name	title	fuMetaTitel	body	fuDCcreator	fuDCcreatorLinks	fuDCpublisher	fuDCpublisherLocation	fuDCSizeOrDuration	fuDCdateYear	fuDCdateMonth	fuDCdateDay	fuDCsubject	fuDCrelationPartOf	fuDCrelation	fuDClanguage	fuDCsource	fuDCcontributor	fuDCtype	fuDCformat	fuDCidentifier	fuDCcoverage	fuDCrights	fuDCdescriptionDE	fuDCdescriptionEN	fuDCIdentifierBibliographicCitation	fuBild	fuDCBibtex	fuLinksZumThema
KA900	Cell-Penetrating Peptide-Bismuth Bicycles			"Voss, S.; Adair, L. D.; Achazi, K.; Kim, H.; Bergemann, S.; Bartenschlager, R.; New, E. J.; Rademann, J.; Nitsche, C."		Angew Chem Int Ed Engl			2024	3	4	"*Cell-Penetrating Peptides/chemistry; Bicycles; Bicycling; Bismuth; Cells; Endocytosis/physiology; Fluorescence; Humans; Peptides; Pinocytosis"				https://doi.org/10.1002/anie.202318615		journalArticle		1521-3773 (Electronic) 1433-7851 (Linking)				Cell-penetrating peptides (CPPs) play a significant role in the delivery of cargos into human cells. We report the first CPPs based on peptide-bismuth bicycles, which can be readily obtained from commercially available peptide precursors, making them accessible for a wide range of applications. These CPPs enter human cells as demonstrated by live-cell confocal microscopy using fluorescently labelled peptides. We report efficient sequences that demonstrate increased cellular uptake compared to conventional CPPs like the TAT peptide (derived from the transactivating transcriptional activator of human immunodeficiency virus 1) or octaarginine (R(8) ), despite requiring only three positive charges. Bicyclization triggered by the presence of bismuth(III) increases cellular uptake by more than one order of magnitude. Through the analysis of cell lysates using inductive coupled plasma mass spectrometry (ICP-MS), we have introduced an alternative approach to examine the cellular uptake of CPPs. This has allowed us to confirm the presence of bismuth in cells after exposure to our CPPs. Mechanistic studies indicated an energy-dependent endocytic cellular uptake sensitive to inhibition by rottlerin, most likely involving macropinocytosis.				
KA901	Photo-responsive hydrogels based on a ruthenium complex: synthesis and degradation			"Tavakkoli Fard, S.; Thongrom, B.; Achazi, K.; Ma, G.; Haag, R.; Tzschucke, C. C."		Soft Matter			2024	2	7					https://doi.org/10.1039/d3sm01232h		journalArticle		1744-6848 (Electronic) 1744-683X (Linking)				We report the synthesis of a photo responsive metallo-hydrogel based on a ruthenium(II) complex as a functional cross-linker. This metal complex contains reactive 4AAMP (= 4-(acrylamidomethyl)pyridine) ligands, which can be cleaved by light-induced ligand substitution. Ru[(bpy)(2)(4AAMP)(2)] cross-links 4-arm-PEG-SH macromonomers by thia-Michael-addition to the photocleavable 4AAMP ligand for the preparation of the hydrogel. Irradiation with green light at 529 nm leads to photodegradation of the metallo-hydrogel due to the ligand dissociation, which can be adjusted by adjusting the Ru[(bpy)(2)(4AAMP)(2)] concentration. The ligand substitution forming [Ru(bpy)(2)(L)(2)](2+) (L = H(2)O and CH(3)CN) can be monitored by (1)H NMR spectroscopy and UV-visible absorption. The control of degradation by light irradiation plays a significant role in modulating the elasticity and stiffness of the light sensitive metallo-hydrogel network. The photo-responsive hydrogel is a viable substrate for cell cultures.				
