Spatio-temporal control of immune cell trafficking by multifunctional nanoconstructs in vivo

This research project ended with the first funding period.

Project history

According to the overall guiding idea of this CRC which is to design and engineer synthetic biomolecular constructs, i.e., nanoagents, that are capable of gaining spatiotemporal control over molecular and cellular reactions, the project aimed in the long run to control/program leukocyte trafficking by using nanoagents, including leukocyte recruitment to the tissue as well as directed leukocyte migration within tissue.
Therefore, this project was designed to explore the potential of nanoconstructs to control the dynamics of immune cell migration in vitro and in murine models in vivo.
To achieve this goal we have proposed to:
(1) investigate the positioning and distribution of (switchable) nanoconstructs in complex 3D microenvironments
(2) use nanoconstructs to influence leukocyte motility in tissue
(3) provide an in vivo platform for other projects of this CRC, thus offering the possibility for fast in vivo translation of nanoagents developed in the CRC
Accordingly, in the first part we have investigated the tissue distribution and cellular interactions of DNA nanotubes (publication together with A06, Sellner et al., Biomaterials 2015) and quantum dots (QD) with different surface chemistry (Nekolla et al, manuscript avallable on CD). In collaboration with A03 and B07 (Arends et al., Lab on a Chip, 2015), we have analyzed the diffusive spreading of molecules with different net charges and molecular weights in vivo. These results correlated well with data obtained in a microfluidic device, thus establishing an in vitro assay to study the behavior of molecules at basal lamina interfaces. Moreover, we have demonstrated that the transport of nanomaterials between macrophages in vivo is mediated by membrane nanotubes (Rehberg et al., submitted; manuscript available on CD).
The work by Sellner et al. also contributed to the second goal of the project. The DNA nanotubes used in this work were bearing immunostimulatory CpG motifs to achieve macrophage-mediated, spatio-temporally controlled leukocyte recruitment in vivo. We found that microinjection of CpG-decorated DNA nanotubes but not of plain DNA nanotubes or CpG oligonucleotides induced a significant recruitment of leukocytes into the muscle tissue as well as activation of the NF-kB pathway in surrounding cells. (Sellner et al. Biomaterials 2015) Currently, we are working on utilizing glucocorticoid-coupled DNA nanotubes as anti- inflammatory nanodevices in vivo. Furthermore, we have started to analyze the impact of different nanomaterials, QDs, DNA nanotubes (together with A06), and mesoporous silica nanoparticles (together with B05), on leukocyte migration in vitro. Additionally, we have started to use latrunculin- as well as diclofenac-releasing multifunctional mesoporous nanoparticles to impact leukocyte recruitment/migration. This project will not be finished in the current funding period.
In the third part, we have contributed in vivo data to a project of Dirk Trauners group (B09 together with B08) in which photoswitchable inhibitors of microtubule dynamics have been introduced. We showed that photostatins (PSTs) achieve fully reversible optical control over mitosis within a living organism, with single-cell spatial precision. This work was published in the journal "Cell" (Borowiak et al. Cell, 2015). We also have contributed to a study of B08 in which the migration mode of endothelial cells, based on matrix composition, was investigated.
Last, we have improved the ability of our lab to analyze nanomaterials in vivo. We have established third harmonic generation multiphoton microscopy to monitor dynamic events in the mouse ear as well as in the cremaster muscle (Dietzel et al., PlosOne, 2014) and multiphoton microscopy of non-fluorescent nanoparticles in vitro and in vivo. (Dietzel et al., manuscript available on CD)