysine. Compared with the prior art, the dual-drug-loading targeting polymeric micelle has advantages that by joint use of paclitaxel and gemcitabine, great antitumor effects can be achieved, the problem of poor water solubility of paclitaxel is solved, efficacy improvement and toxicity reduction are realized by targeting, and probability is provided for cancer targeted low-toxicity treatment.
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Paragraph 0045; 0051; 0052; 0053
(2019/10/01)
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- POLYMER
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A PEGylated polymer is disclosed according to Formula 1 wherein n is any integer from 4 to 200 monomers, and R is a polymer chain comprising a 4 to 200‐monomer moiety.
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Page/Page column 22
(2018/02/28)
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- Redox-Responsive Biomimetic Polymeric Micelle for Simultaneous Anticancer Drug Delivery and Aggregation-Induced Emission Active Imaging
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Intelligent polymeric micelles have been developed as potential nanoplatforms for efficient drug delivery and diagnosis. Herein, we successfully prepared redox-sensitive polymeric micelles combined aggregation-induced emission (AIE) imaging as an outstanding anticancer drug carrier system for simultaneous chemotherapy and bioimaging. The amphiphilic copolymer TPE-SS-PLAsp-b-PMPC could self-assemble into spherical micelles, and these biomimetic micelles exhibited great biocompatibility and remarkable ability in antiprotein adsorption, showing great potential for biomedical application. Anticancer drug doxorubicin (DOX) could be encapsulated during the self-assembly process, and these drug-loaded micelles showed intelligent drug release and improved antitumor efficacy due to the quick disassembly in response to high levels of glutathione (GSH) in the environment. Moreover, the intracellular DOX release could be traced through the fluorescent imaging of these AIE micelles. As expected, the in vivo antitumor study exhibited that these DOX-carried micelles showed better antitumor efficacy and less adverse effects than that of free DOX. These results strongly indicated that this smart biomimetic micelle system would be a prominent candidate for chemotherapy and bioimaging.
- Hu, Jun,Zhuang, Weihua,Ma, Boxuan,Su, Xin,Yu, Tao,Li, Gaocan,Hu, Yanfei,Wang, Yunbing
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p. 1897 - 1910
(2018/05/15)
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- Synthesis and Characterization of Nitric Oxide-Releasing Platinum(IV) Prodrug and Polymeric Micelle Triggered by Light
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Herein, we report the proof of concept of photoresponsive chemotherapeutics comprising nitric oxide-releasing platinum prodrugs and polymeric micelles. Photoactivatable nitric oxide-releasing donors were integrated into the axial positions of a platinum(IV) prodrug, and the photolabile hydrophobic groups were grafted in the block copolymers. The hydrophobic interaction between nitric oxide donors and the photolabile groups allowed for the loading of platinum drugs and nitric oxide-releasing donors in the photolabile polymeric micelles. After cellular uptake of micelles, light irradiation induced the release of nitric oxide, which sensitized the cancer cells. Simultaneously, photolabile hydrophobic groups were cleaved from micelles, and the nitric oxide-releasing donor was altered to be more hydrophilic, resulting in the rapid release of platinum(IV) prodrugs. The strategy of using platinum(IV) prodrugs and nitric oxide led to enhanced anticancer effects.
- Pramanick, Swapan,Kim, Jihoon,Kim, Jinhwan,Saravanakumar, Gurusamy,Park, Dongsik,Kim, Won Jong
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p. 885 - 897
(2018/04/23)
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- Novel 3D Neuron Regeneration Scaffolds Based on Synthetic Polypeptide Containing Neuron Cue
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Neural tissue engineering has become a potential technology to restore the functionality of damaged neural tissue with the hope to cure the patients with neural disorder and to improve their quality of life. This paper reports the design and synthesis of polypeptides containing neuron stimulate, glutamic acid, for the fabrication of biomimetic 3D scaffold in neural tissue engineering application. The polypeptides are synthesized by efficient chemical reactions. Monomer γ-benzyl glutamate-N-carboxyanhydride undergoes ring-opening polymerization to form poly(γ-benzyl-l-glutamate), then hydrolyzes into poly(γ-benzyl-l-glutamate)-r-poly(glutamic acid) random copolymer. The glutamic acid amount is controlled by hydrolysis time. The obtained polymer molecular weight is in the range of 200 kDa for good quality of fibers. The fibrous 3D scaffolds of polypeptides are fabricated using electrospinning techniques. The scaffolds are biodegradable and biocompatible. The biocompatibility and length of neurite growth are improved with increasing amount of glutamic acid in scaffold. The 3D scaffold fabricated from aligned fibers can guide anisotropic growth of neurite along the fiber and into 3D domain. Furthermore, the length of neurite outgrowth is longer for scaffold made from aligned fibers as compared with that of isotropic fibers. This new polypeptide has potential for the application in the tissue engineering for neural regeneration.