KA902	Synthesis of C(3)-symmetric star shaped amphiphiles for drug delivery applications			"Mittal, A.; Aarti; Vats, S.; Zabihi, F.; Achazi, K.; Rancan, F.; Vogt, A.; Haag, R.; Sharma, S. K."		Soft Matter			2024	2	7	"*Drug Delivery Systems; *Micelles; Fluorescent Dyes/chemistry; HeLa Cells; Humans"				https://doi.org/10.1039/d3sm01388j		journalArticle		1744-6848 (Electronic) 1744-683X (Linking)				C (3)-symmetric star-shaped aromatic compounds are known to possess unique characteristics which facilitate their industrial and biomedical applications. Herein, we report the design, synthesis, self-assembly and drug/dye delivery capabilities of C(3)-symmetric, hexa-substituted benzene-based amphiphiles. The synthesis of the hexa-substituted C(3)-symmetric core involves C-acetylation of phloroglucinol to yield the corresponding tri-acetyl derivative. This was further subjected to O-propargylation, followed by the carbonyl reduction of acetyl groups to yield the central core. Various hydrophilic (mPEG) and lipophilic units were then incorporated into this core via click and esterification reactions, respectively, to produce a new type of star shaped amphiphiles. So the obtained amphiphilic architectures have a tendency to aggregate in an aqueous medium forming nanosized assemblies with an inner hydrophobic core, allowing the substituents to control the tension-active properties. The critical aggregation concentration of the amphiphiles was evaluated by fluorescence measurement using the dye Nile red as a fluorescent probe. The hydrodynamic diameter of self-assembled aggregates in aqueous solution was studied by dynamic light scattering, while the actual size and morphology were determined by cryo-transmission electron microscopy (cryo-TEM) analysis. The physicochemical properties of the amphiphiles suggested their suitability for exploring their drug delivery applications. In this endeavor, the amphiphiles were utilized for the encapsulation of model hydrophobic entities and studying their subsequent release from their hydrophobic core in a controlled manner. The transport potential of the synthesised amphiphiles was explored for transdermal drug delivery. Furthermore, cytotoxicity studies were conducted using MCF7 and HeLa cells, which indicated that the nanocarriers had no toxic effect on the cells.				
KA903	Sulfated Cellulose Nanofiber Hydrogel with Mucus-Like Activities for Virus Inhibition			"Long, Y.; Dimde, M.; Adler, J. M.; Vidal, R. M.; Povolotsky, T. L.; Nickl, P.; Achazi, K.; Trimpert, J.; Kaufer, B. B.; Haag, R.; Nie, C."		ACS Appl Mater Interfaces			2024	12	11	"*Antiviral Agents/pharmacology/chemistry; *Cellulose/chemistry/pharmacology/analogs & derivatives; *Herpesvirus 1, Human/drug effects; *Hydrogels/chemistry/pharmacology; *Nanofibers/chemistry; *SARS-CoV-2/drug effects; Animals; Calcium/metabolism/chemistry; Chlorocebus aethiops; COVID-19/virology; Humans; live-cell imaging; mucin-mimetic biopolymeric nanofibers; mucus-like hydrogels; Mucus/metabolism; transwell assay; Vero Cells; virus binding and inhibition"				https://doi.org/10.1021/acsami.4c17998		journalArticle		1944-8252 (Electronic) 1944-8244 (Print) 1944-8244 (Linking)				"Mucus is the first defense barrier against viruses in the human immune system. Inspired by the mucus structure, we designed a highly sulfated hydrogel to bind viruses and prevent infection of the underlying cells. The hydrogel was formed by gelation of sulfated cellulose nanofiber (SCNF) with Ca(2+). SCNF exhibited a mucin-like nanofiber structure with high numbers of sulfated groups. Based on the electrostatic interactions with a virus, SCNF could efficiently inhibit herpes simplex virus-1 (HSV-1) infection with a half-maximal inhibitory concentration (IC(50)) of 0.43 mug/mL, which is comparable to that of heparin (IC(50) = 0.30 mug/mL). Benefiting from the multiporous structure and sulfate groups, the Ca(2+)-SCNF hydrogel could efficiently trap HSV-1 and inhibit the virus from attacking the underlying cells in a transwell model. Furthermore, SCNF also inhibited SARS-CoV-2 infection in a similar experimental setting. By integrating the advantages of high and broad-spectrum virus inhibitory activity as well as low toxicity, it is believed that the Ca(2+)-SCNF hydrogel can promote the development of highly biocompatible and efficient antiviral material with ""binding and inhibition"" capability and other diverse strategies."				
