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Polysaccharide-polypeptide conjugates have gained a broad interest in mimicking the structure and bioactivity of peptidoglycans or proteoglycans for biomedical applications. Efficient and precise preparation of the conjugates is challenging and unresolved, mainly because of the mismatched solubility between polysaccharide initiators and

Surface modification with cationic polymer coatings represented an important strategy to address the medical device-related infection issues. However, limited antibacterial activities and high cytotoxicity have hampered their development. Herein, we report a facile method to enhance the surface antibacterial activity by construction of an imidazolium-based polypeptide with fosfomycin counteranions (i.e., S

Inspired by the charge composition and distribution of proteins and peptides, we designed and prepared a series of brush polypeptides with positive and negative charges separately distributed in the side chains and the backbones. The brush polypeptides can self- or co-deposit on various substrates forming ultrathin and stable coatings. They showed potent bactericidal activity and antibiofilm property, outperforming conventional linear polypeptide coatings with randomly distributed positive and negative charges. Keeping the balance of positive/negative charges and increasing the numbers of positive/negative charges can further improve the antibacterial property of brush polypeptide coatings without sacrificing their biocompatibility.

Dual-function antibacterial surfaces have exhibited promising potential in addressing implant-associated infections. However, both bactericidal and antifouling properties need to be further improved prior to practical uses. Herein, we report the preparation and properties of a linear block copolymer coating (LP-KF) and a single-chain nanoparticle coating (NP-KF) with poly(ethylene glycol) (PEG) and cationic polypeptide segments. NP-KF with cyclic PEG segments and densely charged polypeptide segments was expected to display improved bactericidal and antifouling properties. LP-KF was prepared by the combination of ring-opening polymerization of N-carboxyanhydride (NCA) monomers and subsequent deprotection. NP-KF was prepared by intramolecular cross-linking of LP-KF in diluted solutions. Both LP-KF- and NP-KF-coated PDMS surfaces were prepared by dipping with polydopamine-coated surfaces. They showed superior in vitro bactericidal activity against both Staphylococcus aureus and Escherichia coli with >99.9% killing efficacy, excellent protein adsorption resistance, antibacterial adhesion, and low cytotoxicity. The NP-KF coating showed higher bactericidal activity and antifouling properties than its linear counterpart. It also showed significant anti-infective property and histocompatibility in vivo, which makes it a good candidate for implants and biomedical device applications.

Antimicrobial polypeptides are promising mimics of antimicrobial peptides (AMPs) with low risks of antimicrobial resistance (AMR). Polypeptides with facile and efficient production, high antimicrobial activity, and low toxicity toward mammalian cells are highly desirable for practical applications. Herein, triblock copolypeptides with chloro groups (PPGn-PCPBLGm) and different main-chain lengths were synthesized via an ultrafast ring-opening polymerization (ROP) using a macroinitiator, namely poly(propylene glycol) bis(2-aminopropyl ether), and purified or nonpurified monomer (i.e., CPBLG-NCA). PPGn-PCPBLGm with 90 amino acid residues can be readily prepared within 300 s. Imidazolium-based block copolypeptides (PPGn-PILm) were facilely prepared via nucleophilic substitution of PPGn-PCPBLGm with NaN3 and subsequent "click" chemistry. α-Helical PPGn-PILm can self-assemble into nanostructured and cationic micelles which displayed highly potent antimicrobial activity and low hemolysis. The top-performing material, namely PPG34-PIL70, showed low minimum inhibitory concentration (MIC) against both Gram-positive S. aureus and Gram-negative E. coli (25 μg mL-1). It also displayed low toxicity against mouse embryonic fibroblast (NIH 3T3) and human embryonic kidney (293T) cells at 2× MIC.

Poly(l-cysteine)s with methylthio pendants (PMTLCs) were synthesized by ring-opening polymerization of a new l-cysteine-based N-carboxyanhydride. The thioether bonds of PMTLC can be readily oxidize...

Poly (γ-glutamic acid) (γ-PGA) has been found widespread applications in biomedical field because of its excellent water solubility, biocompatibility, and bioactivity. Herein, a water-insoluble γ-PGA antibacterial compound is facilely fabricated via one-pot electrostatic assembly of γ-PGA with cationic ethyl lauroyl arginate (ELA). The functionalized γ-PGA compound (γ-PGA-ELA) ethanol solution can facilely produce colorless and transparent coatings on various inorganic, metal, and polymeric substrates, especially for the lumen of slender catheters (length up to 2 m, and inner diameter down to 1 mm). The functionalized γ-PGA coating presents remarkable antibacterial efficacy in vitro and in vivo. In addition, the γ-PGA compound is used as antibacterial additives of polyolefin via melting extrusion, and the as-prepared antibacterial polyolefin demonstrates advantageous antibacterial efficacy. More importantly, the functionalized γ-PGA coating exhibit good hemocompatibility, low cytotoxicity, and satisfactory histocompatibility. The as-proposed γ-PGA compound has a great potential to serve as a safe and multifunctional antibacterial candidate to combat biomedical devices-related infections.

