Publications by authors named "Matthias Barz"

75 Publications

Precision Wormlike Nanoadjuvant Governs Potency of Vaccination.

Nano Lett 2021 09 30;21(17):7236-7243. Epub 2021 Aug 30.

School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, China.

It remains unclear how the precise length of one-dimensional nanovehicles influences the characters of vaccination. Here, a unimolecular nanovehicle with tailored size and aspect ratio (AR) is applied to deliver CpG oligodeoxynucleotide, a Toll-like receptor (TLR) 9 agonist, as an adjuvant of recombinant hepatitis B virus surface antigen (rHBsAg), for treating chronic hepatitis B (CHB). Cationic nanovehicles with fixed width (ca. 45 nm) but varied length (46 nm-180 nm), AR from 1 to 4, are prepared through controlled polymerization and are loaded with CpG by electrostatic interaction. We reveal that the nanoadjuvant with AR = 2 shows the highest retention in proximal lymph nodes. Importantly, it is more easily internalized into antigen-presenting cells and accumulates in the late endosome, where TLR9 is located. Such a nanoadjuvant exhibits the strongest immune response with rHBsAg to clear the hepatitis B virus in the CHB mouse model, showing that the AR of nanovehicles governs the efficiency of vaccination.
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http://dx.doi.org/10.1021/acs.nanolett.1c02274DOI Listing
September 2021

Density of Conjugated Antibody Determines the Extent of Fc Receptor Dependent Capture of Nanoparticles by Liver Sinusoidal Endothelial Cells.

ACS Nano 2021 Aug 25. Epub 2021 Aug 25.

Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.

Despite considerable progress in the design of multifunctionalized nanoparticles (NPs) that selectively target specific cell types, their systemic application often results in unwanted liver accumulation. The exact mechanisms for this general observation are still unclear. Here we asked whether the number of cell-targeting antibodies per NP determines the extent of NP liver accumulation and also addressed the mechanisms by which antibody-coated NPs are retained in the liver. We used polysarcosine-based peptobrushes (PBs), which in an unmodified form remain in the circulation for >24 h due to the absence of a protein corona formation and low unspecific cell binding, and conjugated them with specific average numbers (2, 6, and 12) of antibodies specific for the dendritic cell (DC) surface receptor, DEC205. We assessed the time-dependent biodistribution of PB-antibody conjugates by imaging and flow cytometry. We observed that PB-antibody conjugates were trapped in the liver and that the extent of liver accumulation strongly increased with the number of attached antibodies. PB-antibody conjugates were selectively captured in the liver Fc receptors (FcR) on liver sinusoidal endothelial cells, since systemic administration of FcR-blocking agents or the use of F(ab') fragments prevented liver accumulation. Cumulatively, our study demonstrates that liver endothelial cells play a yet scarcely acknowledged role in liver entrapment of antibody-coated NPs and that low antibody numbers on NPs and the use of F(ab') antibody fragments are both sufficient for cell type-specific targeting of secondary lymphoid organs and necessary to minimize unwanted liver accumulation.
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http://dx.doi.org/10.1021/acsnano.1c05713DOI Listing
August 2021

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

J Mater Chem B 2021 Aug 10. Epub 2021 Aug 10.

Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands. and Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.

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'-bipyridine)-ruthenium(ii) ([Ru(bpy)2(H2O)2]2+) or cis-diaquabis(2,2'-biquinoline)-ruthenium(ii) ([Ru(biq)2(H2O)2]2+). Depending on the flexibility and hydrophobicity of the nitrile linker, either small spherical structures (Dh 45 nm, PDI 0.11) or worm-like micelles were obtained. The cross-linking reaction did not affect the overall size distribution but induced a change in the metal-to-ligand charge transfer peak from 482 to 420 nm and 592 to 548 nm. The cross-linked micelles displayed colloidal stability after incubation with human blood plasma and during gel permeation chromatography in hexafluoroisopropanol. Light-induced cleavage of [Ru(bpy)2(H2O)2]2+ was accomplished within 300 s, while [Ru(biq)2(H2O)2]2+ could not be completely released. Analysis in HuH-7 cells revealed increased cytotoxicity via micellar delivery of [Ru(bpy)2(H2O)2]2+ but mostly irradiation damage for [Ru(biq)2(H2O)2]2+. Further evaluation in ovo confirmed stable circulation pointing towards the future development of quick-release complexes.
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http://dx.doi.org/10.1039/d1tb01336jDOI Listing
August 2021

Core Cross-Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages.

Adv Healthc Mater 2021 Jun 16:e2100385. Epub 2021 Jun 16.

Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, Leiden, 2333CC, The Netherlands.

