N-carboxyanhydride Monomers Research Articles

Thermoresponsive Poly(α-peptoid)s: Tuning the Cloud Point Temperatures by Composition and Architecture.

Random copolymers based on poly(N-ethyl glycine) and poly(N-butyl glycine) have been synthesized by NHC-mediated or primary amine-initiated copolymerization of the corresponding N-substituted N-carboxyanhydride monomers (i.e., Et-NCA and Bu-NCA), respectively. The copolymers are thermally responsive and exhibit reversible phase transitions with tunable cloud point temperature (Tcp) in aqueous solution. The Tcp can be readily tuned in the temperature range 20-60 °C by controlling the copoly(α-peptoid) composition and the architecture (i.e., cyclic vs linear). The copoly(α-peptoid)s are noncytotoxic (similar to poly(ethylene glycol) (PEG), a benchmark biocompatible polymer), suggesting their potential use in biotechnology and biomedicine.

Photo-cross-linked mPEG-poly(γ-cinnamyl-l-glutamate) micelles as stable drug carriers

A functionalized L-glutamate N-carboxyanhydride monomer containing a cinnamyl moiety, γ-cinnamyl-L-glutamate N-carboxyanhydride (CLG-NCA), was prepared. Ring-opening polymerization (ROP) of CLG-NCA initiated by n-hexylamine and amino-terminated poly(ethylene glycol) (mPEG-NH2) was successfully performed with controlled polymer molecular weight and molecular weight distribution. The structures of the obtained monomer and polymers were confirmed by 1H NMR, 13C NMR and FTIR. The block copolymer mPEG-b-PCLG could self-assemble into micelles in aqueous solution which consist of a hydrophobic PCLG core and a hydrophilic mPEG shell. Under UV-irradiation at 254 nm, the photo-cross-linking process of the cinnamyl-carrying block copolymer micelles was tracked by UV-Vis spectra, 1H NMR, dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro MTT assay demonstrated that the micelles were biocompatible to L929 cells. Paclitaxel was loaded into the micelles as a model drug. The in vitro paclitaxel release behaviors indicated that cross-linking of the micelle cores results in a slow drug release in comparison with the non-cross-linked micelles. These results indicated that the photo cross-linked mPEG-b-PCLG micelles can be used as drug carriers for intelligent drug delivery.

Facile Synthesis of Glycopolypeptides by Combination of Ring‐Opening Polymerization of an Alkyne‐Substituted N‐carboxyanhydride and Click “Glycosylation”

Synthetic glycopolypeptides have attracted much interest for application in biomedical field as they are structural mimics to the natural glycopeptides or glycoproteins. However, the synthesis methods toward glycopolypeptides are still few or less efficient. Herein, we present a facile route to preparation of glycopolypeptides with highly effective "glycosylation" by click postpolymerization modification. First, an alkyne-substituted N-carboxyanhydride (NCA) monomer was synthesized and subsequently polymerized to afford the polypeptide with "clickable" alkyne pendants. The alkyne-functionalized polypeptide was then "glycosylated" by click reaction of different sugar azides to the alkyne pendants with high efficiency. All the obtained glycopolypeptides were soluble and preferred α-helix conformation in water. Primary studies on the obtained glycopolypeptides binding with Con A lectin were assessed by turbidimetric assay. The more quantitive studies of the interactions between lectin proteins and the synthetic glycopolypeptides, and the application of these materials as the multivalent ligands are in progress.

Glycyrrhetinic acid-modified poly(ethylene glycol)–b-poly(γ-benzyl l-glutamate) micelles for liver targeting therapy

Liver targeted micelles were successfully constructed via self-assembly of glycyrrhetinic acid (GA)-modified poly(ethylene glycol)-b-poly(gamma-benzyl l-glutamate) (GA-PEG-PBLG) block co-polymers, which were fabricated via ring opening polymerization of gamma-benzyl l-glutamate N-carboxyanhydride monomer initiated by GA-modified PEG. The in vivo biodistribution and the in vitro cellular uptake of these micelles were investigated. The results showed that the relative uptake of doxorubicin (DOX)-loaded micelles (DOX/GA-PEG-PBLG) in liver was much higher than in other tissues, and the resulting DOX concentration in liver was about 2.2-fold higher than that from the micelles without modification by GA. Moreover, the cellular uptake study demonstrated that the introduction of GA to the micelles could significantly increase the affinity for human hepatic carcinoma 7703 cells, which induced a 3.7-fold higher endocytosis than unmodified ones. The cytotoxicity of DOX/GA-PEG-PBLG micelles (IC(50) 47 ngml(-1)) was much higher than that of free DOX (IC(50) 90 ngml(-1)). These results indicate that GA-modified micelles have great potential in liver targeting therapy.

