TY - JOUR A1 - Schulz, Anita A1 - Jaksch, Sebastian A1 - Schubel, Rene A1 - Wegener, Erik A1 - Di, Zhenyu A1 - Han, Yingchao A1 - Meister, Annette A1 - Kressler, Jörg A1 - Kabanov, Alexander V. A1 - Luxenhofer, Robert A1 - Papadakis, Christine M. A1 - Jordan, Rainer T1 - Drug-Induced Morphology Switch in Drug Delivery Systems Based on Poly(2-oxazoline)s JF - ACS Nano N2 - Defined aggregates of polymers such as polymeric micelles are of great importance in the development of pharmaceutical formulations. The amount of drug that can be formulated by a drug delivery system is an important issue, and most drug delivery systems suffer from their relatively low drug-loading capacity. However, as the loading capacities increase, i.e., promoted by good drug–polymer interactions, the drug may affect the morphology and stability of the micellar system. We investigated this effect in a prominent system with very high capacity for hydrophobic drugs and found extraordinary stability as well as a profound morphology change upon incorporation of paclitaxel into micelles of amphiphilic ABA poly(2-oxazoline) triblock copolymers. The hydrophilic blocks A comprised poly(2-methyl-2-oxazoline), while the middle blocks B were either just barely hydrophobic poly(2-n-butyl-2-oxazoline) or highly hydrophobic poly(2-n-nonyl-2-oxazoline). The aggregation behavior of both polymers and their formulations with varying paclitaxel contents were investigated by means of dynamic light scattering, atomic force microscopy, (cryogenic) transmission electron microscopy, and small-angle neutron scattering. While without drug, wormlike micelles were present, after incorporation of small amounts of drugs only spherical morphologies remained. Furthermore, the much more hydrophobic poly(2-n-nonyl-2-oxazoline)-containing triblock copolymer exhibited only half the capacity for paclitaxel than the poly(2-n-butyl-2-oxazoline)-containing copolymer along with a lower stability. In the latter, contents of paclitaxel of 8 wt % or higher resulted in a raspberry-like micellar core. KW - amphiphilic poly(2-oxazoline)s KW - paclitaxel KW - drug delivery KW - rod-to-sphere transition Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120766 N1 - This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html), which permits copying and redistribution of the article or any adaptations for non-commercial purposes. VL - 8 IS - 3 ER - TY - JOUR A1 - Borova, Solomiia A1 - Tokarev, Victor A1 - Stahlhut, Philipp A1 - Luxenhofer, Robert T1 - Crosslinking of hydrophilic polymers using polyperoxides JF - Colloid and Polymer Science N2 - Hydrogels that can mimic mechanical properties and functions of biological tissue have attracted great interest in tissue engineering and biofabrication. In these fields, new materials and approaches to prepare hydrogels without using toxic starting materials or materials that decompose into toxic compounds remain to be sought after. Here, we report the crosslinking of commercial, unfunctionalized hydrophilic poly(2-ethyl-2-oxazoline) using peroxide copolymers in their melt. The influence of temperature, peroxide copolymer concentration, and duration of the crosslinking process has been investigated. The method allows to create hydrogels from unfunctionalized polymers in their melt and to control the mechanical properties of the resulting materials. The design of hydrogels with a suitable mechanical performance is of crucial importance in many existing and potential applications of soft materials, including medical applications. KW - hydrogels KW - radical crosslinking KW - poly(2-ethyl-2-oxazoline) KW - thermal crosslinking KW - peroxide containing copolymers Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238109 VL - 298 ER - TY - JOUR A1 - Luxenhofer, Robert A1 - Fetsch, Corinna T1 - Thermal Properties of Aliphatic Polypeptoids JF - Polymers N2 - A series of polypeptoid homopolymers bearing short (C1–C5) side chains of degrees of polymerization of 10–100 are studied with respect to thermal stability, glass transition and melting points. Thermogravimetric analysis of polypeptoids suggests stability to >200 °C. The study of the