- Poly(Sarcosine) Surface Modification Imparts Stealth-Like Properties to Liposomes
-
Circulation lifetime is a crucial parameter for a successful therapy with nanoparticles. Reduction and alteration of opsonization profiles by surface modification of nanoparticles is the main strategy to achieve this objective. In clinical settings, PEGylation is the most relevant strategy to enhance blood circulation, yet it has drawbacks, including hypersensitivity reactions in some patients treated with PEGylated nanoparticles, which fuel the search for alternative strategies. In this work, lipopolysarcosine derivatives (BA-pSar, bisalkyl polysarcosine) with precise chain lengths and low polydispersity indices are synthesized, characterized, and incorporated into the bilayer of preformed liposomes via a post insertion technique. Successful incorporation of BA-pSar can be realized in a clinically relevant liposomal formulation. Furthermore, BA-pSar provides excellent surface charge shielding potential for charged liposomes and renders their surface neutral. Pharmacokinetic investigations in a zebrafish model show enhanced circulation properties and reduction in macrophage recognition, matching the behavior of PEGylated liposomes. Moreover, complement activation, which is a key factor in hypersensitivity reactions caused by PEGylated liposomes, can be reduced by modifying the surface of liposomes with an acetylated BA-pSar derivative. Hence, this study presents an alternative surface modification strategy with similar benefits as the established PEGylation of nanoparticles, but with the potential of reducing its drawbacks.
- Bleher, Stefan,Buck, Jonas,Muhl, Christian,Sieber, Sandro,Barnert, Sabine,Witzigmann, Dominik,Huwyler, J?rg,Barz, Matthias,Süss, Regine
-
-
Read Online
- Mapping the supramolecular assembly space of poly(sarcosine)-: B-poly(propylene sulfide) using a combinatorial copolymer library
-
A combinatorial copolymer library was created to rapidly screen the landscape of self-assembled nanostructure morphologies formed by block copolymers composed of hydrophilic peptoid polysarcosine (PSarc) and hydrophobic poly(propylene sulfide) (PPS) block
- Frey, Molly,Vincent, Michael,Bobbala, Sharan,Burt, Rajan,Scott, Evan,Scott, Evan
-
-
Read Online
- Thermo-Induced Aggregation and Crystallization of Block Copolypeptoids in Water
-
Block copolypeptoids comprising a thermosensitive, crystallizable poly(N-(n-propyl)glycine) block and a water-soluble poly(N-methylglycine) block, P70My (y = 23, 42, 76, 153, and 290), were synthesized by ring-opening polymerization of the corresponding N-alkylglycine N-carboxyanhydrides (NCAs) and examined according to their thermo-induced aggregation and crystallization in water by turbidimetry, micro-differential scanning calorimetry (micro-DSC), cryogenic scanning electron microscopy (cryo-SEM), analytical ultracentrifugation (AUC), and static light scattering (SLS). At a temperature above the cloud point temperature, the initially formed micellar aggregates started to crystallize and grow into larger complex assemblies of about 100-500 nm, exhibiting flower-like (P70M23), ellipsoidal (P70M42 and P70M72), or irregular shapes (P70M153 and P70M290).
- Secker, Christian,V?lkel, Antje,Tiersch, Brigitte,Koetz, Joachim,Schlaad, Helmut
-
-
Read Online
- Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones
-
Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against Clostridioides difficile, a bacterium responsible for nosocomial infections.
