Establishment of a Rodent Glioblastoma Partial Resection Model for Chemotherapy by Local Drug Carriers-Sharing Experience.

Local drug delivery systems (LDDS) represent a promising therapy strategy concerning the most common and malignant primary brain tumor glioblastoma (GBM). Nevertheless, to date, only a few systems have been clinically applied, and their success is very limited. Still, numerous new LDDS approaches are currently being developed. Here, (partial resection) GBM animal models play a key role, as such models are needed to evaluate the therapy prior to any human application. However, such models are complex to establish, and only a few reports detail the process. Here, we report our results of establishing a partial resection glioma model in rats suitable for evaluating LDDS. C6-bearing Wistar rats and U87MG-spheroids- and patient-derived glioma stem-like cells-bearing athymic rats underwent tumor resection followed by the implantation of an exemplary LDDS. Inoculation, tumor growth, residual tumor tissue, and GBM recurrence were reliably imaged using high-resolution Magnetic Resonance Imaging. The release from an exemplary LDDS was verified in vitro and in vivo using Fluorescence Molecular Tomography. The presented GBM partial resection model appears to be well suited to determine the efficiency of LDDS. By sharing our expertise, we intend to provide a powerful tool for the future testing of these very promising systems, paving their way into clinical application.

Overcoming Water Diffusion Limitations in Hydrogels via Microtubular Graphene Networks for Soft Actuators.

Hydrogel-based soft actuators can operate in sensitive environments, bridging the gap of rigid machines interacting with soft matter. However, while stimuli-responsive hydrogels can undergo extreme reversible volume changes of up to ≈90%, water transport in hydrogel actuators is in general limited by their poroelastic behavior. For poly(N-isopropylacrylamide) (PNIPAM) the actuation performance is even further compromised by the formation of a dense skin layer. Here it is shown, that incorporating a bioinspired microtube graphene network into a PNIPAM matrix with a total porosity of only 5.4% dramatically enhances actuation dynamics by up to ≈400% and actuation stress by ≈4000% without sacrificing the mechanical stability, overcoming the water transport limitations. The graphene network provides both untethered light-controlled and electrically powered actuation. It is anticipated that the concept provides a versatile platform for enhancing the functionality of soft matter by combining responsive and 2D materials, paving the way toward designing soft intelligent matter.

Sequential Treatment with Temozolomide Plus Naturally Derived AT101 as an Alternative Therapeutic Strategy: Insights into Chemoresistance Mechanisms of Surviving Glioblastoma Cells.

Glioblastoma (GBM) is a poorly treatable disease due to the fast development of tumor recurrences and high resistance to chemo- and radiotherapy. To overcome the highly adaptive behavior of GBMs, especially multimodal therapeutic approaches also including natural adjuvants have been investigated. However, despite increased efficiency, some GBM cells are still able to survive these advanced treatment regimens. Given this, the present study evaluates representative chemoresistance mechanisms of surviving human GBM primary cells in a complex in vitro co-culture model upon sequential application of temozolomide (TMZ) combined with AT101, the R(-) enantiomer of the naturally occurring cottonseed-derived gossypol. Treatment with TMZ+AT101/AT101, although highly efficient, yielded a predominance of phosphatidylserine-positive GBM cells over time. Analysis of the intracellular effects revealed phosphorylation of AKT, mTOR, and GSK3ß, resulting in the induction of various pro-tumorigenic genes in surviving GBM cells. A Torin2-mediated mTOR inhibition combined with TMZ+AT101/AT101 partly counteracted the observed TMZ+AT101/AT101-associated effects. Interestingly, treatment with TMZ+AT101/AT101 concomitantly changed the amount and composition of extracellular vesicles released from surviving GBM cells. Taken together, our analyses revealed that even when chemotherapeutic agents with different effector mechanisms are combined, a variety of chemoresistance mechanisms of surviving GBM cells must be taken into account.

Fabrication and Modelling of a Reservoir-Based Drug Delivery System for Customizable Release.

Localized therapy approaches have emerged as an alternative drug administration route to overcome the limitations of systemic therapies, such as the crossing of the blood-brain barrier in the case of brain tumor treatment. For this, implantable drug delivery systems (DDS) have been developed and extensively researched. However, to achieve an effective localized treatment, the release kinetics of DDS needs to be controlled in a defined manner, so that the concentration at the tumor site is within the therapeutic window. Thus, a DDS, with patient-specific release kinetics, is crucial for the improvement of therapy. Here, we present a computationally supported reservoir-based DDS (rDDS) development towards patient-specific release kinetics. The rDDS consists of a reservoir surrounded by a polydimethylsiloxane (PDMS) microchannel membrane. By tailoring the rDDS, in terms of membrane porosity, geometry, and drug concentration, the release profiles can be precisely adapted, with respect to the maximum concentration, release rate, and release time. The release is investigated using a model dye for varying parameters, leading to different distinct release profiles, with a maximum release of up to 60 days. Finally, a computational simulation, considering exemplary in vivo conditions (e.g., exchange of cerebrospinal fluid), is used to study the resulting drug release profiles, demonstrating the customizability of the system. The establishment of a computationally supported workflow, for development towards a patient-specific rDDS, in combination with the transfer to suitable drugs, could significantly improve the efficacy of localized therapy approaches.

Microengineered Hollow Graphene Tube Systems Generate Conductive Hydrogels with Extremely Low Filler Concentration.

The fabrication of electrically conductive hydrogels is challenging as the introduction of an electrically conductive filler often changes mechanical hydrogel matrix properties. Here, we present an approach for the preparation of hydrogel composites with outstanding electrical conductivity at extremely low filler loadings (0.34 S m-1, 0.16 vol %). Exfoliated graphene and polyacrylamide are microengineered to 3D composites such that conductive graphene pathways pervade the hydrogel matrix similar to an artificial nervous system. This makes it possible to combine both the exceptional conductivity of exfoliated graphene and the adaptable mechanical properties of polyacrylamide. The demonstrated approach is highly versatile regarding porosity, filler material, as well as hydrogel system. The important difference to other approaches is that we keep the original properties of the matrix, while ensuring conductivity through graphene-coated microchannels. This novel approach of generating conductive hydrogels is very promising, with particular applications in the fields of bioelectronics and biohybrid robotics.