| Popis: |
Despite advances in nanomedicine and immunotherapy that have led to substantial improvements in cancer therapy, effective drug delivery remains a major hurdle for successful long-term treatment. Cell-based delivery systems that exhibit tumor tropism like bacteria have been proposed as therapeutic agents capable of addressing persisting challenges such as off-target effects and insufficient drug distribution inside the tumor. The benefits offered by the intrinsic properties of these living therapeutics can be further enhanced by application of external forces. The human body is transparent to magnetic fields, making this external source of energy an especially promising means for remote manipulation of the cell-based systems in vivo. Intrinsically magnetically responsive bacteria, also referred as magnetotactic bacteria (MTB), present a unique opportunity for combining both innate and external tumor targeting strategies within a single drug delivery platform. This thesis investigates magnetically assisted transport mechanisms to improve tumor drug delivery by using MTB as a model organism. Rotating magnetic fields (RMF) are chosen as the primary stimulus for magnetic actuation due to the scalability of magnetic torque-based techniques for clinical applications. Starting with remote micro manipulation of bacteria, ferrohydrodynamic phenomena associated with dense suspensions of MTB are studied experimentally and computationally, conceptualizing them as a living ferrofluid. Benchmarking against a synthetic ferrofluid composed of a suspension of iron oxide nanoparticles (IONPs) revealed that the MTB suspensions exhibit an increase of more than two orders of magnitude in flow generated per gram of magnetic material. Detailed comparison of the MTB and IONPs further support the use of bacteria as efficient flow mediators, converting the magnetic energy into a more homogeneous torque-driven fluid motion. After identifying MTB as promising torque actuators, the torque-driven transport mechanisms behind their capacity to overcome biological barriers are elucidated through the establishment of computational and in vitro models. Enhanced surface exploration is shown to increase the likelihood of translocation in the presence of dynamic gaps observed in physiological barriers. Microfluidic devices incorporating collagen gels and endothelialized channels were fabricated as physiologically relevant models for identifying suitable actuation parameters. In agreement with the results of these test platforms, a subsequent in vivo study demonstrates enhanced delivery of MTB through actuation with RMF. As a crucial step towards targeted actuation at larger scales, a scheme for spatially selective manipulation of MTB is identified based on application of a static gating field to suppress the magnetic torque in off-target areas. The application of a selection field at small scales is shown to localize the influence of actuation to the target, leaving off-target areas nearly unaffected. Lastly, the scalability of this actuation scheme is demonstrated by steps taken to design and build a mouse scale setup for in vivo studies. The multi-component setup can generate an RMF of up to 20 mT and a field free region (FFR) with an average 1 cm resolution that can be moved in space by addition of the offset fields. The thesis concludes with a summary and remarks on future in vivo studies enabled by the development of a mouse scale setup. Potential extensions of the findings to other magnetically responsive cell-based systems are also discussed. |