Iron is an essential co-factor for cellular processes. In the immune system, it can activate macrophages and represents a potential therapeutic for various diseases. To specifically deliver iron to macrophages, iron oxide nanoparticles are embedded in polymeric micelles of reactive polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine). Upon surface functionalization via dihydrolipoic acid, iron oxide cores act as crosslinker themselves and undergo chemoselective disulfide bond formation with the surrounding poly(S-ethylsulfonyl-l-cysteine) block, yielding glutathione-responsive core cross-linked polymeric micelles (CCPMs). When applied to primary murine and human macrophages, these nanoparticles display preferential uptake, sustained intracellular iron release, and induce a strong inflammatory response. This response is also demonstrated in vivo when nanoparticles are intratracheally administered to wild-type C57Bl/6N mice. Most importantly, the controlled release concept to deliver iron oxide in redox-responsive CCPMs induces significantly stronger macrophage activation than any other iron source at identical iron levels (e.g., Feraheme), directing to a new class of immune therapeutics.
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http://dx.doi.org/10.1002/adhm.202100385DOI Listing
June 2021

Delivery of siHIF-1α to Reconstruct Tumor Normoxic Microenvironment for Effective Chemotherapeutic and Photodynamic Anticancer Treatments.

Small 2021 06 25;17(25):e2100609. Epub 2021 May 25.

National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.

The tumor hypoxic microenvironment not only induces genetic and epigenetic changes in tumor cells, immature vessels formation for oxygen demand, but also compromises the efficiency of therapeutic interventions. On the other hand, conventional therapeutic approaches which kill tumor cells or destroy tumor blood vessels to block nutrition and oxygen supply usually facilitate even harsher microenvironment. Thus, simultaneously relieving the strained response of tumor cells and blood vessels represents a promising strategy to reverse the adverse tumor hypoxic microenvironment. In the present study, an integrated amphiphilic system (RSCD) is designed based on Angiotensin II receptor blocker candesartan for siRNA delivery against the hypoxia-inducible factor-1 alpha (HIF-1α), aiming at both vascular and cellular "relaxation" to reconstruct a tumor normoxic microenvironment. Both in vitro and in vivo studies have confirmed that the hypoxia-inducible HIF-1α expression is down-regulated by 70% and vascular growth is inhibited by 60%. The "relaxation" therapy enables neovascularization with more complete and organized structures to obviously increase the oxygen level inside tumor, which results in a 50% growth inhibition. Moreover, reconstruction of tumor microenvironment enhances tumor-targeted drug delivery, and significantly improves the chemotherapeutic and photodynamic anticancer treatments.
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http://dx.doi.org/10.1002/smll.202100609DOI Listing
June 2021

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

Biomacromolecules 2021 05 8;22(5):2171-2180. Epub 2021 Apr 8.

Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.

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--poly(-ethylsulfonyl-dl-cysteine) (pSar--p(dl)Cys), enantiopure polysarcosine--poly(-ethylsulfonyl-l-cysteine) (pSar--p(l)Cys), and polysarcosine--poly(-ethylsulfonyl-l-homocysteine) (pSar--p(l)Hcy) was prepared by -carboxyanhydride polymerization. The secondary structure of the peptide segment varies from α-helices (pSar--p(l)Hcy) to antiparallel β-sheets (pSar--p(l)Cys) and disrupted β-sheets (pSar--p(dl)Cys). When subjected to nanoprecipitation, copolymers with antiparallel β-sheets display the strongest tendency to self-assemble, whereas disrupted β-sheets hardly induce aggregation. This translates to worm-like micelles, solely spherical micelles, or ellipsoidal structures, as analyzed by atomic force microscopy and cryogenic transmission electron microscopy, which underlines the potential of secondary structure-driven self-assembly of synthetic polypeptides.
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http://dx.doi.org/10.1021/acs.biomac.1c00253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154267PMC
May 2021

Influence of Riboflavin Targeting on Tumor Accumulation and Internalization of Peptostar Based Drug Delivery Systems.

Bioconjug Chem 2020 12 25;31(12):2691-2696. Epub 2020 Nov 25.

Institute for Experimental Molecular Imaging, University Hospital Aachen, Forckenbeckstrasse 55, 52074 Aachen, Germany.