KA904	Mucin-Inspired Polymeric Fibers for Herpes Simplex Virus Type 1 Inhibition			"Arenhoevel, J.; Schmitt, A. C.; Kerkhoff, Y.; Ahmadi, V.; Quaas, E.; Ludwig, K.; Achazi, K.; Nie, C.; Bej, R.; Haag, R."		Macromol Biosci			2024	9		"*Antiviral Agents/pharmacology/chemistry; *Herpesvirus 1, Human/drug effects; *Mucins/chemistry/metabolism; Animals; biocompatible HSV-1 inhibitors; Chlorocebus aethiops; dendronized polyglycerol sulfates; Herpes Simplex/drug therapy/virology; Humans; mucin-inspired polymers; Polymers/chemistry/pharmacology; single-chain fibers; telechelic RAFT polymer; Vero Cells"				https://doi.org/10.1002/mabi.202400120		journalArticle		1616-5195 (Electronic) 1616-5187 (Linking)				Mucus lines the epithelial cells at the biological interface and is the first line of defense against multiple viral infections. Mucins, the gel-forming components of mucus, are high molecular weight glycoproteins and crucial for preventing infections by binding pathogens. Consequently, mimicking mucins is a promising strategy for new synthetic virus inhibitors. In this work, synthetic mucin-inspired polymers (MIPs) as potential inhibitors of herpes simplex virus 1 (HSV-1) are investigated. By using a telechelic reversible addition-fragmentation chain-transfer (RAFT) polymerization technique, a new dendronized polysulfate p(G1AAm-OSO(3))(PDS) with an amide-backbone similar to the native mucin glycoproteins is synthesized. p(G1AAm-OSO(3))(PDS) shows mucin-like elongated fiber structure, as revealed in cryo-electron microscopy (cryo-EM) imaging, and its HSV-1 inhibition activity together with its previously reported methacrylate analogue p(G1MA-OSO(3))(PDS) is tested. Both of the sulfated MIPs show strong HSV-1 inhibition in plaque reduction assays with IC(50) values in lower nanomolar range (<3 x 10(-9) m) and demonstrate a high cell compatibility (CC(50) > 1.0 mg mL(-1)) with lower anticoagulant activity than heparin. In addition, the prophylactic and therapeutic activity of both MIPs is assessed in pre- and post-infection inhibition assays and clearly visualize their high potential for application using fluorescent microscopy imaging of infected cells.				
KA905	Esterase-Responsive Polyglycerol-Based Nanogels for Intracellular Drug Delivery in Rare Gastrointestinal Stromal Tumors			"Schotz, S.; Griepe, A. K.; Goerisch, B. B.; Kortam, S.; Vainer, Y. S.; Dimde, M.; Koeppe, H.; Wedepohl, S.; Quaas, E.; Achazi, K.; Schroeder, A.; Haag, R."		Pharmaceuticals (Basel)			2023	11	16	"drug delivery; Gist; iEDDA; nanogels; polyglycerol"				https://doi.org/10.3390/ph16111618		journalArticle		1424-8247 (Print) 1424-8247 (Electronic) 1424-8247 (Linking)				Rare gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and PDGFRA genes. Avapritinib (BLU-285) is a targeted selective inhibitor for mutated KIT and PDGFRA receptors that can be used to treat these tumors. However, there are subtypes of GISTs that exhibit resistance against BLU-285 and thus require other treatment strategies. This can be addressed by employing a drug delivery system that transports a combination of drugs with distinct cell targets. In this work, we present the synthesis of esterase-responsive polyglycerol-based nanogels (NGs) to overcome drug resistance in rare GISTs. Using inverse nanoprecipitation mediated with inverse electron-demand Diels-Alder cyclizations (iEDDA) between dPG-methyl tetrazine and dPG-norbornene, multi-drug-loaded NGs were formed based on a surfactant-free encapsulation protocol. The obtained NGs displayed great stability in the presence of fetal bovine serum (FBS) and did not trigger hemolysis in red blood cells over a period of 24 h. Exposing the NGs to Candida Antarctica Lipase B (CALB) led to the degradation of the NG network, indicating the capability of targeted drug release. The bioactivity of the loaded NGs was tested in vitro on various cell lines of the GIST-T1 family, which exhibit different drug resistances. Cell internalization with comparable uptake kinetics of the NGs could be confirmed by confocal laser scanning microscopy (CLSM) and flow cytometry for all cell lines. Cell viability and live cell imaging studies revealed that the loaded NGs are capable of intracellular drug release by showing similar IC(50) values to those of the free drugs. Furthermore, multi-drug-loaded NGs were capable of overcoming BLU-285 resistance in T1-alpha-D842V + G680R cells, demonstrating the utility of this carrier system.				
