Tailoring the physicochemical properties of core-crosslinked polymeric micelles for pharmaceutical applications.

2016

To optimally exploit the potential of (tumor-) targeted nanomedicines, platform technologies are needed in which physicochemical and pharmaceutical properties can be tailored according to specific medical needs and applications. We here systematically customized the properties of core-crosslinked polymeric micelles (CCPM). The micelles were based on mPEG-b-pHPMAmLacn (i.e. methoxy poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate]), similar to the block copolymer composition employed in CriPec® docetaxel, which is currently in phase I clinical trials. The CCPM platform was tailored with regard to size (30 to 100 nm), nanocarrier degradation (1 month to 1 year) and drug…

Histidine-rich glycoprotein-induced vascular normalization improves EPR-mediated drug targeting to and into tumors

2018

Tumors are characterized by leaky blood vessels, and by an abnormal and heterogeneous vascular network. These pathophysiological characteristics contribute to the enhanced permeability and retention (EPR) effect, which is one of the key rationales for developing tumor-targeted drug delivery systems. Vessel abnormality and heterogeneity, however, which typically result from excessive pro-angiogenic signaling, can also hinder efficient drug delivery to and into tumors. Using histidine-rich glycoprotein (HRG) knockout and wild type mice, and HRG-overexpressing and normal t241 fibrosarcoma cells, we evaluated the effect of genetically induced and macrophage-mediated vascular normalization on th…

Macromol. Rapid Commun. 1/2015

2015

Programmable assembly of peptide amphiphile via noncovalent-to-covalent bond conversion

2017

Controlling the number of monomers in a supramolecular polymer has been a great challenge in programmable self-assembly of organic molecules. One approach has been to make use of frustrated growth of the supramolecular assembly by tuning the balance of attractive and repulsive intermolecular forces. We report here on the use of covalent bond formation among monomers, compensating for intermolecular electrostatic repulsion, as a mechanism to control the length of a supramolecular nanofiber formed by self-assembly of peptide amphiphiles. Circular dichroism spectroscopy in combination with dynamic light scattering, size-exclusion chromatography, and transmittance electron microscope analyses r…

Cover Picture: Macromol. Biosci. 10/2014

2014

Introducing PeptoPlexes: Polylysine-block-Polysarcosine Based Polyplexes for Transfection of HEK 293T Cells

2014

A series of well-defined polypeptide-polypeptoid block copolymers based on the body's own amino acids sarcosine and lysine are prepared by ring opening polymerization of N-carboxyanhydrides. Block lengths were varied between 200-300 for the shielding polysarcosine block and 20-70 for the complexing polylysine block. Dispersity indexes ranged from 1.05 to 1.18. Polylysine is polymerized with benzyloxycarbonyl as well as trifluoroacetyl protecting groups at the ϵ-amine group and optimized deprotection protocols for both groups are reported. The obtained block ionomers are used to complex pDNA resulting in the formation of polyplexes (PeptoPlexes). The PeptoPlexes can be successfully applied i…

Solution Properties of Polysarcosine: From Absolute and Relative Molar Mass Determinations to Complement Activation

2018

Polysarcosine (pSar) was one of the first polymers synthesized in a controlled living manner, but it was only recently when it was reconsidered as a promising alternative for poly(ethylene glycol) (PEG) in biomedical applications. Despite receiving more and more attention, very little is known about the solution properties of pSar, such as coil dimensions and thermodynamic interactions. In this article, we report on these properties of pSar with degrees of polymerization 50 < X-n < 400 that were prepared by controlled living ring-opening polymerization. The polymers are characterized by gel permeation chromatography (GPC), MALDI-TOF mass spectrometry, dynamic and static light scattering (SL…

PeptoSomes for Vaccination: Combining Antigen and Adjuvant in Polypept(o)ide-Based Polymersomes.

2017

In this work, the first vaccine is reported based on a PeptoSome, which contains a model antigen (SIINFEKL) and adjuvant (CpG). PeptoSomes are polypept(o)ide-based polymersomes built of a block-copolymer with polysarcosine (PSar) as the hydrophilic block (X n = 111) and poly(benzyl-glutamic acid) (PGlu(OBn)) as the hydrophobic one (X n = 46). The polypept(o)ide is obtained with low dispersity index of 1.32 by controlled ring-opening polymerization. Vesicle formation by dual centrifugation technique allows for loading of vesicles up to 40 mol%. PeptoSomes are characterized by multiangle dynamic light scattering, static light scattering, and cryogenic transmission electron microscopy (cryoTEM…

Impact of Branching on the Solution Behavior and Serum Stability of Starlike Block Copolymers.

2019

The size control of nanomedicines for tumor diagnosis and therapy is of high importance, since it enables or disables deep and sufficient tumor penetration. Amphiphilic star-shaped block copolypept(o)ides offer substantial promise to precisely adjust the hydrophobic core and the hydrophilic corona, independent of each other, and therefore simultaneously control the size dimension in the interesting size range from 10 to 30 nm. To gain access to core-shell structures of such sizes, 3-arm and 6-arm PeptoStars, based on poly(gamma-tert-butyloxycarbonyl-L-glutamate)-b-polysarcosine (pGlu(OtBu)-b-pSar), were prepared via controlled living ring-opening polymerization (ROP) of the corresponding N-…

Back Cover: Macromol. Biosci. 1/2015

2015

The Influence of Block Ionomer Microstructure on Polyplex Properties: Can Simulations Help to Understand Differences in Transfection Efficiency?

