Directed transport of bacteria-based drug delivery vehicles: bacterial chemotaxis dominates particle shape

Abstract

Several attenuated and non-pathogenic bacterial species have been demonstrated to actively target diseased sites and successfully deliver plasmid DNA, proteins and other therapeutic agents into mammalian cells. These disease-targeting bacteria can be employed for targeted delivery of therapeutic and imaging cargos in the form of a bio-hybrid system. The bio-hybrid drug delivery system constructed here is comprised of motile Escherichia coli MG1655 bacteria and elliptical disk-shaped polymeric microparticles. The transport direction for these vehicles can be controlled through biased random walk of the attached bacteria in presence of chemoattractant gradients in a process known as chemotaxis. In this work, we utilize a diffusion-based microfluidic platform to establish steady linear concentration gradients of a chemoattractant and investigate the roles of chemotaxis and geometry in transport of bio-hybrid drug delivery vehicles. Our experimental results demonstrate for the first time that bacterial chemotactic response dominates the effect of body shape in extravascular transport; thus, the non-spherical system could be more favorable for drug delivery applications owing to the known benefits of using non-spherical particles for vascular transport (e.g. relatively long circulation time).

Propulsion and Chemotaxis in Bacteria‐Driven Microswimmers

“…The simulations of the model produces 3D trajectories and motility characteristics that resemble those of experiments. The model, in combination with the signaling pathway models of bacterial chemotaxis, also traces out the chemotaxis behavior of bacteria‐driven microswimmers reported by recent studies 14, 17, 20, 21, 22, 23, 24, 25. The agreement between simulation and experiment implies that our model assumptions are reasonable and the model captures the fundamental biophysical mechanisms of the system.…”

“…Most of the studies on bacteria‐driven microswimmers adopt a similar design, which is a sphere‐shaped microbead driven by single or multiple flagellated bacteria attached to it in random locations and orientations 2, 6, 9, 11, 12, 13, 14, 17, 20, 21, 22, 23, 24, 25. This particular design is chosen for its easier fabrication, characterization, and analysis, and also isotropic physical properties, such as drag coefficient, in all orientations.…”

“…Over the past decade, numerous studies have been conducted on harnessing the flagellated bacteria, such as E. coli and S. marcescens , as propellers for biohybrid microswimmers,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 aiming to develop a new type of targeted drug delivery system for tumor therapy 14, 16, 18, 19. Recently, efforts have also been made to guide the motion of such bacteria‐driven microswimmers through taxis‐based14, 17, 20, 21, 22, 23, 24, 25 and magnetic steering16, 26 approaches. Among these studies, the most common way to integrate bacteria into biohybrid microswimmers is attaching intact bacterial cells onto the surfaces of synthetic microstructures, such as polystyrene microbeads, where the attachment could be enabled either by physical attraction2 or through chemical bonding 14.…”

“…Such natural sensing abilities of bacteria are considered to be ideal guiding mechanisms for the motion of biohybrid microsystems, especially for healthcare applications in the human body, where chemical cues are ubiquitous. Thus far, the taxis‐based guiding method constitutes the major way to regulate the otherwise highly stochastic motion of bacteria‐driven microswimmers, which has been studied both in vitro17, 20, 21, 22, 23, 24, 25 and in vivo 14, 16. Chemotaxis, one of the most common taxis behaviors in bacteria, has been well understood36 and its signaling pathway has been mathematically modeled 37, 38, 39, 40, 41, 42, 43.…”

Fabrication of nanocomposites and hybrid materials using microbial biotemplates

“…Besides, functional microparticles can be attached to a single bacterium; such biohybrid microswimmers can be used for targeted drug delivery [58]. In addition, several bacterial cells can get assemble to a whole structure, such as patterning onto a microstructure matrix or surface and thus, it can have a significant impact on motility enhancement of bacteriaactuated microswimmers [59][60][61]. Besides, bacterial cells can be attached onto the surface of microbeads where these selectively get attach on one side of microbead, which can control bacterial movement in same direction (Fig.…”