- Wang, Zhen-Hua,Chang, Yen-Yu,Wu, Jhih-Guang,Lin, Chia-Yu,An, Hsiao-Lung,Luo, Shyh-Chyang,Tang, Tang K.,Su, Wei-Fang
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- Intelligent insulin delivery system with good salt tolerance and preparation process
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The invention discloses an intelligent insulin delivery system with good salt tolerance and a preparation process, and belongs to the field of bio-materials. Amphiphilic mPEG-b-PBLG and mPEG-b-PPBDEMA are self-assembled to obtain a composite nano-drug carrier; the composite nano-drug carrier wraps insulin to form an insulin-wrapped composite nanoparticle drug delivery system; a structure formula of mPEG-b-PBLG is shown in the specification; and a structure formula of mPEG-b-PPBDEMA is shown in P-2 or P-3 of the specification.
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Paragraph 0059; 0060
(2017/08/28)
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- POLYMERIC CONJUGATES AND USES THEREOF
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Polymeric conjugates comprising a polymeric matrix having associated therewith an agent that down-regulates an activity or expression of a polypeptide associated with onset or progression of melanoma, and optionally and preferably, an additional agent that acts in synergy with said agent, are provided. Synthetic methodologies for preparing these conjugates and uses thereof in treating melanoma and other cancerous diseases are also provided.
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Page/Page column 73
(2017/09/15)
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- Large-scale synthesis of α-amino acid-N-carboxyanhydrides
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Hetero- and homopolymers prepared from α-amino acid-N-carboxyanhydrides (NCAs) monomers are widely useful products. The preparation of pure NCA monomers has been extensively studied in the past. Purification methods including repeated crystallizations, extraction, and flash column chromatography have been devised. However, these methods are not easily amendable to large-scale NCA preparations. This article describes the synthesis of numerous highly purified NCAs on a >100 g scale using a simple filtration step through diatomaceous earth (celite). The resulting NCAs provided polyethylene glycol (PEG)–amino acid triblock polymers devoid of low-molecular-weight by-products that were routinely observed when unfiltered batches of NCAs were used. Also disclosed is the preparation of NCAs at ambient temperature. Traditionally, NCA reactions using a phosgene source are heated. This study shows these reactions can be driven by the slight exotherm that forms upon reagent mixing. This eliminates the need for an external heating source, simplifying large-scale reactions.
- Semple, J. Edward,Sullivan, Bradford,Sill, Kevin N.
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- Dual-responsive star-shaped polypeptides for drug delivery
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Core cross-linked star-shaped polypeptides based on poly(l-glutamic acid)-poly(l-phenylalanine-co-l-cystine) copolymer have been successfully synthesized and thoroughly characterized. The star polypeptides can self-assemble to form 50 nm micelles in aqueous medium, which respond rapidly to both pH change within the physiologically relevant pH range and a reduction environment mimicking the intracellular space. Water-soluble doxorubicin hydrochloride and hydrophobic resveratrol are loaded into the star polypeptides micelles through electrostatic and hydrophobic interactions respectively. The drug loading content can be controlled by tuning the composition of the star polypeptides. The in vitro release studies indicate dual sensitivity enabled rapid drug release at pH 5.5 and 10 mM dithiothreitol (DTT), mimicking the intracellular environment. Furthermore, the star polypeptides are biocompatible and interact well with cells in vitro. Confocal fluorescence microscopy and flow cytometry assays show these star polypeptides can be quickly internalized and effectively deliver the drugs into HeLa cells to inhibit cell growth.