2017

Gene therapies enable therapeutic interventions at gene transcription and translation level, providing enormous potential to improve standards of care for multiple diseases. Nonviral transfection agents and in particular polyplexes based on block ionomers are-besides viral vectors and cationic lipid formulations-among the most promising systems for this purpose. Block ionomers combine a hydrophilic noncharged block, e.g., polyethylene glycol (PEG), with a hydrophilic cationic block. For efficient transfection, however, endosomolytic moieties, e.g., imidazoles, are additionally required to facilitate endosomal escape, which raises the general question how to distribute these functionalities …

Photocleavable core cross-linked polymeric micelles of polypept(o)ides and ruthenium(II) complexes

2021

Core cross-linking of polymeric micelles has been demonstrated to contribute to enhanced stability that can improve the therapeutic efficacy. Photochemistry has the potential to provide spatial resolution and on-demand drug release. In this study, light-sensitive polypyridyl-ruthenium(II) complexes were combined with polypept(o)ides for photocleavable core cross-linked polymeric micelles. Block copolymers of polysarcosine-block-poly(glutamic acid) were synthesized by ring-opening N-carboxyanhydride polymerization and modified with aromatic nitrile-groups on the glutamic acid side chain. The modified copolymers self-assembled into micelles and were cross-linked by cis-diaquabis(2,2'-bipyridi…

Secondary Structure-Driven Self-Assembly of Thiol-Reactive Polypept(o)ides

2021

Secondary structure formation differentiates polypeptides from most of the other synthetic polymers, and the transitions from random coils to rod-like α-helices or β-sheets represent an additional parameter to direct self-assembly and the morphology of nanostructures. We investigated the influence of distinct secondary structures on the self-assembly of reactive amphiphilic polypept(o)ides. The individual morphologies can be preserved by core cross-linking via chemoselective disulfide bond formation. A series of thiol-responsive copolymers of racemic polysarcosine-block-poly(S-ethylsulfonyl-dl-cysteine) (pSar-b-p(dl)Cys), enantiopure polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) (pSa…

Investigation of α-amino acid N-carboxyanhydrides by X-ray diffraction for controlled ring-opening polymerization

2019

Abstract The need for a scalable synthesis of not sequence defined polypeptides as biomaterials is met by the ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs). Even though this polymerization technique appears straight forward, it holds pitfalls in terms of reproducibility and overall control over the polymerization conditions, which depends, beside choice of solvent or initiator, significantly on reagent purity. In addition, the synthesis of monomers can lead to the formation of racemic amino acids. Thus, in this work, we describe the benefits of highly pure monomers in order to control nucleophilic ring-opening polymerization NCAs. Hereby, monomer purity is investiga…

Synthesis and Characterization of Stimuli-Responsive Star-Like Polypept(o)ides: Introducing Biodegradable PeptoStars

2017

tar-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 polymerizat…

Polysarcosine-functionalized lipid nanoparticles for therapeutic mRNA delivery

2020

Polysarcosine (pSar) is a polypeptoid based on the endogenous amino acid sarcosine (N-methylated glycine), which has previously shown potent stealth properties. Here, lipid nanoparticles (LNPs) for therapeutic application of messenger RNA were assembled using pSarcosinylated lipids as a tool for particle engineering. Using pSar lipids with different polymeric chain lengths and molar fractions enabled the control of the physicochemical characteristics of the LNPs, such as particle size, morphology, and internal structure. In combination with a suited ionizable lipid, LNPs were assembled, which displayed high RNA transfection potency with an improved safety profile after intravenous injection…

A head-to-head comparison of poly(sarcosine) and poly(ethylene glycol) in peptidic, amphiphilic block copolymers

2015

Abstract 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, X n  = 100 and 200) and PEG (X n  = 121 and 242) of comparable hydrodynamic volume were used to initiate the ring opening polymerization of α-amino acid- N -carboxyanhydrides based on ɣ-benzyl- l -glutamate (Glu(OBn)) or e-carboxybenzyl- l -lysine (Lys(Z)). The second, hydrophobic block was kept at a degree of polymerization of 25 and 50 to enable a direct compar…

Synthesis of Amphiphilic Block Copolypept(o)ides by Bifunctional Initiators: Making PeptoMicelles Redox Sensitive.

2015

In this work, the synthesis of polypeptoid-block-polypeptide copolymers (block copolypept(o)ides) based on bifunctional initiators is described, which introduces a distinct chemical entity at the connection between both blocks. With a view towards redox-sensitive block copolypept(o)ides, a cystamine-based initiator was used to synthesize polysarcosine macroinitiators with degrees of polymerization (Xn) between 100 and 200 displaying monomodal molecular weight distributions and dispersities (Đ) around 1.1 as determined by size exclusion chromatography. Block copolypept(o)ides with a poly(γ-t-butyloxycarbonyl-L-glutamate) (PGlu(O(t) Bu)) block (Xn = 25 or 50) were synthesized by controlled N-…

Polysarcosine-Based Lipids: From Lipopolypeptoid Micelles to Stealth-Like Lipids in Langmuir Blodgett Monolayers.