One-Pot Synthesis of Brush-Like Polymers via Integrated Ring-Opening Metathesis Polymerization and Polymerization of Amino Acid N-Carboxyanhydrides

We report here the integration of ring-opening metathesis polymerization (ROMP) and ring-opening polymerization of the amino acid N-carboxyanhydride (NCA) to allow facile synthesis of brush-like polymers containing polypeptide as the brush side chains. ROMP of N-trimethylsilyl norbornenes rendered the preparation of poly(norbornene)s bearing pendant N-TMS groups. With no need to purify the resulting polymers, such macromolecular initiators could subsequently initiate controlled NCA polymerizations. Brush-like poly(norbornene)s with grafted polypeptides or block copolypeptides were readily obtained with controlled molecular weights and narrow molecular weight distributions. Because numerous ROMP and NCA monomers are widely available, this novel polymerization technique will allow easy access to numerous brush-like hybrid macromolecules with unprecedented properties and broad applications.

SYNTHESIS AND pH-SENSITIVE SELF-ASSEMBLY OF DENDRITIC POLY(AMIDOAMINE)-b-POLY(L-GLUTAMATE) BIOHYBRIDS

Dendritic poly(amidoamine)-b-poly(L-glutamate) (PAMAM-b-PLG) biohybrids were synthesized by the ring-opening polymerization of γ-benzyl-L-glutamate N-carboxyanhydride monomer, followed by the deprotection of benzyl groups on poly(benzyl-L-glutamate), and were characterized by 1H-NMR, FT-IR and gel permeation chromatography. The self-assembly behavior of the PAMAM-b-PLG biohybrid was investigated by means of UV-Vis, dynamic light scattering (DLS), transmission electronic microscopy (TEM) and 1H-NMR. UV-Vis analysis demonstrated that the critical aggregation concentration of PAMAM-b-PLG was dependent on the pH value of aqueous solutios. DLS results further evidenced that the PAMAM-b-PLG biohybrid exhibited a pH-sensitive self-assembly behavior, and the average size of the self-assembled nanoparticles decreased gradually with the increasing pH value of the PAMAM-b-PLG solution. The self-assembled nanoparticles gave a nearly spherical morphology, and the pH-induced self-assembly had no obvious effect on the morphology of nanoparticles.

Phosgene‐free synthesis of N‐carboxyanhydrides of α‐amino acids based on bisarylcarbonates as starting compounds

A new convenient access to N-carboxyanhydride (NCA) monomers has been achieved based on the utilization of bisarylcarbonates as a carbonyl source, which are activated by electron-withdrawing substituents on their aryl groups such as fluorine atom and nitro group. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Controlled Synthesis of a Chitosan‐Based Graft Copolymer Having Polysarcosine Side Chains Using the NCA Method with a Carboxylic Acid Additive

AbstractSummary: A novel chitosan derivative with polysarcosine side chains, i.e., chitosan‐graft‐polysarcosine [chitosan‐graft‐poly(N‐methylglycine)], was synthesized by ring‐opening polymerization of sarcosine N‐carboxyanhydride (NCA) with chitosan as a macroinitiator in the presence of carboxylic acids in dimethyl sulfoxide at 27 °C. Degree of substitution ($\overline {DS}$) for polysarcosine side chains introduced to chitosan was controlled successfully by the feed amount of the additive nicotinic acid ($\overline {DS}$ = 0.21–0.71). Independent of $\overline {DS}$ control, degree of polymerization ($\overline {DP}$) for polysarcosine side chains was controlled by adjusting feed ratios of NCA monomer to chitosan ($\overline {DP}$ = 14–43). Kinetic analysis of the propagation of sarcosine NCA was conducted by measuring CO2 evolution. Apparent kp values decreased with increased feed amounts of nicotinic acid, supporting the theory that propagation of NCA in the presence of nicotinic acid proceeds via equilibrium between active amine and dormant ammonium species.Propagation mechanism of carboxylic acid‐mediated polymerization of sarcosine N‐carboxyanhydride.magnified imagePropagation mechanism of carboxylic acid‐mediated polymerization of sarcosine N‐carboxyanhydride.