glass transition temperatures by differential scanning calorimetry revealed two dependencies. On the one hand an extension of the side chain by constant degree of polymerization decrease the glass transition temperatures (Tg) and on the other hand a raise of the degree of polymerization by constant side chain length leads to an increase of the Tg to a constant value. Melting points were observed for polypeptoids with a side chain comprising not less than three methyl carbon atoms. X-ray diffraction of polysarcosine and poly(N-ethylglycine) corroborates the observed lack of melting points and thus, their amorphous nature. Diffractograms of the other investigated polypeptoids imply that crystalline domains exist in the polymer powder. KW - peptoid KW - biomaterials KW - glass transition temperature KW - DSC KW - TGA KW - XRD Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96333 ER - TY - JOUR A1 - Salman Haider, Malik A1 - Schreiner, Jochen A1 - Kendl, Sabine A1 - Kroiss, Matthias A1 - Luxenhofer, Robert T1 - A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models JF - Macromolecular Bioscience N2 - Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro. KW - adrenocortical carcinoma KW - amphiphilic block copolymer KW - NCI-H295R KW - poly(2-oxazoline) KW - solubility enhancement Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206224 VL - 20 IS - 1 ER - TY - JOUR A1 - Salgarella, Alice Rita A1 - Zahoranová, Anna A1 - Šrámková, Petra A1 - Majerčíková, Monika A1 - Pavlova, Ewa A1 - Luxenhofer, Robert A1 - Kronek, Juraj A1 - Lacík, Igor A1 - Ricotti, Leonardo T1 - Investigation of drug release modulation from poly(2-oxazoline) micelles through ultrasound JF - Scientific Reports N2 - Among external stimuli used to trigger release of a drug from a polymeric carrier, ultrasound has gained increasing attention due to its non-invasive nature, safety and low cost. Despite this attention, there is only limited knowledge about how materials available for the preparation of drug carriers respond to ultrasound. This study investigates the effect of ultrasound on the release of a hydrophobic drug, dexamethasone, from poly(2-oxazoline)-based micelles. Spontaneous and ultrasound-mediated release of dexamethasone from five types of micelles made of poly(2-oxazoline) block copolymers, composed of hydrophilic poly(2-methyl-2-oxazoline) and hydrophobic poly(2-n-propyl-2-oxazoline) or poly(2-butyl-2-oxazoline-co-2-(3-butenyl)-2-oxazoline), was studied. The release profiles were fitted by zeroorder and Ritger-Peppas models. The ultrasound increased the amount of released dexamethasone by 6% to 105% depending on the type of copolymer, the amount of loaded dexamethasone, and the stimulation time point. This study investigates for the first time the interaction between different poly(2-oxazoline)-based micelle formulations and ultrasound waves, quantifying the efficacy of such stimulation in modulating dexamethasone release from these nanocarriers. KW - Acoustics KW - Biomedical engineering KW - Drug delivery KW - Materials chemistry Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227277 VL - 8 ER - TY - JOUR A1 - Hahn, Lukas A1 - Beudert, Matthias A1 - Gutmann, Marcus A1 - Keßler, Larissa A1 - Stahlhut, Philipp A1 - Fischer, Lena A1 - Karakaya, Emine A1 - Lorson, Thomas A1 - Thievessen, Ingo A1 - Detsch, Rainer A1 - Lühmann, Tessa A1 - Luxenhofer, Robert T1 - From Thermogelling Hydrogels toward Functional Bioinks: Controlled Modification and Cytocompatible Crosslinking JF - Macromolecular Bioscience N2 - Hydrogels are key components in bioink formulations to ensure printability and stability in biofabrication. In this study, a well-known Diels-Alder two-step post-polymerization modification approach is introduced into thermogelling diblock copolymers, comprising poly(2-methyl-2-oxazoline) and thermoresponsive poly(2-n-propyl-2-oxazine). The diblock copolymers are partially hydrolyzed and subsequently modified by acid/amine coupling with furan and maleimide moieties. While the thermogelling and shear-thinning properties allow excellent printability, trigger-less cell-friendly Diels-Alder click-chemistry