2016

Amphiphiles and, in particular, PEGylated lipids or alkyl ethers represent an important class of non-ionic surfactants and have become key ingredients for long-circulating (“stealth”) liposomes. While poly-(ethylene glycol) (PEG) can be considered the gold standard for stealth-like materials, it is known to be neither a bio-based nor biodegradable material. In contrast to PEG, polysarcosine (PSar) is based on the endogenous amino acid sarcosine (N-methylated glycine), but has also demonstrated stealth-like properties in vitro, as well as in vivo. In this respect, we report on the synthesis and characterization of polysarcosine based lipids with C14 and C18 hydrocarbon chains and their end g…

Multifunctional Cationic PeptoStars as siRNA Carrier: Influence of Architecture and Histidine Modification on Knockdown Potential.

2019

RNA interference provides enormous potential for the treatment of several diseases, including cancer. Nevertheless, successful therapies based on siRNA require overcoming various challenges, such as poor pharmacokinetic characteristics of the small RNA molecule and inefficient cytosolic accumulation. In this respect, the development of functional siRNA carrier systems is a major task in biomedical research. To provide such a desired system, the synthesis of 3-arm and 6-arm PeptoStars is aimed for. The different branched polypept(o)idic architectures share a stealth-like polysarcosine corona for efficient shielding and a multifunctional polylysine core, which can be independently varied in s…

Directed Interactions of Block Copolypept(o)ides with Mannose-binding Receptors: PeptoMicelles Targeted to Cells of the Innate Immune System

2015

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 ce…

Synthesis and Sequential Deprotection of Triblock Copolypept(o)ides Using Orthogonal Protective Group Chemistry

2014

The synthesis of triblock copolymers based on polysarcosine, poly-N-ε-t-butyloxycarbonyl-l-lysine, and poly-N-ε-t-trifluoroacetyl-l-lysine by ring-opening polymerization of the corresponding α-amino acid N-carboxyanhydrides (NCAs) is described. For the synthesis of N-ε-t-butyloxycarbonyl-l-lysine (lysine(Boc)) NCAs, an acid-free method using trimethylsilylchloride/triethylamine as hydrochloric acid (HCl) scavengers is presented. This approach enables the synthesis of lysine(Boc) NCA of high purity (melting point 138.3 °C) in high yields. For triblock copolypept(o)ides, the degree of polymerization (Xn ) of the polysarcosine block is varied between 200 and 600; poly-N-ε-t-butyloxycarbonyl-l-…

Combining reactive triblock copolymers with functional cross-linkers: A versatile pathway to disulfide stabilized-polyplex libraries and their applic…

2017

Therapeutic nucleic acids such as pDNA hold great promise for the treatment of multiple diseases. These therapeutic interventions are, however, compromised by the lack of efficient and safe non-viral delivery systems, which guarantee stability during blood circulation together with high transfection efficiency. To provide these desired properties within one system, we propose the use of reactive triblock copolypept(o)ides, which include a stealth-like block for efficient shielding, a hydrophobic block based on reactive disulfides for cross-linking and a cationic block for complexation of pDNA. After the complexation step, bifunctional cross-linkers can be employed to bio-reversibly stabiliz…

CCDC 1874607: Experimental Crystal Structure Determination

2019

Related Article: Olga Schäfer, Dieter Schollmeyer, Alexander Birke, Regina Holm, Kerstin Johann, Christian Muhl, Christine Seidl, Benjamin Weber, Matthias Barz|2019|Tetrahedron Lett.|60|272|doi:10.1016/j.tetlet.2018.12.028

CCDC 1874606: Experimental Crystal Structure Determination

2019

Related Article: Olga Schäfer, Dieter Schollmeyer, Alexander Birke, Regina Holm, Kerstin Johann, Christian Muhl, Christine Seidl, Benjamin Weber, Matthias Barz|2019|Tetrahedron Lett.|60|272|doi:10.1016/j.tetlet.2018.12.028

CCDC 1874603: Experimental Crystal Structure Determination

2019

Related Article: Olga Schäfer, Dieter Schollmeyer, Alexander Birke, Regina Holm, Kerstin Johann, Christian Muhl, Christine Seidl, Benjamin Weber, Matthias Barz|2019|Tetrahedron Lett.|60|272|doi:10.1016/j.tetlet.2018.12.028

CCDC 1874604: Experimental Crystal Structure Determination

2019

Related Article: Olga Schäfer, Dieter Schollmeyer, Alexander Birke, Regina Holm, Kerstin Johann, Christian Muhl, Christine Seidl, Benjamin Weber, Matthias Barz|2019|Tetrahedron Lett.|60|272|doi:10.1016/j.tetlet.2018.12.028