- Salas-Ambrosio, Pedro,Tronnet, Antoine,Since, Marc,Bourgeade-Delmas, Sandra,Stigliani, Jean-Luc,Vax, Amelie,Lecommandoux, Sébastien,Dupuy, Bruno,Verhaeghe, Pierre,Bonduelle, Colin
-
supporting information
p. 3697 - 3702
(2021/04/07)
-
- Alkali-metal hexamethyldisilazide initiated polymerization on alpha-amino acid N-substituted N-carboxyanhydrides for facile polypeptoid synthesis
-
Polypeptoids have been explored as mimics of polypeptides, owing to polypeptoids’ superior stability upon proteolysis. Polypeptoids can be synthesized from one-pot ring-opening polymerization of amino acid N-substituted N-carboxyanhydrides (NNCAs). However, the speed of polymerization of NNCAs can be very slow, especially for NNCAs bearing a bulky N-substitution group. This hindered the exploration on polypeptoids with more diverse structures and functions. Therefore, it is in great need to develop advanced strategies that can accelerate the polymerization on inactive NNCAs. Hereby, we report that lithium/sodium/potassium hexamethyldisilazide (Li/Na/KHMDS) initiates a substantially faster polymerization on NNCAs than do commonly used amine initiators, especially for NNCAs with bulky N-substitution group. This fast NNCA polymerization will increase the structure diversity and application of polypeptoids as synthetic mimics of polypeptides.
- Wu, Yueming,Zhou, Min,Chen, Kang,Chen, Sheng,Xiao, Ximian,Ji, Zhemin,Zou, Jingcheng,Liu, Runhui
-
supporting information
p. 1675 - 1678
(2021/03/15)
-
- Superfast and Water-Insensitive Polymerization on α-Amino Acid N-Carboxyanhydrides to Prepare Polypeptides Using Tetraalkylammonium Carboxylate as the Initiator
-
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
-
supporting information
p. 26063 - 26071
(2021/11/12)
-
- METHOD FOR PRODUCING AMINO ACID-N-CARBOXYLIC ACID ANHYDRIDE
-
PROBLEM TO BE SOLVED: To provide: a method for safely and efficiently producing amino acid-N-carboxylic acid anhydride; and a method for producing peptide by using the obtained amino acid-N-carboxylic acid anhydride. SOLUTION: The method for producing an amino acid-N-carboxylic acid anhydride according to the present invention is characterized in that the amino acid-N-carboxylic acid anhydride is represented by the following formula (II), and a step of irradiating a composition containing a halogenated methane and an amino acid compound represented by the following formula (I) with high energy light in the presence of oxygen is included. [In the formula, R1 represents an amino acid side chain group in which the reactive group is protected, and R2 represents H or the like.]. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
- -
-
Paragraph 0084
(2020/08/07)
-
- POLYPEPT(O)ID-BASED GRAFT COPOLYMERS FOR IN VIVO IMAGING BY TETRAZINE TRANSCYCLOOCTENE CLICK CHEMISTRY
-
There is provided novel polypeptide-based carrier systems, which make it possible to label polymeric nanoparticles in the living organism. This enables new approaches in tumor diagnostics (high signal to background ratio) and radiotherapy (radiotherapy of solid tumors). The polypeptide-based carrier system comprises a polypept(o)idic comb (graft) copolymer, and one or more tetrazine bioorthogonal functional groups each linked to a diagnostic agent.
- -
-
Page/Page column 8-9
(2020/01/24)
-
- METHOD OF SYNTHESIZING N-CARBOXYANHYDRIDE USING FLOW REACTOR
-
PROBLEM TO BE SOLVED: To provide a synthesis method that allows high-yield continuous production of a compound of interest in synthesis and production of N-carboxyanhydride (NCA) and the like using a flow reactor. SOLUTION: In a synthesis method using a flow reactor 100, a basic solution adjusted in advance to a pH of 7-14 becomes acidic with a pH of 0-7, or an acidic solution adjusted in advance to a pH of 0-7 becomes basic with a pH of 7-14, within 60 seconds after the start of mixture of at least two ingredient solutions. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2020,JPOandINPIT
- -
-
Paragraph 0092-0096; 0113-0114
(2020/03/26)
-
- SURFACE-MODIFIED POLYMERIC SUBSTRATES GRAFTED WITH A PROPERTIES-IMPARTING COMPOUND USING CLIP CHEMISTRY
-
The present invention relates to an efficient method for grafting a properties-imparting compound onto a polymeric substrate containing carbon-hydrogen (C—H) bonds using clip chemistry. The method of the invention includes coating the substrate with the properties-imparting compound and irradiating it with a reactive light source, and repeating this sequence at least once. The present invention further relates to surface-modified polymeric substrates grafted with a properties-imparting compound, in particular obtained with the method of the invention, medical devices comprising same, and non-medical of said surface-modified polymeric substrates.