Riboflavin carrier protein (RCP) and riboflavin transporters (RFVTs) have been reported to be highly overexpressed in various cancer cells. Hence, targeting RCP and RFVTs using riboflavin may enhance tumor accumulation and internalization of drug delivery systems. To test this hypothesis, butyl-based 3-arm peptostar polymers were synthesized consisting of a lysine core (10 units per arm) and a sarcosine shell (100 units per arm). The end groups of the arms and the core were successfully modified with riboflavin and the Cy5.5 fluorescent dye, respectively. While in phosphate buffered saline the functionalized peptostars showed a bimodal behavior and formed supramolecular structures over time, they were stable in the serum maintaining their hydrodynamic diameter of 12 nm. Moreover, the polymers were biocompatible and the uptake of riboflavin targeted peptostars in A431 and PC3 cells was higher than in nontargeted controls and could be blocked competitively. In vivo, the polymers showed a moderate passive tumor accumulation, which was not significantly different between targeted and nontargeted peptostars. Nonetheless, at the histological level, internalization into tumor cells was strongly enhanced for the riboflavin-targeted peptostars. Based on these results, we conclude that passive accumulation is dominating the accumulation of peptostars, while tumor cell internalization is strongly promoted by riboflavin targeting.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00593DOI Listing
December 2020

Racemic S-(ethylsulfonyl)-dl-cysteine N-Carboxyanhydrides Improve Chain Lengths and Monomer Conversion for β-Sheet-Controlled Ring-Opening Polymerization.

Macromol Rapid Commun 2021 Apr 12;42(8):e2000470. Epub 2020 Oct 12.

Johannes Gutenberg University Mainz, Department of Chemistry, Duesbergweg 10-14, 55128, Mainz, Germany.

The secondary structure formation of polypeptides not only governs folding and solution self-assembly but also affects the nucleophilic ring-opening polymerization of α-amino acid-N-carboxyanhydrides (NCAs). Whereby helical structures are known to enhance polymerization rates, β-sheet-like assemblies reduce the propagation rate or may even terminate chain growth by precipitation or gelation. To overcome these unfavorable properties, racemic mixtures of NCAs can be applied. In this work, racemic S-(ethylsulfonyl)-dl-cysteine NCA is investigated for the synthesis of polypeptides, diblock and triblock copolypept(o)ides. In contrast to the polymerization of stereoregular S-(ethylsulfonyl)-l-cysteine NCA, the reaction of S-(ethylsulfonyl)-dl-cysteine NCA proceeds with a rate constant of up to k  = 1.70 × 10 L mol s and is slightly faster than the enatiopure polymerization. While the polymerization of S-(ethylsulfonyl)-l-cysteine NCA suffers from incomplete monomer conversion and degrees of polymerization (DPs) limited to 30-40, racemic mixtures yield polypeptides with DPs of up to 102 with high conversion rates and well-defined dispersities (1.2-1.3). The controlled living nature of the ring-opening polymerization of S-(ethylsulfonyl)-dl-cysteine NCA thus enables the synthesis of triblock copolymers by sequential monomer addition. This methodology allows for precise control over DPs of individual blocks and yields uniform triblock copolymers with symmetric molecular weight distributions at a reduced synthetic effort.
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http://dx.doi.org/10.1002/marc.202000470DOI Listing
April 2021

A nitroreductase and glutathione responsive nanoplatform for integration of gene delivery and near-infrared fluorescence imaging.

Chem Commun (Camb) 2020 Jun;56(51):6949-6952

National Engineering Research Center for Biomaterials, Sichuan University, No. 29, Wangjiang Road, Chengdu 610064, P. R. China.

A novel platform rationally integrating indocyanine green analogues and an arginine-rich dendritic peptide with both nitroreductase (NTR) and glutathione (GSH) reduction responsive linkers was developed. This multifunctional platform can enable selective and efficient gene delivery and specific turn-on fluorescence imaging in tumors.
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http://dx.doi.org/10.1039/c9cc10071gDOI Listing
June 2020

Polymeric Nanoparticles with Neglectable Protein Corona.

Small 2020 05 6;16(18):e1907574. Epub 2020 Apr 6.

Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, Mainz, D-55128, Germany.

The current understanding of nanoparticle-protein interactions indicates that they rapidly adsorb proteins upon introduction into a living organism. The formed protein corona determines thereafter identity and fate of nanoparticles in the body. The present study evaluates the protein affinity of three core-crosslinked polymeric nanoparticles with long circulation times, differing in the hydrophilic polymer material forming the particle surface, namely poly(N-2-hydroxypropylmethacrylamide) (pHPMA), polysarcosine (pSar), and poly(ethylene glycol) (PEG). This includes the nanotherapeutic CPC634, which is currently in clinical phase II evaluation. To investigate possible protein corona formation, the nanoparticles are incubated in human blood plasma and separated by asymmetrical flow field-flow fractionation (AF4). Notably, light scattering shows no detectable differences in particle size or polydispersity upon incubation with plasma for all nanoparticles, while in gel electrophoresis, minor amounts of proteins can be detected in the particle fraction. Label-free quantitative proteomics is additionally applied to analyze and quantify the composition of the proteins. It proves that some proteins are enriched, but their concentration is significantly less than one protein per particle. Thus, most of the nanoparticles are not associated with any proteins. Therefore, this work underlines that polymeric nanoparticles can be synthesized, for which a protein corona formation does not take place.
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http://dx.doi.org/10.1002/smll.201907574DOI Listing
May 2020

Integration of Indocyanine Green Analogs as Near-Infrared Fluorescent Carrier for Precise Imaging-Guided Gene Delivery.