Synthesis and characterization of glycopolymer-polypeptide triblock copolymers.

Glycopolymer-polypeptide triblock copolymers of the structure, poly(l-alanine)-b-poly(2-acryloyloxyethyl-lactoside)-b-poly(l-alanine) (AGA), have been synthesized by sequential atom transfer radical polymerization (ATRP) and ring-opening polymerization (ROP). Controlled free radical polymerization of 2-O-acryloyl-oxyethoxyl-(2,3,4,6-tetra-O-acetyl-beta-d-galactopyranosyl)-(1-4)-2,3,6-tri-O-acetyl-beta-d-glucopyranoside (AEL) by ATRP with a dibromoxylene (DBX)/CuBr/bipy complex system was used to generate a central glycopolymer block. Telechelic glycopolymers with diamino end groups were obtained by end group transformation and subsequently used as macroinitiators for ROP of l-alanine N-carboxyanhydride monomers (Ala-NCA). Gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR) spectroscopy analysis demonstrated that copolymer molecular weight and composition were controlled by both the molar ratios of the Ala-NCA monomer to macroinitiator and monomer conversion and exhibited a narrow distribution (Mw/Mn = 1.06-1.26). FT-IR spectroscopy of triblock copolymers revealed that the ratio of alpha-helix/beta-sheet increased with poly(l-alanine) block length. Of note, transmission electron microscopy (TEM) demonstrated that selected amphiphilic glycopolymer-polypeptide triblock copolymers self-assemble in aqueous solution to form nearly spherical aggregates of several hundreds nanometer in diameter. Significantly, the sequential application of ATRP and ROP techniques provides an effective method for producing triblock copolymers with a central glycopolymer block and flanking polypeptide blocks of defined architecture, controlled molecular weight, and low polydispersity.

From prebiotic macromolecules to synthetic polypeptides: a new, efficient synthesis of α‐amino acid N‐carboxyanhydrides (NCAs)

AbstractWhile polypeptide materials present important application potentialities, the expense of amino acid N‐carboxyanhydride (NCA) monomers strongly limits their applications. We present here a new, promising synthetic route to NCA through N‐carbamoylamino acid nitrosation by gaseous NOx(1 < x < 2) in the solid–gas phase. This very efficient reaction (which was originally developed in a prebiotic context) works in the absence of solvent and with minimum waste, and presents interesting economic features. Some mechanistic investigations aimed at the optimisation and scale‐up of this reaction in the solid‐gas phase are presented.© 2002 Society of Chemical Industry

Surface Grafting of Poly(l-glutamates). 2. Helix Orientation

In this paper the average helix orientation of surface-grafted poly(γ-benzyl l-glutamate) (PBLG), poly(γ-methyl l-glutamate) (PMLG), and poly(γ-methyl l-glutamate)-co-(γ-n-stearyl l-glutamate) (PMLGSLG 70/30) was investigated by means of FT-IR transmission spectroscopy. The theoretical relation between the average tilt angle (θ) and the absorption peak areas of three different backbone amide bands could be calculated because their transition dipole moment directions with respect to the helix axis were known. From the normalized absorptions, the average tilt angles of grafted helices of PBLG, PMLG, and PMLGSLG 70/30 were determined. The somewhat larger average angle of PMLG helices of 35 ± 5° with respect to the substrate compared to the value of 32 ± 5° of PBLG was due to the higher grafting density of PMLG. Because of the smaller helix diameter as a result of the smaller size of the methyl side group, more PMLG helices grew on the same surface area. Sterical hindrance and unfavorable polar interactions between unidirectional aligned helices forced the PMLG helices in a more upright arrangement. The even more perpendicular orientation of PMLGSLG 70/30 (48 ± 6°) could be the result of incorporation of mainly γ-methyl l-glutamate N-carboxyanhydride (MLG-NCA) monomers during the initiation step. Incorporation of the much larger γ-n-stearyl l-glutamate N-carboxyanhydride (SLG-NCA) monomers afterward lead to enlarged angles with respect to the substrate. Due to swelling, a pronounced change in helix orientation of grafted PMLGSLG 70/30 in n-hexadecane was observed, resulting in an almost perpendicular helix orientation.