- Wang, Wenlong,Zhang, Liang,Liu, Mengtao,Le, Yuan,Lv, Shanshan,Wang, Jiexin,Chen, Jian-Feng
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p. 6368 - 6377
(2016/02/03)
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- Multivalent effect of glycopolypeptide based nanoparticles for galectin binding
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Synthetic glycopolypeptides are versatile glycopolymers used to conceive bioinspired nanoassemblies. In this work, novel amphiphilic glycopolypeptides were designed to incorporate lactose or galactan in order to prepare polymeric nanoassemblies with sizes below 50 nm. The bioactivity of the two different outer surface sugar units was evaluated by defining glycan relative binding affinities to human galectins 1 and 3. A specific multivalent effect was found only for polymeric nanoparticles displaying galactan with a significant increase of the binding activity as compared to free glycan in solution. Such synthetic designs present great potential as therapeutic tools to address galectin related pathologies.
- Bonduelle, Colin,Oliveira, Hugo,Gauche, Cony,Huang, Jin,Heise, Andreas,Lecommandoux, Sébastien
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supporting information
p. 11251 - 11254
(2016/09/21)
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- A LARGE SCALE PROCESS FOR PREPARING POLY (GLUTAMYL-GLUTAMATE) CONJUGATES
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Described herein are processes of making biocompatible water-soluble polymers conjugates. In particular, large scale processes of making poly(L-γ-glutamyl-glutamate) conjugates that can be useful for a variety of drug delivery applications are described herein.
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Paragraph 0046; 0047
(2016/04/10)
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- Self-assembled spin-labeled nanoparticles based on poly(amino acids)
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The development of detectable nanoparticles for controlled drug delivery systems has tremendous practical importance regarding the monitoring of drug pathway in organism. Self-assembly amphiphilic block-copolymer poly(l-glutamic acid)-b-poly(l-phenylalanine) (pGlu-b-pPhe) was chosen for the preparation of discussed nanoparticles. The synthesis of blocks was carried out using ring-opening polymerization (ROP) of N-carboxyanhydrides of mentioned amino acids. To introduce the spin label at C-terminal position of hydrophilic block, (4-amino-2,2,6,6-tetramethylpiperidin-1-yl)oxyl (4-amino-TEMPO) was applied as ROP initiator and the polymerization of hydrophobic block was carried out with previously synthesized macroinitiator. The results obtained by transmission electron microscopy clearly showed that TEMPO-pGlu-b-pPhe polymer was really capable to self-assembling in aqueous solutions followed by polymersome formation. The mean size of nanoparticles was increased in a range of TEMPO-pGlu43-b-pPhe12 43-b-pPhe29 43-b-pPhe49 as 60 200 280 nm, respectively. EPR spectroscopy of the solutions of spin-labeled homopolymer TEMPO-p-γ-Glu(Bzl), block copolymers TEMPO-p-γ-Glu(Bzl)-b-pPhe and suspension of polymersomes formed from TEMPO-p-Glu-b-pPhe was performed and the results were compared. It was proved that in the case of nanoparticles EPR detectable spin labels are located on polymersome surface. The experiments in cell culture demonstrated the absence of cytotoxicity of labeled nanoparticles. Additionally, it was shown that TEMPO-label can be detected inside the cell by EPR method.
- Hubina,Pogodaev,Sharoyko,Vlakh,Tennikova
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p. 173 - 180
(2016/02/18)
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- Highly stable polyglutamate derivatives/siRNA polyplex efficiently down-relegate survivin expression and augment the efficacy of cisplatin
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RNA interfere (RNAi)-based technology holds great promise in cancer treatment. The use of small interfering RNA (siRNA), however, is hampered by its low delivery efficiency in vivo when they are diluted in blood biofluids and in the presence of serum and salt. In this study, we developed the polyglutamate derivative polymer brush, poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (mPEG-b-PG-g-spermine, PPGS), which could efficiently deliver survivin-siRNA under ultra-high dilution and in the presence of salt (NaCl 150 mM) and serum (10% FBS), most likely due to its PEG-shelled polymer brush structure. On the contrary, aggregation occurred when PEI/siRNA polyplex dispersed in saline and serum-containing media and PEI polyplex dissociated after making a 256-fold dilution. PPGS/si-survivin polyplex exhibited high cellular uptake efficiency and efficiently down-regulated the expression of survivin mRNA in the cisplatin-resistance of non-small cell human lung adenocarcinoma (A549/DDP) cells in the presence of serum. However, either PEI polyplex or Lipofectmine 2000 complex was unstable in serum and salt-containing media and at high dilution rates, which resulted in their dramatical decrease of cellular uptake and gene-silencing efficiency in these conditions. The PPGS/si-survivin polyplex also exhibited synergistic effects of killing the cancer cells by combination treatment with cisplatin. Therefore, the PPGS gene carrier showed great potential in systemic siRNA delivery, and its combination with chemotherapeutic drug is promising in treating drug resistant cancers.