OEGylated polypeptide bearing triethylene glycol monomethylether (OEG3) and poly(ethylene glycol) methyl ether 350 (OEG7) were first prepared by copper-mediated 1,3-dipolar cycloaddition. 1H NMR, FTIR, and GPC results indicated the successful conjugation of oligo(ethylene glycol) (OEG) pendants with high grafting efficiency (≥ 98%). Variable temperature UV–vis spectroscopy revealed a reversible lower critical solution temperature (LCST)-type phase transition of the resulting polypeptides. The LCST-type cloud point temperature (Tcp) in the range of 20–60 °C can be readily tuned by changing the OEG3 and OEG7 composition. Thermo- and pH-responsive polypeptide was prepared by first conjugating of OEG and 6-aldehyde hexyl pendants, then crosslinking in the presence of 1,6-hexanediamine, yielding OEGylated polypeptide bearing pH-labile imine bonds. The resulting polypeptide showed pH-responsive property and less pronounced thermoresponsive property at high pH values (i.e., ≥ 6.15) and noticeable thermo- and pH- dual responsive properties at low pH values (i.e., ≤ 5.80).

A series of ABA-type triblock copolymers (PImBF4-b-PPG-b-PImBF4) comprising of poly(propylene glycol) (PPG) as middle block and UCST polypeptide on both sides of PPG was synthesized by ring-opening polymerization of γ-chloropropyl-L-glutamic acid-based N-carboxyanhydride (CPLG-NCA) and then side-chain modification including nucleophilic substitution of the chloro group followed by copper-mediated 1,3-dipolar cycloaddition and subsequent ion-exchange reaction. Variable-temperature UV–vis spectroscopy revealed that the upper critical solution temperature (UCST)-type cloud point temperature (Tcp) was highly dependent on both polypeptide and PPG chain length as well as polymer concentration. Increasing the polymer chain length or concentration frequently results in Tcp increases. Noticeable hysteresis in a cooling/heating cycle was observed for all resulting triblock copolymers owing to a slow disassembly of large aggregates (d = 145 nm) in the heating cycle. Moreover, the resulting UCST triblock copolymers were used to regulate the release property of ciprofloxacin (CIP)-loaded poly(vinyl alcohol) (PVA) hydrogel. The incorporation of PImBF4-b-PPG-b-PImBF4 hampered the burst release of CIP at 37 °C indicating their potential toward sustained release of drug-loaded hydrogels.

The understanding of molecular structure and thermoresponsive property relationships and development of water-soluble thermoresponsive polymers with tunable cloud point temperatures (Tcps) are crucial toward versatile practical uses. Herein, OEGylated polypeptides bearing Y-shaped pendants, namely poly(γ-4-(propoxycarbonyl)benzyl-L-glutamate)-oligo(ethylene glycol) conjugates (8-OEGx, x = 2, 3) were synthesized by the combination of ring-opening polymerization of γ-4-(allyloxycarbonyl)benzyl-L-glutamic acid based N-carboxyanhydride (4) and subsequent side-chain modifications, including bromination of poly(γ-4-(allyloxycarbonyl)benzyl-L-glutamate) (5), nucleophilic substitution of 5 in the presence of NaN3, and subsequent copper-mediated 1,3-dipolar cycloaddition. Both 1H NMR and FTIR analysis confirmed the molecular structures of the intermediates and 8-OEGx. In aqueous solutions, 8-OEGx samples showed reversible lower critical solution temperature (LCST)-type phase transitions in broad polymer concentration range (0–30 mg·mL−1). Variable-temperature UV–vis spectroscopy results revealed that the LCST-type Tcp of 8-OEG2 at high polymer concentrations (e.g., ≥10 mg∙mL−1) was in the range of 37.5–42.5 °C. 8-OEG2 showed a remarkable increase of hydrophilicity than PBLG-OEG4 with the same amount of OEG units as well as linear shaped pendants. The Tcp of OEGylated polypeptides increased by addition of NaI, yet it decreased upon addition of NaCl, NaBr, or KCl, which obeys the Hofmeister effect.

OEGylated homopolypeptide (i.e., P(Azo-S-OEG7)) bearing azobenzene, thioether spacers, and oligo(ethylene glycol) OEG tails were prepared via a copper-mediated 1,3-dipolar cycloaddition. P(Azo-S-OEG7) showed an upper critical solution temperature (UCST)-type thermo-, light-, and oxidation-responsive in ethanol/water solvent mixtures. The UCST-type cloud point temperature (Tcp) decreased after UV irradiation and it increased after visible light irradiation due to the trans-cis isomerization of azobenzene moieties. P(Azo-S-OEG7) can be readily oxidized in the presence of H2O2, yielding P(Azo-SOX-OEG7) with sulfone or sulfoxide spacers. P(Azo-SOX-OEG7) showed an increase of UCST-type Tcp after UV irradiation and the Tcp decreased after visible light irradiation, which is an opposite trend to the UCST-type phase behavior of P(Azo-S-OEG7) as well as previous report. P(Azo-S-OEG7) showed poor water-solubility, yet it underwent H2O2 induced solution phase transition yielding P(Azo-SOX-OEG7) with lower critical solution temperature (LCST)-type phase behavior in water. The P(Azo-SOX-OEG7) aqueous solutions showed a decrease of LCST-type Tcp after UV irradiation and consequently Tcp decreased after visible light irradiation.