Small 2020 03 5;16(10):e1906538. Epub 2020 Feb 5.

National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, P. R. China.

Codelivery of diagnostic probes and therapeutic molecules often suffers from intrinsic complexity and premature leakage from or degradation of the nanocarrier. Inspired by the "Y" shape of indocyanine green (ICG), the dye is integrated in an amphiphilic lipopeptide (RNF). The hydrophilic segment is composed of arginine-rich dendritic peptides, while cyanine dyes are modified with two long carbon chains and employed as the hydrophobic moiety. They are linked through a disulfide linkage to improve the responsivity in the tumor microenvironment. After formulation with other lipopeptides at an optimized ratio, the theranostic system (RNS-2) forms lipid-based nanoparticles with slight positive zeta potential enabling efficient condensation of DNA. The RNS-2 displays glutathione responded gene release, activatable fluorescence recovery, and up to sevenfold higher in vitro transfection than Lipofectamine 2000. Compared with a Cy3 and Cy5 labeled fluorescence resonance energy transfer indicator for gene release, the "turn-on" indocyanine green analogs exhibit longer emission wavelength and better positive correlation with the dynamic processes of gene delivery. More importantly, the RNS-2 system enables efficient near infrared imaging guided gene transfer in tumor-bearing mice and thus provides more precise and accurate information on location of the cargo gene and synthesized carriers.
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http://dx.doi.org/10.1002/smll.201906538DOI Listing
March 2020

Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle-Cell Interactions.

Small 2020 02 15;16(5):e1906719. Epub 2020 Jan 15.

Department of Biosciences, University of Oslo, Blindernveien 31, 0371, Oslo, Norway.

The zebrafish embryo is a vertebrate well suited for visualizing nanoparticles at high resolution in live animals. Its optical transparency and genetic versatility allow noninvasive, real-time observations of vascular flow of nanoparticles and their interactions with cells throughout the body. As a consequence, this system enables the acquisition of quantitative data that are difficult to obtain in rodents. Until now, a few studies using the zebrafish model have only described semiquantitative results on key nanoparticle parameters. Here, a MACRO dedicated to automated quantitative methods is described for analyzing important parameters of nanoparticle behavior, such as circulation time and interactions with key target cells, macrophages, and endothelial cells. Direct comparison of four nanoparticle (NP) formulations in zebrafish embryos and mice reveals that data obtained in zebrafish can be used to predict NPs' behavior in the mouse model. NPs having long or short blood circulation in rodents behave similarly in the zebrafish embryo, with low circulation times being a consequence of NP uptake into macrophages or endothelial cells. It is proposed that the zebrafish embryo has the potential to become an important intermediate screening system for nanoparticle research to bridge the gap between cell culture studies and preclinical rodent models such as the mouse.
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http://dx.doi.org/10.1002/smll.201906719DOI Listing
February 2020

Precision Anisotropic Brush Polymers by Sequence Controlled Chemistry.

J Am Chem Soc 2020 01 26;142(3):1332-1340. Epub 2019 Dec 26.

Max Planck Institute for Polymer Research , Ackermannweg 10 , 55128 Mainz , Germany.

The programming of nanomaterials at molecular length-scales to control architecture and function represents a pinnacle in soft materials synthesis. Although elusive in synthetic materials, Nature has evolutionarily refined macromolecular synthesis with perfect atomic resolution across three-dimensional space that serves specific functions. We show that biomolecules, specifically proteins, provide an intrinsic macromolecular backbone for the construction of anisotropic brush polymers with monodisperse lengths via grafting-from strategy. Using human serum albumin as a model, its sequence was exploited to chemically transform a single cysteine, such that the expression of said functionality is asymmetrically placed along the backbone of the eventual brush polymer. This positional monofunctionalization strategy was connected with biotin-streptavidin interactions to demonstrate the capabilities for site-specific self-assembly to create higher ordered architectures. Supported by systematic experimental and computational studies, we envisioned that this macromolecular platform provides unique avenues and perspectives in macromolecular design for both nanoscience and biomedicine.
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http://dx.doi.org/10.1021/jacs.9b10491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978811PMC
January 2020

-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging.

ACS Nano 2020 01 2;14(1):568-584. Epub 2020 Jan 2.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , 2100 Copenhagen , Denmark.

Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide--polypeptoid polymers (PeptoBrushes) functionalized with -cyclooctene (TCO). The complementary In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.
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http://dx.doi.org/10.1021/acsnano.9b06905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075664PMC
January 2020

Poly(Sarcosine) Surface Modification Imparts Stealth-Like Properties to Liposomes.

Small 2019 12 13;15(50):e1904716. Epub 2019 Nov 13.

Department of Pharmaceutical Technology and Biopharmacy and Freiburger Materialforschungszentrum (FMF), Institute of Pharmaceutical Sciences, Albert Ludwig University of Freiburg, 79104, Freiburg, Germany.

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.
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http://dx.doi.org/10.1002/smll.201904716DOI Listing
December 2019

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

Macromol Biosci 2020 01 20;20(1):e1900152. Epub 2019 Aug 20.

Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany.

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 size and functionality for siRNA complexation-, transport and intra cellular release. The special feature of star-like polypept(o)ides is in their uniform small size (<20 nm) and a core-shell structure, which implies a high stability and stealth-like properties and thus, they may combine long circulation times and a deep penetration of cancerous tissue. Initial toxicity and complement studies demonstrate well tolerated cationic PeptoStars with high complexation capability toward siRNA (N/P ratio up to 3:1), which can lead to potent RNAi for optimized systems. Here, the synthetic development of 3-arm and 6-arm polypept(o)idic star polymers, their modification with endosomolytic moieties, and first in vitro insights on RNA interference are reported on.
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http://dx.doi.org/10.1002/mabi.201900152DOI Listing
January 2020

Ligand density on nanoparticles: A parameter with critical impact on nanomedicine.

Adv Drug Deliv Rev 2019 03 31;143:22-36. Epub 2019 May 31.

Fachbereich Physik and CHyN, Universität Hamburg, Hamburg, Germany. Electronic address:

Nanoparticles modified with ligands for specific targeting towards receptors expressed on the surface of target cells are discussed in literature towards improved delivery strategies. In such concepts the ligand density on the surface of the nanoparticles plays an important role. How many ligands per nanoparticle are best for the most efficient delivery? Importantly, this number may be different for in vitro and in vivo scenarios. In this review first viruses as "biological" nanoparticles are analyzed towards their ligand density, which is then compared to the ligand density of engineered nanoparticles. Then, experiments are reviewed in which in vitro and in vivo nanoparticle delivery has been analyzed in terms of ligand density. These results help to understand which ligand densities should be attempted for better targeting. Finally synthetic methods for controlling the ligand density of nanoparticles are described.
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http://dx.doi.org/10.1016/j.addr.2019.05.010DOI Listing
March 2019

Efficient Shielding of Polyplexes Using Heterotelechelic Polysarcosines.

Polymers (Basel) 2018 Jun 20;10(6). Epub 2018 Jun 20.

Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, D-55128 Mainz, Germany.

Shielding agents are commonly used to shield polyelectrolyte complexes, e.g., polyplexes, from agglomeration and precipitation in complex media like blood, and thus enhance their in vivo circulation times. Since up to now primarily poly(ethylene glycol) (PEG) has been investigated to shield non-viral carriers for systemic delivery, we report on the use of polysarcosine (pSar) as a potential alternative for steric stabilization. A redox-sensitive, cationizable lipo-oligomer structure (containing two cholanic acids attached via a bioreducible disulfide linker to an oligoaminoamide backbone in T-shape configuration) was equipped with azide-functionality by solid phase supported synthesis. After mixing with small interfering RNA (siRNA), lipopolyplexes formed spontaneously and were further surface-functionalized with polysarcosines. Polysarcosine was synthesized by living controlled ring-opening polymerization using an azide-reactive dibenzo-aza-cyclooctyne-amine as an initiator. The shielding ability of the resulting formulations was investigated with biophysical assays and by near-infrared fluorescence bioimaging in mice. The modification of ~100 nm lipopolyplexes was only slightly increased upon functionalization. Cellular uptake into cells was strongly reduced by the pSar shielding. Moreover, polysarcosine-shielded polyplexes showed enhanced blood circulation times in bioimaging studies compared to unshielded polyplexes and similar to PEG-shielded polyplexes. Therefore, polysarcosine is a promising alternative for the shielding of non-viral, lipo-cationic polyplexes.
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http://dx.doi.org/10.3390/polym10060689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404158PMC
June 2018

Coordinative Binding of Polymers to Metal-Organic Framework Nanoparticles for Control of Interactions at the Biointerface.

ACS Nano 2019 04 15;13(4):3884-3895. Epub 2019 Mar 15.

Department of Chemistry and Center for NanoScience (CeNS) , LMU Munich , Butenandtstraße 11 , 81377 Munich , Germany.

