Publications by authors named "Jennifer Schultze"

7 Publications

  • Page 1 of 1

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

Covalently Binding of Bovine Serum Albumin to Unsaturated Poly(Globalide-Co-ε-Caprolactone) Nanoparticles by Thiol-Ene Reactions.

Macromol Biosci 2019 10 6;19(10):e1900145. Epub 2019 Sep 6.

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

When nanoparticles (NPs) are introduced to a biological fluid, different proteins (and other biomolecules) rapidly get adsorbed onto their surface, forming a protein corona capable of giving to the NPs a new "identity" and determine their biological fate. Protein-nanoparticle conjugation can be used in order to promote specific interactions between living systems and nanocarriers. Non-covalent conjugates are less stable and more susceptible to desorption in biological media, which makes the development of engineered nanoparticle surfaces by covalent attachment an interesting topic. In this work, the surface of poly(globalide-co-ε-caprolactone) (PGlCL) nanoparticles containing double bonds in the main polymer chain is covalently functionalized with bovine serum albumin (BSA) by thiol-ene chemistry, producing conjugates which are resistant to dissociation. The successful formation of the covalent conjugates is confirmed by flow cytometry (FC) and fluorescence correlation spectroscopy (FCS). Transmission electron microscopy (TEM) allows the visualization of the conjugate formation, and the presence of a protein layer surrounding the NPs can be observed. After conjugation with BSA, NPs present reduced cell uptake by HeLa and macrophage RAW264.7 cells, in comparison to uncoated NP. These results demonstrate that it is possible to produce stable conjugates by covalently binding BSA to PGlCL NP through thiol-ene reaction.
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http://dx.doi.org/10.1002/mabi.201900145DOI Listing
October 2019

Preparation of Monodisperse Giant Unilamellar Anchored Vesicles Using Micropatterned Hydrogel Substrates.

ACS Omega 2019 May 29;4(5):9393-9399. Epub 2019 May 29.

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

Giant unilamellar vesicles (GUVs) are model membrane systems consisting of a single lipid bilayer separating an inner lumen from the outer solution, with dimensions comparable to that of eukaryotic cells. The importance of these biomimetic systems has recently grown with the development of easy and safe methods to assemble GUVs from complex biorelevant compositions. However, size and position control is still a key challenge for GUV formation and manipulation. Here, a gel-assisted formation method is introduced, able to produce arrays of giant unilamellar anchored vesicles (GUAVs) with a predetermined narrow size distribution. The approach based on micropatterned gel substrates of cross-linked poly(-isopropylacrylamide) allows performing parallel measurements on thousands of immobile unilamellar vesicles. Such power and flexibility will respond to the growing need for developing platforms of biomimetic constructs from cell-sized single bilayers.
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http://dx.doi.org/10.1021/acsomega.9b00912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648857PMC
May 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

Site-Specific DBCO Modification of DEC205 Antibody for Polymer Conjugation.

Polymers (Basel) 2018 Feb 2;10(2). Epub 2018 Feb 2.

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

The design of multifunctional polymer-based vectors, forming pDNA vaccines, offers great potential in cancer immune therapy. The transfection of dendritic immune cells (DCs) with tumour antigen-encoding pDNA leads to an activation of the immune system to combat tumour cells. In this work, we investigated the chemical attachment of DEC205 antibodies (aDEC205) as DC-targeting structures to polyplexes of P(Lys)--P(HPMA). The conjugation of a synthetic block copolymer and a biomacromolecule with various functionalities (aDEC205) requires bioorthogonal techniques to avoid side reactions. Click chemistry and in particular the strain-promoted alkyne-azide cycloaddition (SPAAC) can provide the required bioorthogonality. With regard to a SPAAC of both components, we firstly synthesized two different azide-containing block copolymers, P(Lys)--P(HPMA)-N₃(stat) and P(Lys)--P(HPMA)-N₃(end), for pDNA complexation. In addition, the site-specific incorporation of ring-strained dibenzocyclooctyne (DBCO) moieties to the DEC205 antibody was achieved by an enzymatic strategy using bacterial transglutaminase (BTG). The chemical accessibility of DBCO molecules within aDEC205 as well as the accessibility of azide-functionalities on the polyplex' surface were investigated by various SPAAC experiments and characterized by fluorescence correlation spectroscopy (FCS).
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http://dx.doi.org/10.3390/polym10020141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414842PMC
February 2018

A modular approach for multifunctional polymersomes with controlled adhesive properties.

Soft Matter 2018 Feb 5;14(6):894-900. Epub 2018 Jan 5.

Max Planck Institute for Polymer Research (MPIP), 55128 Mainz, Germany.

The bottom-up approach in synthetic biology involves the engineering of synthetic cells by designing biological and chemical building blocks, which can be combined in order to mimic cellular functions. The first step for mimicking a living cell is the design of an appropriate compartment featuring a multifunctional membrane. This is of particular interest since it allows for the selective attachment of different groups or molecules to the membrane. In this context, we report on a modular approach for polymeric vesicles, so-called polymersomes, with a multifunctional surface, namely hydroxyl, alkyne and acrylate groups. We demonstrate that the surface of the polymersome can be functionalized to facilitate imaging, via fluorescent dyes, or to improve the specific adhesion to surfaces by using a biotin functionalization. This generally applicable multifunctionality allows for the covalent integration of various molecules in the membrane of a synthetic cell.
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http://dx.doi.org/10.1039/c7sm01885aDOI Listing
February 2018

Dendritic Mesoporous Silica Nanoparticles for pH-Stimuli-Responsive Drug Delivery of TNF-Alpha.

Adv Healthc Mater 2017 Jul 29;6(13). Epub 2017 May 29.

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

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune stimulatory cytokine and natural endotoxin that can induce necrosis and regression in solid tumors. However, systemic administration of TNF-α is not feasible due to its short half-life and acute toxicity, preventing its widespread use in cancer treatment. Dendritic mesoporous silica nanoparticles (DMSN) are used coated with a pH-responsive block copolymer gate system combining charged hyperbranched polyethylenimine and nonionic hydrophilic polyethylenglycol to encapsulate TNF-α and deliver it into various cancer cell lines and dendritic cells. Half-maximal effective concentration (EC ) for loaded TNF-α is reduced by more than two orders of magnitude. Particle stability and premature cargo release are assessed with enzyme-linked immunosorbent assay. TNF-α-loaded particles are stable for up to 5 d in medium. Tumor cells are grown in vitro as 3D fluorescent ubiquitination-based cell cycle indicator spheroids that mimic in vivo tumor architecture and microenvironment, allowing real-time cell cycle imaging. DMSN penetrate these spheroids, release TNF-α from its pores, preferentially affect cells in S/G2/M phase, and induce cell death in a time- and dose-dependent manner. In conclusion, DMSN encapsulation is demonstrated, which is a promising approach to enhance delivery and efficacy of antitumor drugs, while minimizing adverse side effects.
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http://dx.doi.org/10.1002/adhm.201700012DOI Listing
July 2017
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