A homopolypeptide with a thioether spacer and a reactive chloro side-chain end group, namely PBLG-S-Cl, can be readily prepared by n-butylamine initiated ring-opening polymerization of γ-4-(substituent)benzyl-L-glutamate acid based N-carboxyanhydride (NCA) monomer. Cationic polypeptides (PBLG-S-ImX, X = I, BF4) with upper critical solution temperature (UCST)-type thermo- and oxidation-responsive properties were prepared by nucleophilic substitution of PBLG-S-Cl and subsequent ion-exchange reaction. OEGylated polypeptides (PBLG-S-OEG7) with lower critical solution temperature (LCST)-type thermo- and oxidation-responsive properties were prepared by nucleophilic substitution of PBLG-S-Cl with NaN3 yielding PBLG-S-N3, followed by 1,3-dipolar cycloaddition. CD analysis revealed a thermally stable α-helical conformation of the resulting cationic polypeptides in aqueous solution. The α-helical conformation and long hydrophobic spacer enable PBLG-S-ImX (X = Cl, I, BF4) samples with good growth inhibition of S. aureus. The antimicrobial activity of PBLG-S-ImX (X = I, BF4) samples was found to be temperature independent. Yet, the antimicrobial activity was affected by the oxidation of thioether bonds as well as the oxidation/degradation of counteranions.

Polypeptide based single-chain nanoparticles (SCNPs) were synthesized via intramolecular crosslinking between ABA-type triblock copolymers and 1,4-diiodobutane in dilute solution (0.25 mg·mL−1). Alkylation of the thioether containing SCNPs in the presence of propargyl bromide yielded sulfonium containing SCNPs with “clickable” alkyne pendants, which can be readily modified by azido compounds. Copper-mediated 1,3-dipolar cycloaddition between the alkyne containing SCNPs and (3-azidopropyl)triphenylphosphonium bromide (TPP-N3) afforded SCNPs bearing TPP pendants. An ion-exchange reaction endowed the TPP containing SCNPs with tunable hydrophilicity/hydrophobicity by adjusting the types of counteranions. All the resulting polypeptide based SCNPs adopt α-helical conformation in both the solid-state and solutions. SCNPs bearing triphenylphosphonium iodide formed self-assembled structures in aqueous solutions and showed upper critical solution temperature (UCST)-type thermoresponsive properties. The UCST SCNPs showed increased UCST-type phase transition temperature (Tpt) and improved biocompatibility compared to their linear polymer counterparts. The Tpt increased by intrachain crosslinking, increasing the crosslinking density or concentration. Our work provides a new and facile route to prepare side-chain “clickable” and α-helical SCNPs.

SO2-responsive homopolypeptide with tri(ethylene glycol), 1,2,3-triazole linkages and N-butylimidazolium iodide pendants (P4) were prepared by the ring-opening polymerization of γ-2-(2-(2-chloroethoxy)ethoxy)ethyl- l -glutamic acid based N-carboxyanhydride then post-polymerization to the side-chain, by the nucleophilic substitution of the chloro group in the presence of NaN3, followed by the copper-mediated 1,3-dipolar cycloaddition, and subsequent ion-exchange reaction. 1H NMR analysis revealed that SO2 interacted with 1,2,3-triazole group leading to polymer aggregation. The P4/SO2 aqueous solution is multi-responsive that can be triggered by gas (N2/SO2), temperature, and oxidation (i.e., H2O2). Poly(vinyl alcohol) (PVA) hydrogel modified by P4 and BaSO3 particles were prepared, the resulting hydrogel showed improved mechanical properties in terms of both stiffness and toughness.

A series of cationic polypeptide imidazolium conjugates were prepared by ring-opening polymerization (ROP) of γ-4-(3-chloropropoxycarbonyl)benzyl-L- glutamic acid-based N-carboxyanhydride (CPBLG-NCA) initiated by various mono- or diamine initiators and subsequent side-chain modification with high grafting efficiency. Rapid and controlled ROP was achieved by polymerizing CPBLG-NCA in a dichloromethane/NaHCO3/H2O solvent mixture with the amine initiators. The resulting polypeptides bearing imidazolium iodide pendants showed reversible upper critical solution temperature (UCST)-type thermoresponsive properties in both ethanol and DI water while the polypeptides with tetrafluoroborate counter-anions showed a UCST in phosphate buffer saline (PBS). The cloud point temperature (Tcp) in ethanol and aqueous solutions can be tuned by both molecular weight and the end- or linkage-groups in the main chain. The cationic polypeptides showed good antibacterial activity against Staphylococcus aureus and low hemolysis. Our results provide a facile and rapid ROP strategy to develop new families of stimuli-responsive polypeptides with tunable properties as well as antibacterial polypeptides with optimized selectivity.

Hyaluronic-acid (HA)-coated LOX-1-specific siRNA-condensed cell-penetrating peptide (CPP) nanocomplexes (NCs) were developed for targeted gene delivery to macrophages and suppression of lipid accumulation. The HA coating facilitated the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors and was further degraded by hyaluronidase (HAase) intraplaques for exposing the naked CPP NCs and achieving the ultimate location into macrophages. The surface coating of HA was verified by the increased particle size, inverted zeta potential, and TEM images. The targeting mechanism was studied on the established injured endothelium-macrophage coculture system, which revealed that modification of higher molecular weight HA and higher HA coating density on NCs, termed as NPs-3, improved the intracellular uptake of nanoparticles by macrophages. Macrophages internalized NCs via caveolae-mediated endocytosis pathway. Moreover, NPs-3 exhibited better cellular drug efficacy in preventing macrophage-derived foam cell formation than other preparations. Compared with NCs, HA decoration showed enhanced atherosclerotic-lesion-targeting efficiency, proven by results from ex vivo imaging. Furthermore, atheroprotective efficacy study in apoE-deficient mice showed that NPs-3 had the best potent efficacy, which was demonstrated by the fewest atherosclerotic lesions sizes and lipid accumulation, the lowest macrophage infiltration, and the lowest expression of monocyte chemoattractant protein-1 (MCP-1), respectively. Collectively, the HA-coated CPP NCs were promising nanocarriers for efficient macrophage-targeted gene delivery and antiatherogenic therapy.