- Wang, Zhongjuan,Zou, Haijuan,Wang, Zirui,Wu, Jiamin,Xia, Zhongsheng,Feng, Min
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- Primary ammonium/tertiary amine-mediated controlled ring opening polymerisation of amino acid N-carboxyanhydrides
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Stable commercial primary ammonium chlorides were combined with tertiary amines to initiate the controlled ring opening polymerisation of amino acid N-carboxyanhydrides to yield polypeptides with defined end group structure, predetermined molar mass and narrow molar mass distribution.
- Vacogne, Charlotte D.,Schlaad, Helmut
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supporting information
p. 15645 - 15648
(2015/11/02)
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- Protein-Induced Supramolecular Disassembly of Amphiphilic Polypeptide Nanoassemblies
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Mimicking noncovalent interaction based processes in nature has been an important goal of supramolecular chemistry. Here, we report on amphiphilic polypeptides that self-assemble to form nanoscale supramolecular assemblies and are programmed to disassemble in response to a specific protein. Benzenesulfonamide and carbonic anhydrase have been chosen as the ligand and protein, respectively, to demonstrate this possibility. Since the amphiphilic nanoassembly sequesters hydrophobic guest molecules, the protein-specific disassembly event provides a protein-sensitive molecular release as well. We envision that the binding induced disassembly and guest release might open up new opportunities for the next generation of supramolecular assemblies for protein-specific delivery and diagnostics.
- Molla, Mijanur Rahaman,Prasad, Priyaa,Thayumanavan
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supporting information
p. 7286 - 7289
(2015/06/30)
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- Block copolypeptide nanoparticles for the delivery of ocular therapeutics
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Self-assembling block copolypeptides were prepared by sequential ring-opening polymerization of N-carboxyanhydride (NCA) derivatives of g-benzyl-L-glutamic acid and e-carbobenzyloxy-L-lysine, followed by selective deprotection of the benzyl glutamate block. The synthesized polymers had number average molecular weights close to theoretical values, and had low dispersities (DM =1.15-1.28). Self-assembly of the amphiphilic block copolymers into nanoparticles was achieved using the "solvent-switch" method, whereby the polymer was dissolved in THF and water and the organic solvent removed by rotary evaporation. The type of nanostructures formed varied from spherical micelles to a mixture of spherical and worm-like micelles, depending on copolymer composition. The spherical micelles had an average diameter of 43nm by dynamic light scattering, while the apparent diameter of the mixed phase system was around 200nm. Reproducibility of nanoparticle preparation was demonstrated to be excellent; almost identical DLS traces were obtained over three repeats. Following qualitative dye-solubilization experiments, the nanoparticles were loaded with the ocular anti-inflammatory drug dexamethasone. Loading efficiency of the nanoparticles was 90% and the cumulative drug release was 94% over 16d, with a20% burst release in the first 24h.
- Stukenkemper, Timo,Dose, Anica,Gonzalez, Maria Caballo,Groenen, Alexander J.J.,Hehir, Sarah,Andres-Guerrero, Vanessa,Vanrell, Rocio Herrero,Cameron, Neil R.
