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International audience; Micro- and nanomotors have seen substantial progress in recent years for biomedical applications. However, three grand challenges remain: (i) high velocities to overcome the blood flow, (ii) spatially selective control to enable complex navigation, and (iii) integration of a medical, tomographic real-time imaging method to acquire feedback information. Here, we report the combination of active magnetic matter and a medical imaging technique, namely magnetic particle imaging (MPI), which addresses these needs. We synthesize ∼200 nm magnetic nanoparticles and observe a macroscopic, collective effect in a homogeneous magnetic field with a rotating field vector. The nanoparticles form a millimeter-sized cloud and reach speeds of 8 mm s–1. This cloud is imaged and selectively steered with an MPI scanner. Our experimental results are supported by a model that highlights the role of the Mason number, the particle’s volume fraction, and the height of the cloud. The successful introduction of a fast swarm of microscopic units and the spatial selectivity of the technique suggest an effective approach to translate the use of micro- and nanobots into a clinical application.

Microswimmers are smart devices with potential applications in medicine and biotechnology at the micrometer-scale. Magnetic micropropellers with their remote control via rotating magnetic fields are especially auspicious. Helicoidal propellers with a linear velocity-frequency dependence emerged as the standard propulsion mechanism over the last decade. However, with their functions becoming more pivotal on the way to practical uses, deviations in shape and swimming behavior are inevitable. Consequently, propellers with nonlinear velocity-frequency relationships arise that not only pose different challenges but also offer advanced possibilities. The most critical nonlinearities are the wobbling behavior with its solution branching that has potential for bimodal swimming and the swimming characteristics in the step-out regime that are essential for selection and swarm control. Here, we show experimentally and with numerical calculations how the previously unpredictable branching can be controlled and, thus, becomes utilizable with an example 3D-printed swimmer device. Additionally, we report how two step-out modes arise for propellers with a nonlinear velocity-frequency dependence that have the potential to accelerate future microswimmer sorting procedures., Max Planck Society; Deutsche Forschungs-gemeinschaft; Priority Program 1726 Microswimmers

International audience; Glioblastoma (GBM) are aggressive brain tumors with limited treatment options. Cancer stem-like cells (CSLCs) contribute to GBM invasiveness, representing promising targets. BAL101553, a prodrug of BAL27862, is a novel small molecule tubulin-binding agent, promoting tumor cell death through spindle assembly checkpoint activation, which is currently in Phase 1/2a in advanced solid tumor patients including GBM. This study aimed to evaluate long-term daily oral BAL101553 treatment of mice orthotopically grafted with GBM CSLCs (GBM6) according to EB1 expression-level, and to decipher its mechanism of action on GBM stem cells. Oral treatment with BAL101553 for 100 days provoked a large EB1 expression level-dependent survival benefit, together with a decrease in tumor growth and brain invasion. Formation of vascular structures by the fluorescent GBM6-GFP-sh0 cells, mimicking endothelial vascular networks, was observed in the brains of control grafted mice. Following BAL101553 treatment, vessels were no longer detectable, suggesting inhibition of the endothelial trans-differentiation of GBM stem cells. In vitro, BAL27862 treatment resulted in a switch to the endothelial-like phenotype of GBM6 towards an astrocytic phenotype. Moreover, the drug inhibited secretion of VEGF, thus preventing normal endothelial cell migration activated by CSLCs. The decrease in VEGF secretion was confirmed in a human GBM explant following drug treatment. Altogether, our data first confirm the potential of EB1 expression as a response-predictive biomarker of BAL101553 in GBM we previously published and add new insights in BAL101553 long-term action by counteracting CSLCs mediated tumor angiogenesis. Our results strongly support BAL101553 clinical studies in GBM patients.

Funder: Max-Planck-Gesellschaft; FundRef: http://dx.doi.org/10.13039/501100004189, Funder: IMPRS on Multiscale Biosystems, Funder: French National Research Agency; FundRef: http://dx.doi.org/10.13039/501100001665; Grant(s): ANR Tremplin-ERC: ANR-16-TERC-0025-01, Bacteria propel and change direction by rotating long, helical filaments, called flagella. The number of flagella, their arrangement on the cell body and their sense of rotation hypothetically determine the locomotion characteristics of a species. The movement of the most rapid microorganisms has in particular remained unexplored because of additional experimental limitations. We show that magnetotactic cocci with two flagella bundles on one pole swim faster than 500 µm·s-1 along a double helical path, making them one of the fastest natural microswimmers. We additionally reveal that the cells reorient in less than 5 ms, an order of magnitude faster than reported so far for any other bacteria. Using hydrodynamic modeling, we demonstrate that a mode where a pushing and a pulling bundle cooperate is the only possibility to enable both helical tracks and fast reorientations. The advantage of sheathed flagella bundles is the high rigidity, making high swimming speeds possible.