Poly(vinyl alcohol) (PVA)-polypeptide double-network hydrogels with various ionic liquid (IL)-based polypeptides were prepared by a freezing/thawing method. Tensile tests revealed that the stiffness and toughness of the PVA hydrogels were significantly improved (e.g., 6.3 times the Young’s modulus and 5.8 times the work of extension) by incorporation of IL-based polypeptides. An optimized mechanical property was achieved by incorporation of α-helical imidazolium-based polypeptides at x = 0.03. Rheological tests revealed a thermally induced transition at 51.4–58.1 °C for the double network PVA/PPLG-ImBF4-x-67 (x = 0.01, 0.02, 0.03) hydrogels due to the rupture of the electrostatic interactions. Field emission scanning electron microscopy (FESEM) and wide-angle X-ray diffraction (WAXD) results suggested that the strong and tough double-network hydrogel was constructed by PVA crystallites and ionic bonds of IL-based polypeptide as the double physical cross-linkers.

Water-soluble homopolypeptides bearing di(ethylene glycol) (DEG) linkages and various ionic liquid (IL) pendants with both lower and upper critical solution temperature (LCST and UCST) or a UCST were prepared and systematically investigated. Poly (γ-2-(2-chloroethoxy)ethyl l -glutamate) (PCEELG) with DEG linkage and reactive chloro groups can be readily prepared from ring-opening polymerization of γ-2-(2-chloroethoxy)ethyl l -glutamic acid based N-carboxyanhydride. Homopolypeptides were conjugated with various IL pendants and counteranions by nucleophilic substitutions and subsequent ion-exchange reactions. Homopolypeptide with DEG linkages and tributylphosphonium iodide (PEELG-TBP-I) showed interesting LCST

A series of glycopolypeptides with constant main-chain lengths and bearing various mannose pendants and 3-methyl-1,2,3-triazolium linkages were synthesized by N-alkylation, ion-exchange reaction, and subsequent deprotection. 1H NMR and FTIR analysis verified their molecular structures. Their solubility and thermoresponsive properties were collectively affected by polymer structure, polymer concentration, and the nature of solvent. Glycopolypeptides bearing tetra-O-acetyl-d-(+)-mannopyranoside and 3-methyl-1,2,3-triazolium chloride linkages showed a reversible upper critical solution temperature (UCST)-type phase behavior in ethanol (EtOH) with a solution phase transition temperature (T pt) in the range of 39.7–47.4 °C depending on polymer concentration. Glycopolypeptides bearing tetra-O-acetyl-d-(+)-mannopyranoside and 3-methyl-1,2,3-triazolium iodide or 3-methyl-1,2,3-triazolium tetrafluoroborate linkages showed a reversible UCST-type phase behavior in EtOH/H2O solvent mixtures. The T pt can be adjusted in the range of about 10–50 °C by polymer concentration or the weight percentage of ethanol (f w). It increased as the polymer concentration or f w increased.

Poly(γ-3-methylthiopropyl-L-glutamate) (PMTPLG) with “clickable” thioether groups can be readily prepared from n-butylamine initiated ring-opening polymerization of γ-3-methylthiopropyl-L-glutamic acid based N-carboxyanhydride (MTPLG-NCA). Polypeptides bearing sulfonium moieties and different alkyl (i.e., methyl, n-butyl, and propargyl) pendants were prepared via the alkylation of PMTPLG. They are able to show upper critical solution temperature (UCST)-type thermoresponsive properties in methanol or ethanol depending on the alkyl pendants and counter-anions. Polypeptides bearing sulfonium linkages, ammonium pendants and tetrafluoroborate (BF4−) counter-anions (PPLG-MSEA-BF4) were prepared via the copper-mediated [2 + 3] alkyne–azide 1,3-dipolar cycloaddition of polypeptides bearing sulfonium moieties and propargyl pendants, and subsequently ion-exchange reaction. They showed UCST-type thermo and pH dual responsiveness in aqueous solutions. The sharp solution phase separation of PPLG-MSEA-BF4 occurred in a very small pH range (ΔpH = 0.05) when the pH increased from 7.37 to 7.42 as suggested by dynamic light scattering (DLS). The UCST-type phase transition temperature (Tpt) of PPLG-MSEA-BF4 increased by 20 °C as the pH increased from 7.42 to 7.50 as revealed by variable-temperature UV-vis spectroscopy. Increasing polymer or NaBF4 concentrations or decreasing NaCl concentration can further increase the Tpt.