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p. 138 - 145
(2015/02/19)
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- CISPLATIN COMPLEX AND PREPARATION METHOD THEREOF
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A CDDP complex is formed by complexation of CDDP and a polymer having a structure of Formula (I). The CDDP complex has good biocompatibility and is degradable. A side chain of the polymer is grafted with polyethylene glycol, which gives the CDDP complex good dissolvability. When dissolved in an aqueous medium, the CDDP is protected by a hydrophilic polyethylene glycol chain segment and a hydrophobic amino acid chain segment, which can effectively avoid a sudden release of the CDDP due to the influence of the blood circulation system after intravenous injection, thus improving the stability of the CDDP complex. A carboxyl group contained in the CDDP complex has pH value sensitivity and tends to be deprotonated in a low pH environment, which is advantageous for promoting the release of a drug, and improving the efficiency of the drug.
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Paragraph 0101
(2015/09/22)
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- Amino acid modified hyperbranched poly(ethylene imine) with disaccharide decoration as anionic core-shell architecture: Influence of the pH and molecular architecture on solution behaviour
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Dendritic polymers represent a class of materials for prospective drug delivery application. For that purpose we present the synthesis and characterization of hydrophilic, anionic core-shell architectures based on poly(ethylene imine) (PEI) as core molecule and polyamino acid chains (composed of glutamic acid or aspartic acid) as shell component. NCA polymerization is used for coupling polyamino acid chains to PEI scaffold. Modifying these structures with sugar molecules result in the formation of new core-shell architectures combining a mixture of binary and double shell. For their potential biomedical applications the solution properties of these anionic core-shell architectures at various pH values (3-9) were studied by different analytical tools (zeta potential, streaming potential pH titration, DLS, AFM, in-situ AFM, TEM and cryo-TEM). Especially, the sugar-decorated core-shell architectures mainly provide isolated macromolecules over a broad pH range. Furthermore, the anionic core-shell architectures are suited to interact with cationic molecules.
- Striegler, Christin,Franke, Markus,Müller, Martin,Boye, Susanne,Oertel, Ulrich,Janke, Andreas,Schellkopf, Leonard,Voit, Brigitte,Appelhans, Dietmar
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p. 188 - 204
(2015/11/17)
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- Directed interactions of block copolypept(o) ides with mannose-binding receptors: Peptomicelles targeted to cells of the innate immune system
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Core-shell structures based on polypept(o)ides combine stealth-like properties of the corona material polysarcosine with adjustable functionalities of the polypeptidic core. Mannose-bearing block copolypept(o)ides (PSar-block-PGlu(OBn)) have been synthesized using 11-amino-3,6,9-trioxa-undecyl-2,3,4,6-tetra-O-acetyl-O-α-D-mannopyranoside as initiator in the sequential ring-opening polymerization of α-amino acid N-carboxyanhydrides. These amphiphilic block copolypept(o)ides self-assemble into multivalent PeptoMicelles and bind to mannose-binding receptors as expressed by dendritic cells. Mannosylated micelles showed enhanced cell uptake in DC 2.4 cells and in bone marrow-derived dendritic cells (BMDCs) and therefore appear to be a suitable platform for immune modulation.
- Heller, Philipp,Mohr, Nicole,Birke, Alexander,Weber, Benjamin,Reske-Kunz, Angelika,Bros, Matthias,Barz, Matthias
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- A head-to-head comparison of poly(sarcosine) and poly(ethylene glycol) in peptidic, amphiphilic block copolymers
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In this work we compare chemical and solution properties, like critical aggregate concentrations (CAC) and hydrodynamic radii of aggregates based on either poly(ethylene glycol) or poly(sarcosine) block copolymers in aqueous solution. The amine functionalized, hydrophilic polymers poly(sarcosine) (degree of polymerization, Xn = 100 and 200) and PEG (Xn = 121 and 242) of comparable hydrodynamic volume were used to initiate the ring opening polymerization of α-amino acid-N-carboxyanhydrides based on ε-benzyl-l-glutamate (Glu(OBn)) or ε-carboxybenzyl-l-lysine (Lys(Z)). The second, hydrophobic block was kept at a degree of polymerization of 25 and 50 to enable a direct comparison of solution properties of block copolymers. In both cases block length could be precisely adjusted and all synthesized block copolymers have narrow molecular weight distributions and dispersities between 1.1 and 1.2. Both types of block copolymers display critical aggregate concentrations in the range of 6?10-8-3?10-7 mol/L and aggregates possess hydrodynamic radii in a range of 40-100 nm. PEG based systems, however, have a slightly lower CAC and tend to form smaller micelles, while PSar based systems have commonly smaller μ2 parameter indication more uniform aggregates.
