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- ItemDendritic glycopolymers based on dendritic polyamine scaffolds: view on their synthetic approaches, characteristics and potential for biomedical applications(London : Soc., 2014) Appelhans, Dietmar; Klajnert-Maculewicz, Barbara; Janaszewska, Anna; Lazniewska, Joanna; Voit, BrigitteIn this review we highlight the potential for biomedical applications of dendritic glycopolymers based on polyamine scaffolds. The complex interplay of the molecular characteristics of the dendritic architectures and their specific interactions with various (bio)molecules are elucidated with various examples. A special role of the individual sugar units attached to the dendritic scaffolds and their density is identified, which govern ionic and H-bond interactions, and biological targeting, but to a large extent are also responsible for the significantly reduced toxicity of the dendritic glycopolymers compared to their polyamine scaffolds. Thus, the application of dendritic glycopolymers in drug delivery systems for gene transfection but also as therapeutics in neurodegenerative diseases has great promise.
- ItemLong-Term Retarded Release for the Proteasome Inhibitor Bortezomib through Temperature-Sensitive Dendritic Glycopolymers as Drug Delivery System from Calcium Phosphate Bone Cement(Weinheim : Wiley-VCH, 2021) Lai, Thu Hang; Keperscha, Bettina; Qiu, Xianping; Voit, Brigitte; Appelhans, DietmarFor the local treatment of bone defects, highly adaptable macromolecular architectures are still required as drug delivery system (DDS) in solid bone substitute materials. Novel DDS fabricated by host–guest interactions between β-cyclodextrin-modified dendritic glycopolymers and adamantane-modified temperature-sensitive polymers for the proteasome inhibitor bortezomib (BZM) is presented. These DDS induce a short- and long-term (up to two weeks) retarded release of BZM from calcium phosphate bone cement (CPC) in comparison to a burst release of the drug alone. Different release parameters of BZM/DDS/CPC are evaluated in phosphate buffer at 37 °C to further improve the long-term retarded release of BZM. This is achieved by increasing the amount of drug (50–100 µg) and/or DDS (100–400 µg) versus CPC (1 g), by adapting the complexes better to the porous bone cement environment, and by applying molar ratios of excess BZM toward DDS with 1:10, 1:25, and 1:100. The temperature-sensitive polymer shells of BZM/DDS complexes in CPC, which allow drug loading at room temperature but are collapsed at body temperature, support the retarding long-term release of BZM from DDS/CPC. Thus, the concept of temperature-sensitive DDS for BZM/DDS complexes in CPC works and matches key points for a local therapy of osteolytic bone lesions.
- ItemMatrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis(New York, NY [u.a.] : Elsevier, 2021) Geervliet, Eline; Moreno, Silvia; Baiamonte, Luca; Booijink, Richell; Boye, Susanne; Wang, Peng; Voit, Brigitte; Lederer, Albena; Appelhans, Dietmar; Bansal, RuchiLiver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable therapies available, liver transplantation is the only curative treatment for advanced diseased patients. Excessive accumulation of aberrant extracellular matrix (ECM) proteins, mostly collagens, produced by activated hepatic stellate cells (HSCs), is a hallmark of liver fibrosis. Several studies have suggested an inverse correlation between collagen-I degrading matrix metalloproteinase-1 (MMP-1) serum levels and liver fibrosis progression highlighting reduced MMP-1 levels are associated with poor disease prognosis in patients with liver fibrosis. We hypothesized that delivery of MMP-1 might potentiate collagen degradation and attenuate fibrosis development. In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes (MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of liver fibrosis. The storage-stable and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1. MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization, stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes versus MMP-1, empty polymersomes (Psomes) and MMP-1 + Psomes on gene and protein expression of collagen-I, MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in carbon-tetrachloride (CCl4)-induced early liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1 surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl4-induced early liver fibrosis mouse model, MMPsomes inhibited intra-hepatic collagen-I (ECM marker, indicating early liver fibrosis) and F4/80 (marker for macrophages, indicating liver inflammation) expression. In conclusion, our results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating liver fibrosis.
- ItemReconstitution properties of biologically active polymersomes after cryogenic freezing and a freeze-drying process(London : RSC Publishing, 2018) Ccorahua, Robert; Moreno, Silvia; Gumz, Hannes; Sahre, Karin; Voit, Brigitte; Appelhans, DietmarReconstitution of biologically active polymersomes from the frozen or solid state into any fluid state is still a challenging issue for the design of new biological experiments and for the formulation of therapeutic agents. To gain knowledge about the reconstitution of pH-responsive and photo-crosslinked polymersomes, surface-functionalized and enzyme-containing polymersomers were cryogenically frozen (-20 °C) or freeze-dried with inulin as the lyoprotectant (0.1% w/v) and stored for a defined time period. Reconstituting those polymersomes in solution by thawing or a re-dispersing process revealed their original physical properties as well as their function as a pH-switchable enzymatic nanoreactor.