A homopolypeptide, namely poly(S-(2-carboxylethyl)-L-cysteine) (PCELC), with pH and redox dual responsiveness was prepared by ring-opening polymerization of S-(2-(methoxycarbonyl)ethyl)-L-cysteine based N-carboxyanhydride (MCELC-NCA) and subsequent hydrolysis. The pH-induced solution phase transition of PCELC was at pH = ∼4.50 as revealed by DLS and UV-vis spectroscopy. The thioether linkages of PCELC can be readily oxidized by H2O2 at 40 °C yielding PCELCox with sulfoxide and sulfone linkages as revealed by 1H NMR and FTIR. PCELCox also showed pH responsiveness with the variation of polymer aggregation sizes, but without solution phase separation. PCELCox can be partially reduced by 3-mercaptopropionic acid as suggested by 1H NMR and FTIR analysis. The pH-induced solution phase transition behavior of the reduction product (i.e., PCELCre) was different from that of the as-prepared PCELC. Moreover, PCELC can be used as a pH and oxidation dual responsive stabilizer to control the aggregation of single-walled carbon nanotubes (SWCNTs) in aqueous solution.

Polyelectrolyte complexes (PECs) are attractive soft materials with many promising applications, such as drug delivery and coatings. Study on the solution properties of α-helical polypeptide based PECs are still rare. Herein, new PECs composed of α-helical sulfonium-based polypeptides (PPBLG-DMS-I) and polysaccharides (i.e., carboxymethyldextran sodium salt, CMD) were prepared and investigated on their solution property. PPBLG-DMS-I were synthesized by an ultrafast ring-opening polymerization (ROP) and subsequent alkylation of methylthio groups with high grafting efficiency. The aggregation size of the polypeptide-polysaccharide based PECs was in the range of 450–600 nm at room temperature depending on the cationic/anionic weight ratios (RCAs) and polypeptide concentrations. It decreased by about 300 nm with increasing of the temperature by 40 °C. PEC solutions showed salt induced sharp phase transitions accompanied by the formation of coacervate droplets at low salt concentrations (e.g., 1.5 mg·mL−1). pH induced phase transitions of PEC solutions at both acidic (e.g., pH = 2.5) and basic conditions (e.g., pH = 11.5).

A series of glycopolypeptides with constant main-chain lengths and various compositions of mannose moieties and biphenyl pendants were synthesized by copper-mediated 1,3-dipolar cycloadditions. 1H NMR and Fourier transform IR (FTIR) analysis confirmed the molecular structures of the resulting polypeptides. FTIR analysis characterized the molar contents of the mannose pendants and α-helical conformations in the solid state. Glycopolypeptides conjugated with tetra-O-acetyl-d-(+)-mannopyranoside showed a reversible upper-critical-solution-temperature-type (UCST-type) phase behavior both in MeOH/H2O and EtOH/H2O binary solvent mixtures depending on the weight percentage of alcohols (fw). Incorporation of a low content of biphenyl pendants (≤0.20) can broaden the range of fw at which polymers showed UCST-type phase behaviors. The UCST-type transition temperature (Tpt) was highly related to the incorporation of biphenyl pendants, polymer concentrations, and the nature and weight percentage of alcohols. It decreased as the polymer concentration decreased and increased on incorporation of biphenyl groups. © 2016 Society of Chemical Industry

A series of OEGylated random copolypeptides with similar main-chain lengths and different oligo(ethylene glycol) (OEG) molar content and chain lengths were prepared from triethylamine initiated ring-opening polymerization (ROP) of OEGylated γ-benzyl-L-glutamic acid based N-carboxyanhydride (OEGmBLG–NCA, m = 2, 3) and γ-benzyl-L-glutamic acid based N-carboxyanhydride (BLG–NCA). 1H NMR analysis verified copolypeptides structures and determined the OEG molar content (x). FTIR analysis further confirmed the molecular structures, indicated α-helical conformations of copolypeptides in the solid-state, and revealed H-bonding interactions between OEG pendants and alcoholic solvents. The copolypeptides exhibited a reversible upper critical solution temperature (UCST)-type phase behavior in various alcoholic solvents (i.e., methanol, ethanol, 1-propanol, 1-butanol, and 1-pentanol) depending on the x values and OEG side-chain lengths (m). Variable-temperature UV–vis analysis revealed that the UCST-type transition temperatures (Tpts) of the copolypeptides in alcohols decreased as x or m value increased or as polymer concentration decreased. Tpts of copolypeptides with high x values (x ≥ 0.50) increased as the number of methylene of the alcoholic solvent increased from 3 (i.e., 1-propanol) to 5 (i.e., 1-pentanol). © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 3444–3453

A series of thermoresponsive polypeptides bearing 1-butyl, 1-hexyl, or 1-dodecyl side-chains (i.e., 6a-6c) were synthesized by copper-mediated 1,3-dipolar cycloaddition with high grafting efficiency (>95%) between side-chain “clickable” polypeptide, namely poly(γ-4-(propargoxycarbonyl)benzyl-L-glutamate) (5) and 1-azidoalkanes. 5 with different degree of polymerization (DP = 48–86) were prepared from triethylamine initiated ring-opening polymerization of γ-4-(propargoxycarbonyl)benzyl-L-glutamic acid based N-carboxyanhydride (4). 1H NMR, FTIR, and GPC results revealed the successful preparation of the resulting polypeptides. 6a-6c showed reversible UCST-type phase behaviors in methanol, ethanol, and ethanol/water solvent mixtures depending on the polymer main-chain length, alkyl side-chain length, weight percentage of ethanol (fw) in the binary solvent, and so forth. FTIR analysis revealed the presence of the van der Waals interaction between the alkyl pendants of polypeptides and alkyl groups of alcoholic solvents. Variable-temperature UV-vis spectroscopy revealed that the UCST-type phase transition temperature (Tpt) increased as polymer main-chain length or concentration increased. In ethanol/water solvent mixtures, polypeptide with short alkyl pendant (i.e., 1-butyl group) and short main-chain length (DP = 41) showed the widest fw range and Tpts in the range of 61.0–71.1 °C. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 3425–3435