- Huesmann, David,Sevenich, Adrian,Weber, Benjamin,Barz, Matthias
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p. 240 - 248
(2015/05/27)
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- Controlled Synthesis of Polyglutamates with Low Polydispersity and Versatile Architectures
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Polyglutamates are well known to be highly biocompatible, biodegradable and multifunctional polymers, which have been already used as building blocks in polymer drug conjugates and polymeric micelles. Those systems have been applied to various medical applications ranging from therapy to molecular imaging. Furthermore a polyglutamic acid (PGA) paclitaxel conjugate has already entered clinical studies (Opaxio? PGA-PTX conjugate currently in phase III of Clinical trials). In this context, a synthetic pathway to a plethora functional polyglutamates (homopolymers, block-co-polymers, triblocks) with well-defined structure, adjustable molecular weight (Mw) and low dispersity (D=Mw/Mn1.2) applying the ring opening polymerization (ROP) of N-carboxyanhydrides (NCA) has been developed. Additionally, the acid moieties of the polyglutamates can be activated with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium (DMTMM) and various functionalities can be easily introduced by “post-polymerization modification” yielding a set orthogonal reactive attachment sides. The reactive moieties, such as azides, maleimides, thiols, alkynes (linear or cyclic) offer the opportunity of specific conjugation of the drugs, targeting moieties or markers. Besides introducing reactive groups the functionalization strategy was also used for PEGylation of PGA reducing charge induced interactions and therefore pharmacological properties, such as blood circulation time may be adjusted. In summary, a tool kit of various polyglutamates has been developed enabling the synthesis of a variety of polymer drug conjugates or polymer based imaging agents. The functional polymeric precursors developed will allow us to functionalize and therefore adjust the polymer properties to a desired application.
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Paragraph 0059; 0065; 0066; 0067; 0068;
(2015/03/31)
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- COPOLYMERS FOR STABLE MICELLE FORMULATIONS
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The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same. Compositions herein are useful for drug-delivery applications.
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Paragraph 0363; 0364; 0365
(2014/09/29)
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- Bulky toroidal and vesicular self-assembled nanostructures from fullerene end-capped rod-like polymers
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In this work, we present novel fullerene (C60) end-capped rod-like polypeptide-polymers, obtained by one-pot thiol-ene chemistry. These systems are able to self-assemble in water creating precise bulky microstructures of toroidal or vesicular shapes. Independent molecular dynamics simulations supported the observed experimental results. the Partner Organisations 2014.
- Mazzier,Mba,Zerbetto,Moretto
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supporting information
p. 4571 - 4574
(2014/05/06)
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- Synthesis and self-assembly of thermoresponsive amphiphilic biodegradable polypeptide/poly(ethyl ethylene phosphate) block copolymers
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We report the design and synthesis of new fully biodegradable thermoresponsive amphiphilic poly(γ-benzyl L-glutamate)/poly(ethyl ethylene phosphate) (PBLG-b-PEEP) block copolymers by ring-opening polymerization of N-carboxy-γ-benzyl L-glutamate anhydride (BLG-NCA) with amine-terminated poly(ethyl ethylene phosphate) (H2N-PEEP) as a macroinitiator. The fluorescence technique demonstrated that the block copolymers could form micelles composed of a hydrophobic core and a hydrophilic shell in aqueous solution. The morphology of the micelles as determined by transmission electron microscopy (TEM) was spherical. The size and critical micelle concentration (CMC) values of the micelles showed a decreasing trend as the PBLG segment increased. However, UV/Vis measurements showed that these block copolymers exhibited a reproducible temperature-responsive behavior with a lower critical solution temperature (LCST) that could be tuned by the block composition and the concentration.
- Wu, Qiuhua,Zhou, Dan,Kang, Renyu,Tang, Xiuping,Yang, Qi,Song, Ximing,Zhang, Guolin
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p. 2850 - 2858
(2015/02/19)
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