KA906	pH-Degradable Polyglycerol-Based Nanogels for Intracellular Protein Delivery			"Schotz, S.; Goerisch, B. B.; Mavroskoufis, A.; Dimde, M.; Quaas, E.; Achazi, K.; Haag, R."		Acs Applied Nano Materials			2023	8	29	"acetals; antibodies; cytochrome-c; drug-delivery; encapsulation; iedda; immunogenicity; nanocapsules; nanogels; nanoprecipitation; polyglycerol; protein delivery; release; stability; targeted delivery"				https://doi.org/10.1021/acsanm.3c02824		journalArticle						The growing interest in therapeutic proteins for biomedical applications is still limited by their tendency to degrade and undergo opsonization when exposed to physiological conditions. To protect them from external stimuli and mask their immunogenic sites, poly(ethylene glycol) can be covalently attached to the biomolecules. While this process requires a chemical modification of the original structure and can cause immunogenic reactions, therapeutic proteins can be masked by noncovalent encapsulation into nanocarriers such as nanogels (NGs). Here, we present the synthesis of four new pH-degradable NGs and evaluate their potential to serve as a cytochrome C (CC) delivery platform. Our surfactant-free encapsulation protocol for CC relies on forming NGs through inverse nanoprecipitation using inverse electron-demand Diels-Alder cyclizations (iEDDA) between methyl tetrazines and norbornenes. We compare an aliphatic acetal with different benzacetals and evaluate the substituents' influence on the NGs' cleavability and the subsequent intracellular release of CC. Introducing an aromatic pi-system beside the acetal framework increased the NG stability against buffer ions and shifted the acetal hydrolysis to the desired lyso- and endosomal pH values. Increasing the degree of substitution in the meta-position with methoxy groups, smaller NGs and more acid-stable acetals were obtained. The BA(OMe)-NGs emerged as the most promising candidate, exhibiting great stability at pH 7.4 and acetal hydrolysis at pH <= 6.5 without aggregation. Remarkably, this system released up to 60% of the loaded CC after 96 hours of incubation at endosomal pH values, causing apoptosis of McF7 cells with IC50 values of 8.25 mu M.				
KA907	Dendritic Glycerol-Cholesterol Amphiphiles as Drug Delivery Systems: A Comparison between Monomeric and Polymeric Structures			"Romero, J. F.; Herziger, S.; Cherri, M.; Dimde, M.; Achazi, K.; Mohammadifar, E.; Haag, R."		Pharmaceutics			2023	10		"architectures; block-copolymers; cellular uptake; cholesterol; dendrons; drug delivery; micelles; polyglycerol dendron; polymeric amphiphiles; radical polymerization; raft polymerization"				https://doi.org/10.3390/pharmaceutics15102452		journalArticle						The application of micelles as drug delivery systems has gained a great deal of attention as a means to overcome the current several drawbacks present in conventional cancer treatments. In this work, we highlight the comparison of polymeric and monomeric amphiphilic systems with a similar hydrophilic-lipophilic balance (HLB) in terms of their biocompatibility, aggregation behavior in aqueous solution, and potential in solubilizing hydrophobic compounds. The polymeric system consists of non-ionic polymeric amphiphiles synthesized via sequential RAFT polymerization of polyglycerol first-generation [G1] dendron methacrylate and cholesterol methacrylate to obtain poly(G1-polyglycerol dendron methacrylate)-block-poly(cholesterol methacrylate) (pG1MA-b-pCMA). The monomeric system is a polyglycerol second-generation [G2] dendron end-capped to a cholesterol unit. Both amphiphiles form spherical micellar aggregations in aqueous solution, with differences in size and the morphology in which hydrophobic molecules can be encapsulated. The polymeric and monomeric micelles showed a low critical micelle concentration (CMC) of 0.2 and 17 mu g/mL, respectively. The results of our cytotoxicity assays showed that the polymeric system has significantly higher cell viability compared to that of the monomeric amphiphiles. The polymeric micelles were implemented as drug delivery systems by encapsulation of the hydrophobic small molecule doxorubicin, achieving a loading capacity of 4%. In summary, the results of this study reveal that using cholesterol as a building block for polymer synthesis is a promising method of preparation for efficient drug delivery systems while improving the cell viability of monomeric cholesterol.				