In this study, a novel polymeric prodrug based on norbornene-functional polylactide with functionalized paclitaxels (LEV-PTXL) covalently conjugated to water-soluble polymer carrier via a pH-sensitive hydrazone bond was developed. A series of water-soluble PTXL prodrugs with decent drug contents of 17.3 and 24.7 wt% (denoted as PTXL prodrugs 1 and 2) were prepared. The molecular structures and characteristics were confirmed by 1H NMR, Fourier transform infrared, and gel permeation chromatography. In vitro release studies showed that PTXL release rate from polymeric prodrug were significantly accelerated under acidic medium, due to the acid-cleavable hydrazone linkage. As illustrated by cytotoxicity study, while the corresponding polymer carrier was nontoxic, the polymeric prodrug exhibited higher therapeutic efficacy toward MCF-7 and A549 (IC50 = 0.19 and 4.94 µg PTXL equiv/mL, respectively) cancer cells. The norbornene-functional polylactide-based polymeric prodrug has appeared as a novel antican...

Water-soluble random copolypeptides bearing pyridinium tetrafluoroborate (PyBF4) and oligo-ethylene glycol (OEG) pendants (PPLG-PyBF4-r-OEG) showed SO2-induced solution phase transition. They were prepared by sequential postpolymerizations including nucleophilic substitution of poly(γ-3-chloropropyl-l-glutamate) with sodium azide to partially convert chloro groups into azido groups, copper-mediated [2 + 3] alkyne–azide 1,3-dipolar cycloaddition to conjugate OEG pendants, another nucleophilic substitution to conjugate pyridinium chloride, and ion-exchange reaction. FTIR and CD analysis revealed that PPLG-PyBF4-r-OEG samples with suitable molar content of PyBF4 (x ≤ 0.4) were water-soluble and adopted α-helical conformation in both the solid-state and aqueous solution. UV–vis spectroscopy and dynamic light scattering (DLS) results revealed that PPLG-PyBF4-r-OEG aqueous solution underwent a reversible solution phase transition by sequentially bubbling SO2 and N2. 1H NMR analysis suggested that SO2 interacted...

Water-soluble thermoresponsive poly(γ-4-methylbenzyl-L-glutamate) bearing Y-shaped (i.e., oligo-ethylene-glycol and alkyl groups, such as 1-butyl, 1-hexyl, or 1-dodecyl) and triazolium tetrafluoroborate side-chains (PMBLG-OEG7/Cm-BF4, m = 4, 6, and 12) have been prepared by nucleophilic substitution of poly(γ-4-methylbenzyl-L-glutamate)-oligo-ethylene-glycol conjugates (PMBLG-OEG7) and various 1-alkyl bromide and ion-exchange reactions of triazolium bromide and NaBF4. Poly(γ-4-chloromethylbenzyl-L-glutamate) (PCMBLG) was derivatized into poly(γ-4-azidomethylbenzyl-L-glutamate) (PAMBLG), followed by reaction with propargyl functionalized polyethylene glycol monomethylether 350 (Pr-OEG7) via a copper-mediated 1,3-dipolar cycloaddition to yield PMBLG-OEG7. PMBLG-OEG7/Cm-BF4, m = 4, 6, and 12) adopted an α-helical conformation and showed lower critical solution temperature (LCST)-type phase behaviors in aqueous solutions. The cloud point temperature (Tcp) was significantly decreased with an increase in polymer concentration and salt (e.g., NaBF4) concentration. Elongating the alkyl chain length can further decrease the Tcp.

Thermoresponsive polypeptides with Y-shaped and ionic liquid (IL) pendants (PPLG-(ImX)2, X = Br, I, or BF4) were synthesized by bromination of poly(γ-allyl-L-glutamate) with bromine, nucleophilic substitution with NaN3, copper-mediated 1,3-dipolar cycloaddition, and ion-exchange reaction. FTIR and CD analyses revealed α-helical conformations in both the solid-state and aqueous solution. UV-vis spectroscopy results revealed reversible upper critical solution temperature (UCST)-type phase behaviors in methanol and water for PPLG-(ImBF4)2, and in ethanol for PPLG-(ImI)2. The UCST-type solution phase transition temperature (Tpt) of PPLG-(ImX)2 (X = I or BF4) increased with increasing of polymer concentration. The Tpt of PPLG-(ImBF4)2 increased with increasing of NaBF4 concentration, whereas it decreased with increasing of NaI or NaCl concentrations. Moreover, PPLG-(ImI)2 with a Y-shaped pendant showed a higher Tpt in ethanol than PPLG-ImI which was a traditional IL-based polypeptide with a single IL group per repeating unit, whereas PPLG-(ImBF4)2 with a Y-shaped pendant showed a lower Tpt in methanol and water than its counterpart, PPLG-ImBF4, indicating that the Tpt can be collectively adjusted by incorporation of Y-shaped pendants and counter-anions.