Metal-organic framework nanoparticles (MOF NPs) are of growing interest in diagnostic and therapeutic applications, and due to their hybrid nature, they display enhanced properties compared to more established nanomaterials. The effective application of MOF NPs, however, is often hampered by limited control of their surface chemistry and understanding of their interactions at the biointerface. Using a surface coating approach, we found that coordinative polymer binding to Zr- fum NPs is a convenient way for peripheral surface functionalization. Different polymers with biomedical relevance were assessed for the ability to bind to the MOF surface. Carboxylic acid and amine containing polymers turned out to be potent surface coatings and a modulator replacement reaction was identified as the underlying mechanism. The strong binding of polycarboxylates was then used to shield the MOF surface with a double amphiphilic polyglutamate-polysarcosine block copolymer, which resulted in an exceptional high colloidal stability of the nanoparticles. The effect of polymer coating on interactions at the biointerface was tested with regard to cellular association and protein binding, which has, to the best of our knowledge, never been discussed in literature for functionalized MOF NPs. We conclude that the applied approach enables a high degree of chemical surface confinement, which could be used as a universal strategy for MOF NP functionalization. In this way, the physicochemical properties of MOF NPs could be tuned, which allows for control over their behavior in biological systems.
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http://dx.doi.org/10.1021/acsnano.8b06287DOI Listing
April 2019

Improved radiosynthesis and preliminary in vivo evaluation of the C-labeled tetrazine [C]AE-1 for pretargeted PET imaging.

Bioorg Med Chem Lett 2019 04 13;29(8):986-990. Epub 2019 Feb 13.

Department for Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine and PET, University Hospital Copenhagen, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. Electronic address:

Pretargeted nuclear imaging based on the ligation between tetrazines and nano-sized targeting agents functionalized with trans-cyclooctene (TCO) has recently been shown to improve both imaging contrast and dosimetry in nuclear imaging of nanomedicines. Herein, we describe the improved radiosynthesis of a C-labeled tetrazine ([C]AE-1) and its preliminary evaluation in both mice and pigs. Pretargeted imaging in mice was carried out using both a new TCO-functionalized polyglutamic acid and a previously reported TCO-functionalized bisphosphonate system as targeting agents. Unfortunately, pretargeted imaging was not successful using these targeting agents in pair with [C]AE-1. However, brain imaging in pig indicated that the tracer crossed the blood-brain-barrier. Hence, we suggest that this tetrazine scaffold could be used as a starting point for the development of pretargeted brain imaging, which has so far been a challenging task.
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http://dx.doi.org/10.1016/j.bmcl.2019.02.014DOI Listing
April 2019

Monitoring drug nanocarriers in human blood by near-infrared fluorescence correlation spectroscopy.

Nat Commun 2018 12 13;9(1):5306. Epub 2018 Dec 13.

Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.

Nanocarrier-based drug delivery is a promising therapeutic approach that offers unique possibilities for the treatment of various diseases. However, inside the blood stream, nanocarriers' properties may change significantly due to interactions with proteins, aggregation, decomposition or premature loss of cargo. Thus, a method for precise, in situ characterization of drug nanocarriers in blood is needed. Here we show how the fluorescence correlation spectroscopy that is a well-established method for measuring the size, loading efficiency and stability of drug nanocarriers in aqueous solutions can be used to directly characterize drug nanocarriers in flowing blood. As the blood is not transparent for visible light and densely crowded with cells, we label the nanocarriers or their cargo with near-infrared fluorescent dyes and fit the experimental autocorrelation functions with an analytical model accounting for the presence of blood cells. The developed methodology contributes towards quantitative understanding of the in vivo behavior of nanocarrier-based therapeutics.
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http://dx.doi.org/10.1038/s41467-018-07755-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294246PMC
December 2018

Poly-sarcosine and Poly(Ethylene-Glycol) Interactions with Proteins Investigated Using Molecular Dynamics Simulations.

Comput Struct Biotechnol J 2018 8;16:543-550. Epub 2018 Nov 8.

Institut für Physik, Johannes Gutenberg University, Mainz, Germany.

Nanoparticles coated with hydrophilic polymers often show a reduction in unspecific interactions with the biological environment, which improves their biocompatibility. The molecular determinants of this reduction are not very well understood yet, and their knowledge may help improving nanoparticle design. Here we address, using molecular dynamics simulations, the interactions of human serum albumin, the most abundant serum protein, with two promising hydrophilic polymers used for the coating of therapeutic nanoparticles, poly(ethylene-glycol) and poly-sarcosine. By simulating the protein immersed in a polymer-water mixture, we show that the two polymers have a very similar affinity for the protein surface, both in terms of the amount of polymer adsorbed and also in terms of the type of amino acids mainly involved in the interactions. We further analyze the kinetics of adsorption and how it affects the polymer conformations. Minor differences between the polymers are observed in the thickness of the adsorption layer, that are related to the different degree of flexibility of the two molecules. In comparison poly-alanine, an isomer of poly-sarcosine known to self-aggregate and induce protein aggregation, shows a significantly larger affinity for the protein surface than PEG and PSar, which we show to be related not to a different patterns of interactions with the protein surface, but to the different way the polymer interacts with water.
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http://dx.doi.org/10.1016/j.csbj.2018.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259037PMC
November 2018

Biomolecule-corona formation confers resistance of bacteria to nanoparticle-induced killing: Implications for the design of improved nanoantibiotics.