KA908	Functionalized Fullerene for Inhibition of SARS-CoV-2 Variants			"Page, T. M.; Nie, C.; Neander, L.; Povolotsky, T. L.; Sahoo, A. K.; Nickl, P.; Adler, J. M.; Bawadkji, O.; Radnik, J.; Achazi, K.; Ludwig, K.; Lauster, D.; Netz, R. R.; Trimpert, J.; Kaufer, B.; Haag, R.; Donskyi, I. S."		Small			2023	4		"*covid-19; *Fullerenes/pharmacology; covalent functionalization; fullerene; Glycerol; Humans; Polymers; Protein Binding; SARS-CoV-2; sulfated materials; virus inhibition"				https://doi.org/10.1002/smll.202206154		journalArticle		1613-6829 (Electronic) 1613-6810 (Linking)				As virus outbreaks continue to pose a challenge, a nonspecific viral inhibitor can provide significant benefits, especially against respiratory viruses. Polyglycerol sulfates recently emerge as promising agents that mediate interactions between cells and viruses through electrostatics, leading to virus inhibition. Similarly, hydrophobic C(60) fullerene can prevent virus infection via interactions with hydrophobic cavities of surface proteins. Here, two strategies are combined to inhibit infection of SARS-CoV-2 variants in vitro. Effective inhibitory concentrations in the millimolar range highlight the significance of bare fullerene's hydrophobic moiety and electrostatic interactions of polysulfates with surface proteins of SARS-CoV-2. Furthermore, microscale thermophoresis measurements support that fullerene linear polyglycerol sulfates interact with the SARS-CoV-2 virus via its spike protein, and highlight importance of electrostatic interactions within it. All-atom molecular dynamics simulations reveal that the fullerene binding site is situated close to the receptor binding domain, within 4 nm of polyglycerol sulfate binding sites, feasibly allowing both portions of the material to interact simultaneously.				
KA909	Poly(-acryloylmorpholine) Nanogels as Promising Materials for Biomedical Applications: Low Protein Adhesion and High Colloidal Stability			"Neumann-Tran, T. M. P.; Lopez-Iglesias, C.; Navarro, L.; Quaas, E.; Achazi, K.; Biglione, C.; Klinger, D."		Acs Applied Polymer Materials			2023	9	16	"accelerated blood clearance; acryloylmorpholine; antifoulingcoating; drug delivery; drug-release; miniemulsion; nanocomposite hydrogels; nanogels; nanomedicine; particles; ph; poly(ethylene glycol); polymerization; polymers; protein repellent; smart materials"				https://doi.org/10.1021/acsapm.3c00890		journalArticle		2637-6105				Poly(N-acryloylmorpholine) (P(NAM))-based materials have been developed to prevent protein adhesion to surfaces due to their biocompatibility and protein-repellent properties. However, transferring the benefits of P(NAM) to nanoscale materials such as nanogels has not yet been studied. This can be attributed to the challenging colloidal synthesis of such particles with highly hydrophilic networks. To address this challenge, we have developed an inverse miniemulsion approach for free radical polymerization of NAM in dispersed nanodroplets. This strategy allows preparation of well-defined P(NAM) nanogels with a controllable size (250-350 nm). To impart additional functionality, our approach can easily be adapted to include ionic co-monomers and degradable cross-linkers. The resulting pH-responsive swelling and redox-triggered degradation profiles were demonstrated by dynamic light scattering measurements. To test the influence of such additional functionality on the protein-repellent properties, protein adsorption on the nanogels was assessed. For surface-immobilized nanogels, reduced unspecific binding of albumin was demonstrated for all nanogels via fluorescence microscopy. For nanogels in suspension, nanoparticle tracking analysis showed no increase in nanogel size upon incubation in serum and plasma, thus suggesting limited protein adsorption and colloidal high stability for over 2 months. Finally, cytotoxicity essays demonstrated the potential of these materials for bio-applications. Overall, these results suggest that biocompatibility and protein-repellent properties of P(NAM) can be transferred to nanogels and are maintained upon integration of additional chemical functionality. Thus, our synthetic strategy builds the foundation for utilizing such versatile colloidal materials in biomedical applications, e.g., as versatile drug delivery systems.