A series of OEGylated poly(γ-benzyl-l-glutamate) with different oligo-ethylene-glycol side-chain length, molecular weight (MW = 8.4 × 103 to 13.5 × 104) and narrow molecular weight distribution (PDI = 1.12–1.19) can be readily prepared from triethylamine initiated ring-opening polymerization of OEGylated γ-benzyl-l-glutamic acid based N-carboxyanhydride. FTIR analysis revealed that the polymers adopted α-helical conformation in the solid-state. While they showed poor solubility in water, they exhibited a reversible upper critical solution temperature (UCST)-type phase behavior in various alcoholic organic solvents (i.e., methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, and isopropanol). Variable-temperature UV–vis analysis revealed that the UCST-type transition temperatures (Tpts) of the resulting polymers were highly dependent on the type of solvent, polymer concentration, side- and main-chain length. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015

A series of side-chain-functionalized α-helical polypeptides, i.e., poly(γ-4-(3-chloropropoxycarbonyl)benzyl-L-glutamate) (6) have been prepared from n-butylamine initiated ring-opening polymerization (ROP) of γ-4-(3-chloropropoxycarbonyl)benzyl-L-glutamic acid-based N-carboxyanhydride. Polypeptides bearing oligo-ethylene-glycol (OEG) groups or 1-butylimidazolium salts were prepared from 6 via copper-mediated [2+3] alkyne-azide 1,3-dipolar cycloaddition or nuleophilic substitution, respectively. CD and FTIR analysis revealed that the polymers adopt α-helical conformations both in solution and the solid state. Polymers bearing OEG (m = 3) side-chains showed reversible LCST-type phase transition behaviors in water while polymers bearing 1-butylimidazolium and I− counter-anions exhibited reversible UCST-type transitions in water. Variable-temperature UV-vis analysis revealed that the phase transition temperatures (Tpts) were dependent on the main-chain length and polymeric concentration. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2469–2480

A series of polypeptides bearing biphenyl mesogenic side-chains and oligo-ethylene-glycol (OEG) tails (PPLG n -g-BPOEG m , n = 26 and 63, m = 2, 3, and 7) has been synthesized via a 1,3-dipolar cycloaddition with quantitative grafting density. FTIR results revealed that the polypeptides adopted highly stable α-helix in the temperature range of 25–200 °C. DSC, POM and WAXS analysis revealed that PPLG n -g-BPOEG m (m ≤ 3) samples with short OEG tail length showed two main phase transitions including crystal to liquid crystalline (smectic C, SmC) phase transition and the melting transition of crystalline E-phase, while PPLG n -g-BPOEG7 with longer OEG tail length (m = 7) exhibited the melting transitions without the formation of liquid crystalline phase.

Polypeptides bearing imidazolium and p -tolyl groups have been synthesized by click chemistry between poly(γ-3-azidopropyl- l -glutamate) (PAPLG) and 3-butyl-1-propargyl imidazolium bromide (BPIB) and 1-methyl-4-prop-2-ynyloxybenzene (MPB). The FTIR results revealed α -helical conformation of all resulting polypeptides in the solid-state. POM and WAXS study revealed that polypeptides with high p -tolyl contents (molar percentage ⩾54%) possessed nematic liquid crystalline phases and hexagonal packing in the solid-state. DSC analysis revealed the solid to liquid crystalline transitions in the temperature range of 35–42 °C.

Hyperbranched poly(aryl ether ketone)s with hydroxyl end groups (HBP-OH) and high degree of branching value (83%) were synthesized via an A2 + B3 approach. The polymerization conditions (e.g., polymerization temperature and time, monomer concentration, stoichiometric ratio of functional groups) were explored to avoid the gelation. Allyl-terminated hyperbranched PAEKs (HBP-AL) with low molecular weight (Mn = 3.4 × 103) and narrow polydispersity (PDI = 1.65) were obtained via the etherification of HBP-OH and it has been used for the modification of bismaleimide (BMI) resins. The prepolymers showed good processibilities with a viscosity below 0.6 Pa s at 110°C, though the viscosities slightly increased as the increase of HBP-AL contents. The cured BMI resins showed high glass transition temperatures (Tg > 320°C) and good thermal stabilities (Td > 400°C, both in nitrogen and air). It is inspiring to note that the incorporation of HBP-AL into BMI matrix results in a significant enhancement of toughness without any noticeable loss in modulus, processibility, and Tg. POLYM. ENG. SCI., 54:1675–1685, 2014. © 2013 Society of Plastics Engineers