Biomaterials 2019 02 21;192:551-559. Epub 2018 Nov 21.

Department of Nanobiomedicine/ENT, University Medical Center of Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany. Electronic address:

Multidrug-resistant bacterial infections are a global health threat. Nanoparticles are thus investigated as novel antibacterial agents for clinical practice, including wound dressings and implants. We report that nanoparticles' bactericidal activity strongly depends on their physical binding to pathogens, including multidrug-resistant primary clinical isolates, such as Staphylococcus aureus, Klebsiella pneumoniae or Enterococcus faecalis. Using controllable nanoparticle models, we found that nanoparticle-pathogen complex formation was enhanced by small nanoparticle size rather than material or charge, and was prevented by 'stealth' modifications. Nanoparticles seem to preferentially bind to Gram-positive pathogens, such as Listeria monocytogenes, S. aureus or Streptococcus pyrogenes, correlating with enhanced antibacterial activity. Bacterial resistance to metal-based nanoparticles was mediated by biomolecule coronas acquired in pathophysiological environments, such as wounds, the lung, or the blood system. Biomolecule corona formation reduced nanoparticles' binding to pathogens, but did not impact nanoparticle dissolution. Our results provide a mechanistic explanation why nano-sized antibiotics may show reduced activity in clinically relevant environments, and may inspire future nanoantibiotic designs with improved and potentially pathogen-specific activity.
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http://dx.doi.org/10.1016/j.biomaterials.2018.11.028DOI Listing
February 2019

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

Biomacromolecules 2019 01 11;20(1):375-388. Epub 2018 Dec 11.

Institute of Organic Chemistry , Johannes Gutenberg-Universität Mainz , Duesbergweg 10-14 , 55128 Mainz , Germany.

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(γ- tert-butyloxycarbonyl-l-glutamate)- b-polysarcosine (pGlu(O tBu)- b-pSar), were prepared via controlled living ring-opening polymerization (ROP) of the corresponding N-carboxyanhydrides. Moreover, size exclusion chromatography (SEC) proves the presence of well-defined star shaped polymers with molecular weights from 38 to 88 kg/mol with low polymer dispersities of 1.16 to 1.23. By varying the α-helical peptide core and maintain a constant polysarcosine corona, hydrodynamic size analyses revealed the importance of using a sufficiently large and dense hydrophilic shielding corona to prevent aggregation of the hydrophobic core and obtain uniform-sized spherical-shaped particles with hydrodynamic diameters below 24 nm. Fluorescence correlation spectroscopy (FCS) additionally demonstrates the absence of protein adsorption in human plasma for 6-arm polypept(o)ide stars and thus confirms polysarcosine as stealthlike material.
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http://dx.doi.org/10.1021/acs.biomac.8b01545DOI Listing
January 2019

Nanomedicine and macroscale materials in immuno-oncology.

Chem Soc Rev 2019 Jan;48(1):351-381

Department of Nanomedicines and Theranostics, Institute for Experimental Molecular Imaging, Uniklinik RWTH Aachen and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany.

Immunotherapy is revolutionizing the treatment of cancer. It can achieve unprecedented responses in advanced-stage patients, including complete cures and long-term survival. However, immunotherapy also has limitations, such as its relatively low response rates and the development of severe side effects. These drawbacks are gradually being overcome by improving our understanding of the immune system, as well as by establishing combination regimens in which immunotherapy is combined with other treatment modalities. In addition to this, in recent years, progress made in chemistry, nanotechnology and materials science has started to impact immuno-oncology, resulting in more effective and less toxic immunotherapy interventions. In this context, multiple different nanomedicine formulations and macroscale materials have been shown to be able to boost anti-cancer immunity and the efficacy of immunomodulatory drugs. We here review nanotechnological and materials chemistry efforts related to endogenous and exogenous vaccination, to the engineering of antigen-presenting cells and T cells, and to the modulation of the tumor microenvironment. We also discuss limitations, current trends and future directions. Together, the insights provided and the evidence obtained indicate that there is a bright future ahead for engineering nanomedicines and macroscale materials for immuno-oncology applications.
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http://dx.doi.org/10.1039/c8cs00473kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115880PMC
January 2019

Enhanced Permeability and Retention-like Extravasation of Nanoparticles from the Vasculature into Tuberculosis Granulomas in Zebrafish and Mouse Models.