Surface Grafting of Poly(l-glutamates). 1. Synthesis and Characterization

The ring-opening polymerization of N-carboxyanhydrides (NCA) of γ-benzyl l-glutamate and γ-methyl l-glutamate from (γ-aminopropyl)triethoxysilane (APS) pretreated substrates such as silicon wafers and quartz slides was investigated. FT-IR transmission spectroscopy, circular dichroism measurements, and UV/vis spectroscopy confirmed the pure α-helix conformation of the grafted polypeptide layers. FT-IR spectroscopy also showed that the most important part of the polymer growth took place in the first 5 h of the polymerization. The average orientation of the rather rigid α-helical polypeptides, grown during a short period of time, was more perpendicular with respect to the substrate than the orientation of the polymers grown over a longer reaction time. For concentrations up to 2.0 M, the polymer growth from both NCA monomers showed a pronounced dependence on the monomer concentration. Moreover, it appeared that the higher the monomer concentration, the more perpendicular the average orientation of the helices with respect to the substrate. The thickness of the grafted polypeptide layers up to 400 Å was determined with ellipsometry and small-angle X-ray reflection measurements. The absence of chemical chain termination was demonstrated by additional polymer growth in a renewed polymerization.

Polypeptide Ultrathin Films by Vacuum Deposition: Preparation and Characterization

ABSTRACTPolypeptide ultrathin films covalently grafted on solid substrates have attracted considerable attention in the interfacial polymer science community over the past couple of years. The potential applications of these films ranges from applications in liquid crystal displays, biosensors, optical devices, etc.. Their study may address important biocompatibility issues. We have synthesized polypeptide ultrathin films through the use of the physical vapor deposition technique. We expect to gain better insight into the polymerization process of the NCA monomers, as well as, possible control of the secondary structure.Through use of the vapor deposition technique and the amino acid n-carboxy anhydride (NCA) benzyl serine we have been able to prepare polymeric amino acids for analysis. Benzyl serine NCA was evaporated in high vacuum at a temperature of 95-130°C. Different substrates have been used to examine the effects of chemical binding sites on polymerization and secondary structure formation. From IR-spectroscopy and optical microscopy it was evident that without a free amine initiator on the surface of the substrate, polymerization would not occur. Analysis of the films with IR and optical microscopy were used to determine optimum deposition and polymerization conditions. The methyl peak around 3000 cm-1, amide peak at 1650 cm-1 and the carbonyl stretching at 1750 cm-1 evidence of the monomer are greatly reduced or disappear in the deposition range of 40-100nm/min.Analysis of the films with attenuated total reflectance (ATR) Infrared spectroscopy was used to examine the secondary structure. Values of amide 1 peak at 1632 cm-1, representing the carbonyl stretching, and the peak at 1530 cm-1, representing the carbon nitrogen stretching, match with literature values of beta sheet conformation.

Organophilic Colloidal Particles with a Synthetic Polypeptide Coating

Composite colloidal particles with a silica core and a synthetic, homopolypeptide shell have been produced by initiation of benzyl-l-glutamate N-carboxyanhydride monomer from primary amine functionalized silica particles. The resulting poly(γ-benzyl-α,l-glutamate)-coated spheres were characterized by electron microscopy, dynamic light scattering, infrared spectroscopy, and thermogravimetry. The polypeptide shell accounts for about 20% of the total mass of the particles, which are reasonably uniform in size. Infrared spectra show an α-helical secondary structure, but other conformations are not excluded. A geometrical analysis is applied to calculate the maximum number of amino groups that might realistically participate in initiation. The actual shell thickness is smaller than expected on the basis of these geometrical considerations, which reflects undesired termination steps or the conversion of some monomer to unattached polymer by trace initiator impurities.

Synthetic Polypeptide Mimics of Marine Adhesives.

Water soluble copolypeptides containing l-dihydroxyphenylalanine (DOPA) and l-lysine were prepared by ring-opening polymerization of alpha-amino acid N-carboxyanhydride (NCA) monomers. We have prepared a range of different copolymers to probe the effects of functional group composition on adhesive and cross-linking behavior. Aqueous solutions of these copolymers, when mixed with a suitable oxidizing agent (e.g., O2, mushroom tyrosinase, Fe3+, H2O2, or IO4-), formed cross-linked networks that were found to form moisture-resistant adhesive bonds to a variety of substrates (e.g., aluminum, steel, glass, and plastics). It was found that successful adhesive formation was dependent on oxidation conditions, with chemical oxidants giving the best results. Optimized systems were found to form adhesive bonds that rival in strength those formed by natural marine adhesive proteins. Our synthetic systems are readily prepared in large quantities and require no enzymes or other biological components.