yields long-term shape-fidelity. The introduced platform enables easy incorporation of cell-binding moieties (RGD-peptide) for cellular interaction. The hydrogel is functionalized with RGD-peptides using thiol-maleimide chemistry and cell proliferation as well as morphology of fibroblasts seeded on top of the hydrogels confirm the cell adhesion facilitated by the peptides. Finally, bioink formulations are tested for biocompatibility by incorporating fibroblasts homogenously inside the polymer solution pre-printing. After the printing and crosslinking process good cytocompatibility is confirmed. The established bioink system combines a two-step approach by physical precursor gelation followed by an additional chemical stabilization, offering a broad versatility for further biomechanical adaptation or bioresponsive peptide modification. KW - chemical crosslinking KW - biofabrication KW - bioprinting KW - hydrogels Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257542 VL - 21 IS - 10 ER - TY - JOUR A1 - Haider, Malik Salman A1 - Ahmad, Taufiq A1 - Yang, Mengshi A1 - Hu, Chen A1 - Hahn, Lukas A1 - Stahlhut, Philipp A1 - Groll, Jürgen A1 - Luxenhofer, Robert T1 - Tuning the thermogelation and rheology of poly(2-oxazoline)/poly(2-oxazine)s based thermosensitive hydrogels for 3D bioprinting JF - Gels N2 - As one kind of “smart” material, thermogelling polymers find applications in biofabrication, drug delivery and regenerative medicine. In this work, we report a thermosensitive poly(2-oxazoline)/poly(2-oxazine) based diblock copolymer comprising thermosensitive/moderately hydrophobic poly(2-N-propyl-2-oxazine) (pPrOzi) and thermosensitive/moderately hydrophilic poly(2-ethyl-2-oxazoline) (pEtOx). Hydrogels were only formed when block length exceeded certain length (≈100 repeat units). The tube inversion and rheological tests showed that the material has then a reversible sol-gel transition above 25 wt.% concentration. Rheological tests further revealed a gel strength around 3 kPa, high shear thinning property and rapid shear recovery after stress, which are highly desirable properties for extrusion based three-dimensional (3D) (bio) printing. Attributed to the rheology profile, well resolved printability and high stackability (with added laponite) was also possible. (Cryo) scanning electron microscopy exhibited a highly porous, interconnected, 3D network. The sol-state at lower temperatures (in ice bath) facilitated the homogeneous distribution of (fluorescently labelled) human adipose derived stem cells (hADSCs) in the hydrogel matrix. Post-printing live/dead assays revealed that the hADSCs encapsulated within the hydrogel remained viable (≈97%). This thermoreversible and (bio) printable hydrogel demonstrated promising properties for use in tissue engineering applications. KW - poly(2-ethyl-2-oxazoline) KW - shear thinning KW - shape fidelity KW - cyto-compatibility KW - bio-printability Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241781 SN - 2310-2861 VL - 7 IS - 3 ER - TY - JOUR A1 - Borova, Solomiia A1 - Schlutt, Christine A1 - Nickel, Joachim A1 - Luxenhofer, Robert T1 - A Transient Initiator for Polypeptoids Postpolymerization α‐Functionalization via Activation of a Thioester Group JF - Macromolecular Chemistry and Physics N2 - Here, a postpolymerization modification method for an α-terminal functionalized poly-(N-methyl-glycine), also known as polysarcosine, is introduced. 4-(Methylthio)phenyl piperidine-4-carboxylate as an initiator for the ring-opening polymerization of N-methyl-glycine-N-carboxyanhydride followed by oxidation of the thioester group to yield an α-terminal reactive 4-(methylsulfonyl)phenyl piperidine-4-carboxylate polymer is utilized. This represents an activated carboxylic acid terminus, allowing straightforward modification with nucleophiles under mild reaction conditions and provides the possibility to introduce a wide variety of nucleophiles as exemplified using small molecules, fluorescent dyes, and model proteins. The new initiator yielded polymers with well-defined molar mass, low dispersity, and high end-group fidelity, as observed by gel permeation