ACS Nano 2018 08 15;12(8):8646-8661. Epub 2018 Aug 15.

Department of Biosciences , University of Oslo , Blindernveien 31 , 0371 Oslo , Norway.

The enhanced permeability and retention (EPR) effect is the only described mechanism enabling nanoparticles (NPs) flowing in blood to reach tumors by a passive targeting mechanism. Here, using the transparent zebrafish model infected with Mycobacterium marinum we show that an EPR-like process also occurs allowing different types of NPs to extravasate from the vasculature to reach granulomas that assemble during tuberculosis (TB) infection. PEGylated liposomes and other NP types cross endothelial barriers near infection sites within minutes after injection and accumulate close to granulomas. Although ∼100 and 190 nm NPs concentrated most in granulomas, even ∼700 nm liposomes reached these infection sites in significant numbers. We show by confocal microscopy that NPs can concentrate in small aggregates in foci on the luminal side of the endothelium adjacent to the granulomas. These spots are connected to larger foci of NPs on the ablumenal side of these blood vessels. EM analysis suggests that NPs cross the endothelium via the paracellular route. PEGylated NPs also accumulated efficiently in granulomas in a mouse model of TB infection with Mycobacterium tuberculosis, arguing that the zebrafish embryo model can be used to predict NP behavior in mammalian hosts. In earlier studies we and others showed that uptake of NPs by macrophages that are attracted to infection foci is one pathway for NPs to reach TB granulomas. This study reveals that when NPs are designed to avoid macrophage uptake, they can also efficiently target granulomas via an alternative mechanism that resembles EPR.
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http://dx.doi.org/10.1021/acsnano.8b04433DOI Listing
August 2018

Secondary Structure-Driven Hydrogelation Using Foldable Telechelic Polymer-Peptide Conjugates.

Macromol Rapid Commun 2018 Sep 24;39(17):e1800459. Epub 2018 Jul 24.

Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, D-55128, Mainz, Germany.

The synthesis of ABA and ABA' triblock polyethylene glycol-and polysarcosine-peptide conjugates is reported. The A/A' peptides are based on phenylalanine(F)-histidine(H) pentapeptide sequences FHFHF, which promote pH-switchable β-sheet self-assembly into nanorods in water. Only parallel β-sheet-driven folding and intermolecular assembly using ABA triblock polymer-peptide conjugates leads to interstrand cross-linking and hydrogelation, highlighting the impact of supramolecular interactions-directed structure formation at the nano- and mesoscopic level.
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http://dx.doi.org/10.1002/marc.201800459DOI Listing
September 2018

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

J Control Release 2018 07 4;282:25-34. Epub 2018 May 4.

Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic and Helmholtz Institute for Biomedical Engineering, Aachen, Germany; Department of Targeted Therapeutics, Biomaterial Science and Technology, University of Twente, Enschede, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address:

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 the tumor accumulation and penetration of 10-20 nm-sized polymeric drug carriers based on poly(N-(2-hydroxypropyl)methacrylamide). Multimodal and multiscale optical imaging was employed to show that normalizing the tumor vasculature improves the accumulation of fluorophore-labeled polymers in tumors, and promotes their penetration out of tumor blood vessels deep into the interstitium.
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http://dx.doi.org/10.1016/j.jconrel.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130770PMC
July 2018

Of Thiols and Disulfides: Methods for Chemoselective Formation of Asymmetric Disulfides in Synthetic Peptides and Polymers.

Chemistry 2018 Aug 6;24(47):12131-12142. Epub 2018 Jul 6.

Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany.

In protein or peptide chemistry, thiols are frequently chosen as a chemical entity for chemoselective modification reactions. Although it is a well-established methodology to address cysteines and homocysteines in aqueous media to form S-C bonds, possibilities for the chemoselective formation of asymmetric disulfides have been less approached. Focusing on bioreversibility in conjugation chemistry, the formation of disulfide bonds is highly desirable for the attachment of thiol-containing bioactive agents to proteins or in cross-linking reactions, because disulfide bonds can combine stability in blood with degradability inside cells. In this Concept article, recent approaches in the field of activating groups for thiol moieties incorporated in peptide and polymer materials are highlighted. Advantageous combinations of stability during synthesis of the material with high reactivity towards thiols are explored focusing on simplification and prevention of side reactions as well as additional deprotection and activation steps prior to disulfide formation. Moreover, applications of this chemistry are highlighted and future perspectives are envisioned.
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http://dx.doi.org/10.1002/chem.201800681DOI Listing
August 2018
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