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Adv Sci (Weinh). 2018 Dec 5;6(3):1801309. doi: 10.1002/advs.201801309. eCollection 2019 Feb 6.

Nanoscale Bacteria-Enabled Autonomous Drug Delivery System (NanoBEADS) Enhances Intratumoral Transport of Nanomedicine.

Author information

1
Department of Mechanical Engineering Virginia Tech Blacksburg VA 24061 USA.
2
Department of Chemical Engineering Macromolecules Innovation Institute Virginia Tech Blacksburg VA 24061 USA.
3
Department of Biomedical Sciences and Pathobiology Virginia Tech Blacksburg VA 24061 USA.
4
Macromolecules Innovation Institute School of Biomedical Engineering & Sciences Virginia Tech Blacksburg VA 24061 USA.

Abstract

Cancer drug delivery remains a formidable challenge due to systemic toxicity and inadequate extravascular transport of nanotherapeutics to cells distal from blood vessels. It is hypothesized that, in absence of an external driving force, the Salmonella enterica serovar Typhimurium could be exploited for autonomous targeted delivery of nanotherapeutics to currently unreachable sites. To test the hypothesis, a nanoscale bacteria-enabled autonomous drug delivery system (NanoBEADS) is developed in which the functional capabilities of the tumor-targeting S. Typhimurium VNP20009 are interfaced with poly(lactic-co-glycolic acid) nanoparticles. The impact of nanoparticle conjugation is evaluated on NanoBEADS' invasion of cancer cells and intratumoral transport in 3D tumor spheroids in vitro, and biodistribution in a mammary tumor model in vivo. It is found that intercellular (between cells) self-replication and translocation are the dominant mechanisms of bacteria intratumoral penetration and that nanoparticle conjugation does not impede bacteria's intratumoral transport performance. Through the development of new transport metrics, it is demonstrated that NanoBEADS enhance nanoparticle retention and distribution in solid tumors by up to a remarkable 100-fold without requiring any externally applied driving force or control input. Such autonomous biohybrid systems could unlock a powerful new paradigm in cancer treatment by improving the therapeutic index of chemotherapeutic drugs and minimizing systemic side effects.

KEYWORDS:

Salmonella enterica serovar Typhimurium; bacteria‐based therapies; biohybrid systems; extravascular transport; intratumoral penetration; tumor‐targeting bacteria

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