A series of pyrenyl-terminated poly(γ-benzyl-l-glutamate)s (py-PBLGs) with controlled polymer molecular weight (MW = 2.3–14.8 kg mol−1) and molecular weight distribution (PDI = 1.17–1.55) have been prepared from 1-pyrenemethylamine hydrochloride-mediated ring-opening polymerization (ROP) of γ-benzyl-l-glutamic acid based N-carboxyanhydride (BLG-NCA). FTIR analysis revealed that the py-PBLG9 was conformationally heterogeneous with 35.0% α-helix, 55.6% β-sheet, and 9.4% random coil conformations in the solid state, whereas the py-PBLG66 adopts 100% α-helix conformation. Py-PBLGs promote the dispersion of SWCNTs in organic solvents and in the PBLG solid through π–π interaction, as evidenced by the Raman spectroscopic studies. WAXD analysis revealed that the SWCNTs significantly affect the ordering of the py-PBLG self-assembly: the long range hexagonal packing of py-PBLG66 rods is notably enhanced by the addition of SWCNTs, whereas the lamellar packing of py-PGLG9 β-sheets is weakened. In the hexagonal lattice, the SWCNTs are intercalated parallel to the py-PBLG66 rods, in contrast to the normal orientation of the SWCNTs with respect to the extended py-PBLG9 chains in the β-sheets. The relative packing structure also affects the intermolecular interaction among the PBLGs: SWCNTs promote the interaction among the py-PBLG9 chains packed in a lamellar structure and weaken the intermolecular interaction among the py-PBLG66 columnar hexagonal array. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4489–4497

This paper describes the steric hindrance effect on thermoresponsive behaviors of pyrrolidone-based water-soluble polymers. Two polymers, poly[N-(1-meth-2-acryloyloxyethyl)pyrrolidone] (PMEP) and poly[N-(2-acryloyloxypropyl)pyrrolidone] (PAPP) with different pyrrolidone-based side groups were synthesized via conventional free-radical polymerization. PMEP and PAPP with approximate molecular weights (MW) and polydispersities were confirmed by gel permeation chromatography. Their thermoresponsive phase transition behaviors in aqueous media were studied using dynamic light scattering (DLS) and temperature-variation 1H NMR. The cloud points of PMEP and PAPP decreased exponentially rather than linearly with the increase in concentration. PMEP exhibited a lower cloud point than PAPP at the same mass concentration. Both PMEP and PAPP showed a solvent isotopic effect, as their cloud points in deuterium oxide (D2O) were lower than those in hydrogen oxide (H2O). We also noted that the ΔCP [CPPAPP − CPPMEP] was 5.2 °C in D2O and 4.2 °C in H2O at 20.0 mg ml−1. In addition, PAPP showed more noticeable changes in proton resonance signal intensities during the temperature elevation. The differences in thermoresponsive phase transition behaviors between PMEP and PAPP resulted from the steric hindrance effect of their side groups.

Water-soluble poly(L-serine)s bearing long side-chain with terminal charge groups were synthesized via ring-opening polymerization of O-pentenyl-L-serine N-carbox- yanhydride followed by thiolene reactions. These side-chain modified poly(L-serine)s adopt β-sheet conformation in aqueous solution with excellent stability against changes in pH and temperature. These water-soluble poly(L-serine) derivatives with charged side-chain functional groups and stable β-sheet conformations showed membrane-penetrating capabilities in different cell lines with low cytotoxicity.

Single-walled carbon nanotubes (SWCNTs) have been functionalized with poly(γ-benzyl-L-glutamate)s (PBLGs) having well-defined polymer molecular weight (Mn = 7.5–21.1 kg·mol−1) and molecular weight distribution (PDI = 1.05–1.20) by a graft-to method. Toluene solutions containing 5 wt % free PBLG and variable amounts of PBLG-functionalized SWCNTs (PBLG-SWCNTs) form gels at room temperature. Differential scanning calorimetry (DSC) analysis reveals that the gelation occurs thermoreversibly, in accord with previous studies on the pristine PBLG/toluene gels. The heat of gel melting (ΔHm) is slightly elevated for the composite gels compared with the pristine gel, which suggests enhanced interactions between PBLGs in the former. But the gelation temperatures of the composites are unaffected by the presence of PBLG-SWCNTs. Small-angle X-ray scattering (SAXS) analysis of the composite and pristine gels at different temperatures by the Guinier method suggests that PBLG-SWCNTs promote interactions between PBLG rods, as indicated by the larger PBLG bundle size with increasing PBLG-SWCNT content in the gel and the melt state. W/SAXS analysis of the dry gels reveals that PBLG-SWCNTs induce significant changes in the PBLG packing order, resulting in a nematic phase, in contrast to a weakly ordered smectic C phase containing tilted PBLG rods that is observed in the pristine gel. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011

A series of core−shell molecular bottlebrushes with helical polypeptide backbone and polylactide-b-poly(ethylene glycol) block copolymer side chains [PPLG-g-(PLA-b-PEG)] have been synthesized via a grafting-to method. The structurally well-defined side chains with low molecular weight distribution (PDI < 1.03) have been synthesized by ring-opening polymerization (ROP) of dl-lactides using PEG-OH macroinitiator and AlEt3 catalyst. Postpolymerization modification by esterification enables the quantitative installation of an alkynyl functionality at the block polymer chain ends. Grafting of alkynyl-terminated PLA-b-PEG onto poly(γ-azidopropyl-l-glutamate) (PAPLG) via copper-mediated [2 + 3] alkyne−azide 1,3-dipolar cycloaddition yields the targeted molecular bottlebrushes with high grafting density under mild conditions. A combination of the Langmuir−Blodgett (LB) technique with atomic force microscopy (AFM) has allowed for direct imaging of the synthesized molecular brushes and characterization of their mol...