- -
-
Paragraph 0358-0359
(2019/08/27)
-
- Poly(sarcosine)-Based Nano-Objects with Multi-Protease Resistance by Aqueous Photoinitiated Polymerization-Induced Self-Assembly (Photo-PISA)
-
Poly(sarcosine) (PSar) is a non-ionic hydrophilic polypeptoid with numerous biologically relevant properties, making it an appealing candidate for the development of amphiphilic block copolymer nanostructures. In this work, the fabrication of poly(sarcosine)-based diblock copolymer nano-objects with various morphologies via aqueous reversible addition-fragmentation chain-transfer (RAFT)-mediated photoinitiated polymerization-induced self-assembly (photo-PISA) is reported. Poly(sarcosine) was first synthesized via ring-opening polymerization (ROP) of sarcosine N-carboxyanhydride, using high-vacuum techniques. A small molecule chain transfer agent (CTA) was then coupled to the active ω-amino chain end of the telechelic polymer for the synthesis of a poly(sarcosine)-based macro-CTA. Controlled chain-extensions of a commercially available water-miscible methacrylate monomer (2-hydroxypropyl methacrylate) were achieved via photo-PISA under mild reaction conditions, using PSar macro-CTA. Upon varying the degree of polymerization and concentration of the core-forming monomer, morphologies evolving from spherical micelles to worm-like micelles and vesicles were accessed, as determined by dynamic light scattering and transmission electron microscopy, resulting in the construction of a detailed phase diagram. The resistance of both colloidally stable empty vesicles and enzyme-loaded nanoreactors against degradation by a series of proteases was finally assessed. Overall, our findings underline the potential of poly(sarcosine) as an alternative corona-forming polymer to poly(ethylene glycol)-based analogues of PISA assemblies for use in various pharmaceutical and biomedical applications.
- Varlas, Spyridon,Georgiou, Panagiotis G.,Bilalis, Panayiotis,Jones, Joseph R.,Hadjichristidis, Nikos,O'Reilly, Rachel K.
-
p. 4453 - 4462
(2018/11/23)
-
- Rapid and Mild Synthesis of Amino Acid N-Carboxy Anhydrides: Basic-to-Acidic Flash Switching in a Microflow Reactor
-
Polymerization of N-carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid-labile substrates unusable and results in an undesired ring opening of NCAs. Basic-to-acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid-labile functional groups. The basic-to-acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid-labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods.
- Otake, Yuma,Nakamura, Hiroyuki,Fuse, Shinichiro
-
supporting information
p. 11389 - 11393
(2018/08/28)
-
- Synthesis and Characterization of Stimuli-Responsive Star-Like Polypept(o)ides: Introducing Biodegradable PeptoStars
-
Star-like polymers are one of the smallest systems in the class of core crosslinked polymeric nanoparticles. This article reports on a versatile, straightforward synthesis of three-arm star-like polypept(o)ide (polysarcosine-block-polylysine) polymers, which are designed to be either stable or degradable at elevated levels of glutathione. Polypept(o)ides are a recently introduced class of polymers combining the stealth-like properties of the polypeptoid polysarcosine with the functionality of polypeptides, thus enabling the synthesis of materials completely based on endogenous amino acids. The star-like homo and block copolymers are synthesized by living nucleophilic ring opening polymerization of the corresponding N-carboxyanhydrides (NCAs) yielding polymeric stars with precise control over the degree of polymerization (Xn = 25, 50, 100), Poisson-like molecular weight distributions, and low dispersities (? = 1.06–1.15). Star-like polypept(o)ides display a hydrodynamic radius of 5 nm (μ2 –3m glutathione concentration. The disulfide cleavage yields the respective polymeric arms, which possess Poisson-like molecular weight distributions and low dispersities (? = 1.05–1.12). Initial cellular uptake and toxicity studies reveal that PeptoStars are well tolerated by HeLa, HEK 293, and DC 2.4 cells. (Figure presented.).