chromatography, nuclear magnetic resonance spectroscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy. The introduced method can be of great interest for bioconjugation, but requires optimization, especially for protein conjugation. KW - ring-opening polymerization KW - bioconjugation KW - functional initiators KW - polypeptoids KW - postpolymerization modification Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257587 VL - 223 IS - 3 ER - TY - JOUR A1 - Haider, Malik Salman A1 - Ahmad, Taufiq A1 - Groll, Jürgen A1 - Scherf-Clavel, Oliver A1 - Kroiss, Matthias A1 - Luxenhofer, Robert T1 - The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging JF - European Journal of Drug Metabolism and Pharmacokinetics N2 - Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren®). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably. Mitotane as tablet form is currently the standard treatment for adrenocortical carcinoma. It has been used for 5 decades but suffers from highly variable responses in patients, subsequent adverse effects and overall lower response rate. This can be fundamentally linked to the exceedingly poor water solubility of mitotane itself. In terms of enhancing water solubility, a few research groups have attempted to develop better formulations of mitotane to overcome the issues associated with tablet dosage form. However, the success rate was limited, and these formulations did not make it into the clinics. In this article, we have comprehensively reviewed the properties of these formulations and discuss the reasons for their limited utility. Furthermore, we discuss a recently developed mitotane nanoformulation that led us to propose a novel approach to mitotane therapy, where intravenous delivery supplements the standard oral administration. With this article, we combine the current state of knowledge as a single piece of information about the various problems associated with the use of mitotane tablets, and herein we postulate the development of a new injectable mitotane formulation, which can potentially circumvent the major problems associated to mitotane's poor water solubility. KW - Mitotane KW - cancer KW - adrenal gland Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270476 SN - 2107-0180 VL - 46 IS - 5 ER - TY - JOUR A1 - Lübtow, Michael M. A1 - Lorson, Thomas A1 - Finger, Tamara A1 - Gröber-Becker, Florian-Kai A1 - Luxenhofer, Robert T1 - Combining Ultra-High Drug-Loaded Micelles and Injectable Hydrogel Drug Depots for Prolonged Drug Release JF - Macromolecular Chemistry and Physics N2 - Hydrogel‐based drug depot formulations are of great interest for therapeutic applications. While the biological activity of such drug depots is often characterized well, the influence of incorporated drug or drug‐loaded micelles on the gelation properties of the hydrogel matrix is less investigated. However, the latter is of great importance from fundamental and application points of view as it informs on the physicochemical interactions of drugs and water‐swollen polymer networks and it determines injectability, depot stability, as well as drug‐release kinetics. Here, the impact of incorporated drug, neat polymer micelles, and drug‐loaded micelles on the viscoelastic properties of a cytocompatible hydrogel is investigated systematically. To challenge the hydrogel with regard to the desired application as injectable drug depot, curcumin (CUR) is chosen as a model compound due to its very low‐water solubility and limited stability. CUR is either directly solubilized by the hydrogel or pre‐incorporated into polymer micelles. Interference of CUR with the temperature‐induced gelation process can be suppressed by pre‐incorporation into polymer micelles forming a binary drug delivery system. Drug release from a collagen matrix is studied in a trans‐well setup. Compared to direct injection of drug formulations, the hydrogel‐based systems show improved and extended drug release over 10 weeks. KW - curcumin KW - drug depots KW - drug-loaded hydrogels KW - poly(2-oxazine) KW - sustained release KW - poly(2- oxazoline) Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208115 VL - 221 IS - 1 ER -