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

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.

Ditelluride-Bridged PEG-PCL Copolymer as Folic Acid-Targeted and Redox-Responsive Nanoparticles for Enhanced Cancer Therapy

“…The nanoparticles are able to increase drug accumulation in tumors via enhanced permeability and retention (EPR) effect (Maeda et al, 2013;Wilhelm et al, 2016). Among the nanoparticles reported, most of them have been decorated by PEGylation to improve the biocompatibility and stability after the administration (Butcher et al, 2016;Huckaby and Lai, 2018;Suh et al, 2019). Although outside PEG layer can validly preserve nanoparticles from rapid clearance by the reticuloendothelial system (RES) to extend their blood circulation, its application would significantly impede cellular uptake by tumor cells and result in unsatisfactory therapeutic efficiency (Zhu et al, 2012;Fang et al, 2017;Chen et al, 2018).…”

Mesoporous Silica Nanoparticles for the Treatment of Complex Bone Diseases: Bone Cancer, Bone Infection and Osteoporosis

“…In addition, there are certain types of cells with migratory properties that can transport nanoparticles directly to tumors tissues. For instance, nanoparticles can be attached to hypoxic bacteria that migrate to the hypoxic areas of tumors [116,117]. In addition, mesenchymal stem cells have been shown to migrate to tumors in response to the secretion of various signaling molecules.…”

Advances on Non-Genetic Cell Membrane Engineering for Biomedical Applications

“…The microbots successfully enter tumor cells and release nanoparticles, resulting in intracellular drug delivery [98][99][100][101][102]. For example, Dr. Behkam et al used a weakened version of salmonella (VNP20009) as tumor-targeting bacteria and conjugated PLGA nanoparticle to the surface of modified salmonella via streptavidin-biotin noncovalent affinity-based bonds [16]. The results showed that this engineered bacteria coupled with nanoparticles had a similar tumor infiltration property to the native bacteria.…”

“…In addition, MSC can suppress lymphocyte proliferation, which have been utilized clinically to treat lymphocyte cell-dependent diseases, such as amylotrophic lateral sclerosis, acute graft-versus-host disease, or transplant rejection [12,14,15]. As the nature of pathogens is to penetrate through the tissue to invade a host and stay alive, some bacteria (such as salmonella) were found out to move between cells to reach tumors, which has been engineered as therapeutics or drug delivery systems for tumor treatment [16,17].…”