The field of synthetic microswimmers, micro-robots moving in aqueous environments, has evolved significantly in the last years. Micro-robots actuated and steered by external magnetic fields are of particular interest because of the biocompatibility of this energy source and the possibility of remote control, features suited for biomedical applications. While initial work has mostly focused on helical shapes, the design space under consideration has widened considerably with recent works, opening up new possibilities for optimization of propellers to meet specific requirements. Understanding the relation between shape on the one hand and targeted actuation and steerability on the other hand requires an understanding of their propulsion behavior. Here we propose hydrodynamic simulations for the characterization of rigid micropropellers of any shape, actuated by rotating external magnetic fields. We approximate the shape of micropropellers by an ensemble of rigidly connected spheres, for which the mobility matrices can be calculated via the method of reflections. We characterize the influence of model parameters such as bead size, distance between beads and magnetic properties on the swimming behavior of helical propellers to identify optimal simulation parameters. We then apply the simulation to randomly shaped propeller, specifically to a recently characterized propeller shape and study their frequency- dependent swimming behaviors. The simulations show that the orientation of the magnetic moment with respect to the propeller’s internal coordinate system has a strong impact on the propulsion behavior and has to be known with a precision of ≤ 5 ◦ to predict the propeller’s velocity-frequency curve. This result emphasizes the importance of the magnetic properties of the micropropellers for the design of desired functionalities for potential biomedical applications, and in particular the importance of their orientation within the propeller’s structure.

International audience; Many motile microorganisms swim and navigate in chemically and mechanically complex environments. These organisms can be functionalized and directly used for applications (biohybrid approach), but also inspire designs for fully synthetic microbots. The most promising designs of biohybrids and bioinspired microswimmers include one or several magnetic components, which lead to sustainable propulsion mechanisms and external controllability. This Review addresses such magnetic microswimmers, which are often studied in view of certain applications, mostly in the biomedical area, but also in the environmental field. First, propulsion systems at the microscale are reviewed and the magnetism of microswimmers is introduced. The review of the magnetic biohybrids and bioinspired microswimmers is structured gradually from mostly biological systems toward purely synthetic approaches. Finally, currently less explored parts of this field ranging from in situ imaging to swarm control are discussed.

Glioblastoma patients have limited treatment options. Cancer stem-like cells (CSLC) contribute to glioblastoma invasiveness and repopulation; hence, they represent promising targets for novel therapies. BAL101553 is a prodrug of BAL27862, a novel microtubule-destabilizing agent inhibiting tumor cell proliferation through activation of the spindle assembly checkpoint, which is currently in phase I/II clinical development. Broad anticancer activity has been demonstrated against human cancer models, including tumors refractory to conventional treatments. We have shown that overexpression of microtubule + end-binding 1-protein (EB1) correlates with glioblastoma progression and poor survival. Here, we show that BAL27862 inhibits the growth of two glioblastoma CSLCs. As EB1 is overexpressed in the CSLC line GBM6, which displays a high tumorigenicity and infiltrative pattern of migration in vivo, we investigated drug activity on GBM6 according to EB1 expression. BAL27862 inhibited migration and colony formation at subcytotoxic concentrations in EB1-expressing control cells (GBM6-sh0) but only at cytotoxic concentrations in EB1-downregulated (GBM-shE1) cells. Three administrations of BAL101553 were sufficient to provoke an EB1-dependent survival benefit in tumor-bearing mice. Patterns of invasion and quantification of tumor cells in brain demonstrated that GBM6-sh0 cells were more invasive than GBM6-shEB1 cells, and that the antiproliferative and anti-invasive effects of BAL101553 were more potent in mice bearing control tumors than in EB1-downregulated tumors. This was associated with inhibition of stem cell properties in the GBM6-sh0 model. Finally, BAL27862 triggered astrocytic differentiation of GBM6 in an EB1-dependent manner. These results support the potential of BAL101553 for glioblastoma treatment, with EB1 expression as a predictive biomarker of response. Mol Cancer Ther; 15(11); 2740–9. ©2016 AACR.