Engineering Cell‐Based Systems for Smart Cancer Therapy

Mirkhani, Nima; Gwisai, Tinotenda; Schuerle, Simone

doi:10.1002/aisy.202100134

Cited by 15 publications

(10 citation statements)

References 319 publications

(372 reference statements)

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“…This enhanced accumulation is likely attributable to autonomous taxis-based navigation. Spheroids over 400 μm in diameter can develop a hypoxic core, and preferential accumulation of MTB in this region might result from oxygen-sensing mechanisms that facilitate their navigation toward hypoxic environments (47)(48)(49).…”

Section: Rmf-based Control Improves Mtb Transport and Colonization Of...mentioning

confidence: 99%

Magnetic torque–driven living microrobots for increased tumor infiltration

et al. 2022

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Biohybrid bacteria–based microrobots are increasingly recognized as promising externally controllable vehicles for targeted cancer therapy. Magnetic fields in particular have been used as a safe means to transfer energy and direct their motion. Thus far, the magnetic control strategies used in this context rely on poorly scalable magnetic field gradients, require active position feedback, or are ill-suited to diffuse distributions within the body. Here, we present a magnetic torque–driven control scheme for enhanced transport through biological barriers that complements the innate taxis toward tumor cores exhibited by a range of bacteria, shown for Magnetospirillum magneticum as a magnetically responsive model organism. This hybrid control strategy is readily scalable, independent of position feedback, and applicable to bacterial microrobots dispersed by the circulatory system. We observed a fourfold increase in translocation of magnetically responsive bacteria across a model of the vascular endothelium and found that the primary mechanism driving increased transport is torque-driven surface exploration at the cell interface. Using spheroids as a three-dimensional tumor model, fluorescently labeled bacteria colonized their core regions with up to 21-fold higher signal in samples exposed to rotating magnetic fields. In addition to enhanced transport, we demonstrated that our control scheme offers further advantages, including the possibility for closed-loop optimization based on inductive detection, as well as spatially selective actuation to reduce off-target effects. Last, after systemic intravenous injection in mice, we showed significantly increased bacterial tumor accumulation, supporting the feasibility of deploying this control scheme clinically for magnetically responsive biohybrid microrobots.

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Section: Rmf-based Control Improves Mtb Transport and Colonization Of...mentioning

confidence: 99%

Magnetic torque–driven living microrobots for increased tumor infiltration

et al. 2022

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“…This method is greatly beneficial for reducing the potential systemic toxicity of live GEBs (Taniguchi et al, 2010). The intratumoral injected bacteria actively or passively colonize necrosis because of their homing instincts, chemotactic effects (Mirkhani et al, 2021), and cumulative effects (Ganai et al, 2011). Then, they activate immunogenicity and release toxic molecules to induce cell apoptosis and restrain tumor growth (Yaghoubi et al, 2020;Lin et al, 2021).…”

Section: Administration Route and Performance Indicators Geb Administ...mentioning

confidence: 99%

Genetically engineered bacterium: Principles, practices, and prospects

et al. 2022

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Advances in synthetic biology and the clinical application of bacteriotherapy enable the use of genetically engineered bacteria (GEB) to combat various diseases. GEB act as a small ‘machine factory’ in the intestine or other tissues to continuously produce heterologous proteins or molecular compounds and, thus, diagnose or cure disease or work as an adjuvant reagent for disease treatment by regulating the immune system. Although the achievements of GEBs in the treatment or adjuvant therapy of diseases are promising, the practical implementation of this new therapeutic modality remains a grand challenge, especially at the initial stage. In this review, we introduce the development of GEBs and their advantages in disease management, summarize the latest research advances in microbial genetic techniques, and discuss their administration routes, performance indicators and the limitations of GEBs used as platforms for disease management. We also present several examples of GEB applications in the treatment of cancers and metabolic diseases and further highlight their great potential for clinical application in the near future.

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“…[2][3][4][5] Similar hurdles have been encountered by self-propelled therapeutic bacteria, for which delivery efficiency is especially crucial because tolerable doses are low. [6][7][8][9] Recently, the scope of investigation into biomedical microrobots suited for drug delivery has expanded remarkably. [10][11][12] Microrobots designed to convert externally applied magnetic stimuli to locomotion, convection, or other modes of therapeutic activity are particularly useful for deep physiological targets, which magnetic fields can access unencumbered.…”

Section: Introductionmentioning

confidence: 99%

Spatially selective open loop control of magnetic microrobots for drug delivery

Mirkhani

Christiansen

Gwisai

et al. 2023

Preprint

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Rotating magnetic fields (RMFs), when used to actuate biomedical microrobots for targeted delivery to tumors, have been shown to enable them to overcome physiological barriers and promote their accumulation and penetration into tissue. Nevertheless, directly applying a RMF to a deeply situated target site also leads to off-target actuation in surrounding healthy tissue. Here, we investigate an open-loop control strategy for delivering torque density to diffuse distributions of microrobots at focal points by combining RMFs with magnetostatic gating fields. Taking magnetotactic bacteria (MTB) as a model biohybrid microrobotic system for torque-based actuation, we first use simulation to elucidate off-target torque suppression and find that resolution is set by the relative magnitude of the magnetostatic field and RMF. We study focal torque delivery in vitro, observing off-target suppression of translational velocity of MTB, convection-driven accumulation of companion nanoparticles, and tumor spheroid colonization. We then design, construct, and validate a mouse-scale torque-focusing apparatus incorporating a permanent magnet array, three-phase RMF coils, and offset coils to maneuver the focal point. Our control scheme enables the advantages of torque-based actuation to be combined with spatial targeting, and could be broadly applied to other microrobotic designs for improved drug delivery.

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Engineering Cell‐Based Systems for Smart Cancer Therapy

Cited by 15 publications

References 319 publications

Magnetic torque–driven living microrobots for increased tumor infiltration

Magnetic torque–driven living microrobots for increased tumor infiltration

Genetically engineered bacterium: Principles, practices, and prospects

Spatially selective open loop control of magnetic microrobots for drug delivery

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