- Holm, Regina,Weber, Benjamin,Heller, Philipp,Klinker, Kristina,Westmeier, Dana,Docter, Dominic,Stauber, Roland H.,Barz, Matthias
-
-
- Secondary-Structure-Driven Self-Assembly of Reactive Polypept(o)ides: Controlling Size, Shape, and Function of Core Cross-Linked Nanostructures
-
Achieving precise control over the morphology and function of polymeric nanostructures during self-assembly remains a challenge in materials as well as biomedical science, especially when independent control over particle properties is desired. Herein, we report on nanostructures derived from amphiphilic block copolypept(o)ides by secondary-structure-directed self-assembly, presenting a strategy to adjust core polarity and function separately from particle preparation in a bioreversible manner. The peptide-inherent process of secondary-structure formation allows for the synthesis of spherical and worm-like core-cross-linked architectures from the same block copolymer, introducing a simple yet powerful approach to versatile peptide-based core–shell nanostructures.
- Klinker, Kristina,Sch?fer, Olga,Huesmann, David,Bauer, Tobias,Capel?a, Leon,Braun, Lydia,Stergiou, Natascha,Schinnerer, Meike,Dirisala, Anjaneyulu,Miyata, Kanjiro,Osada, Kensuke,Cabral, Horacio,Kataoka, Kazunori,Barz, Matthias
-
supporting information
p. 9608 - 9613
(2017/08/01)
-
- Multidentate polysarcosine-based ligands for water-soluble quantum dots
-
We describe the synthesis of heterotelechelic polysarcosine polymers and their use as multidentate ligands in the preparation of stable water-soluble quantum dots (QDs). Orthogonally functionalized polysarcosine with amine and dibenzocyclooctyl (DBCO) end groups is obtained by ring-opening polymerization of N-methylglycine N-carboxyanhydride with DBCO amine as initiator. In a first postpolymerization modification step, the future biological activity of the polymeric ligands is adjusted by modification of the amine terminus. Then, in a second postpolymerization modification step, azide functionalized di- and tridentate anchor compounds are introduced to the DBCO terminus of the polysarcosine via strain-promoted azide-alkyne cycloaddition (SPAAC). Through the separate synthesis of the anchor compounds, it is possible to ensure reproducible introduction of a well-defined number of multiple anchor groups to all polymers studied. Finally, the obtained multidentate polymeric ligands are successfully used in the ligand exchange procedures to yield stable, water-soluble QDs. As polysarcosine-based ligands can provide biocompatibility, prevent nonspecific interactions, and simultaneously enable specific targeting, the systems presented here are promising candidates to provide QDs well suitable for ex vivo analytics or bioimaging.
