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A hyperbranched dopamine-containing PEG-based polymer for the inhibition of α-synuclein fibrillation
2015, Breydo, Leonid, Newland, Ben, Zhang, Hong, Rosser, Anne, Werner, Carsten, Uversky, Vladimir N., Wang, Wenxin
Aggregation of α-synuclein is believed to play an important role in Parkinson's disease and in other neurodegenerative maladies. Small molecule inhibitors of this process are among the most promising drug candidates for neurodegenerative diseases. Dendrimers have also been studied for anti-fibrillation applications but they can be difficult and expensive to synthetize. Here we show that RAFT polymerization can be used to produce a hyperbranched polyethylene glycol structure via a one-pot reaction. This polymer included a dopamine moiety, a known inhibitor of α-synuclein fibril formation. Dopamine within the polymer structure was capable of aggregation inhibition, although not to the same degree as free dopamine. This result opens up new avenues for the use of controlled radical polymerizations as a means of preparing hyperbranched polymers for anti-fibrillation activity, but shows that the incorporation of functional groups from known small molecules within polymers may alter their biological activity.
Magnetically Controllable Polymer Nanotubes from a Cyclized Crosslinker for Site-Specific Delivery of Doxorubicin
2015, Newland, Ben, Leupelt, Daniel, Zheng, Yu, Thomas, Laurent S.V., Werner, Carsten, Steinhart, Martin, Wang, Wenxin
Externally controlled site specific drug delivery could potentially provide a means of reducing drug related side effects whilst maintaining, or perhaps increasing therapeutic efficiency. The aim of this work was to develop a nanoscale drug carrier, which could be loaded with an anti-cancer drug and be directed by an external magnetic field. Using a single, commercially available monomer and a simple one-pot reaction process, a polymer was synthesized and crosslinked within the pores of an anodized aluminum oxide template. These polymer nanotubes (PNT) could be functionalized with iron oxide nanoparticles for magnetic manipulation, without affecting the large internal pore, or inherent low toxicity. Using an external magnetic field the nanotubes could be regionally concentrated, leaving areas devoid of nanotubes. Lastly, doxorubicin could be loaded to the PNTs, causing increased toxicity towards neuroblastoma cells, rendering a platform technology now ready for adaptation with different nanoparticles, degradable pre-polymers and various therapeutics.
Poly(ethylene glycol) based nanotubes for tuneable drug delivery to glioblastoma multiforme
2020, Alghamdi, Majed, Chierchini, Filippo, Eigel, Dimitri, Taplan, Christian, Miles, Thomas, Pette, Dagmar, Welzel, Petra B., Werner, Carsten, Wang, Wenxin, Neto, Catia, Gumbleton, Mark, Newland, Ben
Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumour, which is associated with a poor two-year survival rate and a high rate of fatal recurrence near the original tumour. Focal/local drug delivery devices hold promise for improving therapeutic outcomes for GBM by increasing drug concentrations locally at the tumour site, or by facilitating the use of potent anti-cancer drugs that are poorly permeable across the blood brain barrier (BBB). For inoperable tumours, stereotactic delivery to the tumour necessitates the development of nanoscale/microscale injectable drug delivery devices. Herein we assess the ability of a novel class of polymer nanotube (based on poly(ethylene glycol) (PEG)) to load doxorubicin (a mainstay breast cancer therapeutic with poor BBB permeability) and release it slowly. The drug loading properties of the PEG nanotubes could be tuned by varying the degree of carboxylic acid functionalisation and hence the capacity of the nanotubes to electrostatically bind and load doxorubicin. 70% of the drug was released over the first seven days followed by sustained drug release for the remaining two weeks tested. Unloaded PEG nanotubes showed no toxicity to any of the cell types analysed, whereas doxorubicin loaded nanotubes decreased GBM cell viability (C6, U-87 and U-251) in a dose dependent manner in 2Din vitroculture. Finally, doxorubicin loaded PEG nanotubes significantly reduced the viability ofin vitro3D GBM models whilst unloaded nanotubes showed no cytotoxicity. Taken together, these findings show that polymer nanotubes could be used to deliver alternative anti-cancer drugs for local therapeutic strategies against brain cancers. © The Royal Society of Chemistry 2020.
Injectable Glycosaminoglycan-Based Cryogels from Well-Defined Microscale Templates for Local Growth Factor Delivery
2021, Newland, Ben, Newland, Heike, Lorenzi, Francesca, Eigel, Dimitri, Dieter FischerWelzel, Petra B., Fischer, Dieter, Wang, Wenxin, Freudenberg, Uwe, Rosser, Anne, Werner, Carsten
Glycosaminoglycan-based hydrogels hold great potential for applications in tissue engineering and regenerative medicine. By mimicking the natural extracellular matrix processes of growth factor binding and release, such hydrogels can be used as a sustained delivery device for growth factors. Since neural networks commonly follow well-defined, high-aspect-ratio paths through the central and peripheral nervous system, we sought to create a fiber-like, elongated growth factor delivery system. Cryogels, with networks formed at subzero temperatures, are well-suited for the creation of high-aspect-ratio biomaterials, because they have a macroporous structure making them mechanically robust (for ease of handling) yet soft and highly compressible (for interfacing with brain tissue). Unlike hydrogels, cryogels can be synthesized in advance of their use, stored with ease, and rehydrated quickly to their original shape. Herein, we use solvent-assisted microcontact molding to form sacrificial templates, in which we produced highly porous cryogel microscale scaffolds with a well-defined elongated shape via the photopolymerization of poly(ethylene glycol) diacrylate and maleimide-functionalized heparin. Dissolution of the template yielded cryogels that could load nerve growth factor (NGF) and release it over a period of 2 weeks, causing neurite outgrowth in PC12 cell cultures. This microscale template-assisted synthesis technique allows tight control over the cryogel scaffold dimensions for high reproducibility and ease of injection through fine gauge needles. ©