- Fokina, Ana,Klinker, Kristina,Braun, Lydia,Jeong, Byeong Guk,Bae, Wan Ki,Barz, Matthias,Zentel, Rudolf
-
p. 3663 - 3671
(2016/06/09)
-
- Directed interactions of block copolypept(o) ides with mannose-binding receptors: Peptomicelles targeted to cells of the innate immune system
-
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
-
-
- A head-to-head comparison of poly(sarcosine) and poly(ethylene glycol) in peptidic, amphiphilic block copolymers
-
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
-
p. 240 - 248
(2015/05/27)
-
- Polypeptoid-block-polypeptide copolymers: Synthesis, characterization, and application of amphiphilic block copolypept(o)ides in drug formulations and miniemulsion techniques
-
We report the synthesis of polysarcosine-blockpolyglutamic acid benzylester (PSar-block-PGlu(OBn)) and polysarcosine-block-polylysine-ε-N- benzyloxycarbonyl (PSarblock-PLys(Z)) copolymers. The novel polypeptoid- blockpolypeptide copolymers (Copolypept(o)ides) have been synthesized by ring-opening polymerization (ROP) of Ncarboxyanhydrides (NCAs). Polymerization conditions were optimized regarding protecting groups, block sequence and length. While the degree of polymerization of the PSar block length was set to be around 200 or 400, PGlu(OBn) and PLys(Z) block lengths were varied between 20 to 75. The obtained block copolymers had a total degree of polymerization of 220.475 and dispersity indices between 1.1 and 1.2. Having ensured a nontoxic behavior up to a concentration of 3 mg/mL in HEK293 cells, the novel block copolymers have been applied to the synthesis of organic colloids (by miniemulsion polymerization and miniemulsion solvent evaporation process). Colloids of around 100 nm (miniemulsion polymerization) to 200 nm (miniemulsion process) have been prepared. Additionally, PSar-block-PGlu(OBn) copolymers have been used in a drug formulation of an adenylate cyclase inhibitor. Micelles of 28.0 nm (without drug) and 33.0 nm (with drug) diameter have been observed by fluorescence correlation spectroscopy (FCS). The polypeptoid-block-polypeptide formulation increased solubility of the drug and enhances its bioavailability, which leads to a reduction of intracellular cAMP levels in MaMel 91 melanoma cells.
- Birke, Alexander,Huesmann, David,Kelsch, Annette,Weilbaecher, Martin,Xie, Jing,Bros, Matthias,Bopp, Tobias,Becker, Christian,Landfester, Katharina,Barz, Matthias
-
p. 548 - 557
(2014/04/03)
-
- Polypeptoids from n-substituted glycine n-carboxyanhydrides: Hydrophilic, hydrophobic, and amphiphilic polymers with poisson distribution
-
Preparation of defined and functional polymers has been one of the hottest topics in polymer science and drug delivery in the recent decade. Also, research on (bio)degradable polymers gains more and more interest, in particular at the interface of these t
- Fetsch, Corinna,Grossmann, Arlett,Holz, Lisa,Nawroth, Jonas F.,Luxenhofer, Robert
-
experimental part
p. 6746 - 6758
(2012/03/10)
-
- Cyclic poly(α-peptoid)s and their block copolymers from N-heterocyclic carbene-mediated ring-opening polymerizations of N-substituted N-carboxylanhydrides
-
(Chemical Equation Presented) N-Heterocyclic carbene (NHC)-mediated ring-opening polymerization (ROP) of N-substituted N-carboxylanhydride ( NR-NCA) yields cyclic poly(4-peptoid)s with controlled molecular weights (Mn = 3-30 kg mol-1) and narrow molecular weight distributions (PDI = 1.04-1.12). The reactions exhibit characteristics of a living polymerization with minimal chain transfer. This enables the facile synthesis of cyclic diblock copoly(4-peptoid)s through sequential monomer addition. The cyclic polymer architectures were verified by MALDI-TOF mass spectrometry and intrinsic viscosity measurements. Mark-Houwink-Sakurada plot analyses revealed that cyclic poly(4-peptoid)s prepared from NHC-mediated polymerizations exhibit lower intrinsic viscosities than their linear analogues prepared from primary amine-initiated polymerizations. The ratio of their intrinsic viscosities is consistent with the former being mostly cyclic.
- Li, Guo,Donghui, Zhang
-
supporting information; experimental part
p. 18072 - 18074
(2010/03/25)
-
- New routes to 1,4-benzodiazepin-2,5-diones
-
1,4-benzodiazepin-2,5-diones have been synthesized in good overall yields by two routes, the first one by cyclisation of dipeptides prepared from Boc anthranilic acid and α-amino acid methyl esters, the second one by reaction of N-carboxy α-amino acid anhydrides with Boc anthranilic acid.
- Akssira,Boumzebra,Kasmi,Dahdouh,Roumestant,Viallefont
-
p. 9051 - 9060
(2007/10/02)
-
