Abstract
Bacteria‐mediated drug delivery systems comprising nanotherapeutics conjugated onto bacteria synergistically augment the efficacy of both therapeutic modalities in cancer therapy. Nanocarriers preserve therapeutics’ bioavailability and reduce systemic toxicity, while bacteria selectively colonize the cancerous tissue, impart intrinsic and immune‐mediated antitumor effects, and propel nanotherapeutics interstitially. The optimal bacteria–nanoparticle (NP) conjugates will carry the maximal NP load with minimal motility speed hindrance for effective interstitial distribution. Furthermore, a well‐defined and repeatable NP attachment density distribution is crucial to determining these biohybrid systems’ efficacious dosage and robust performance. Herein, our nanoscale bacteria‐enabled autonomous delivery system (NanoBEADS) platform is utilized to investigate the effects of assembly process parameters of mixing method, volume, and duration on NP attachment density and repeatability. The effect of linkage chemistry and NP size on NP attachment density, viability, growth rate, and motility of NanoBEADS is also evaluated. It is shown that the linkage chemistry impacts NP attachment density while the self‐assembly process parameters affect the repeatability and, to a lesser extent, attachment density. Lastly, the attachment density affects NanoBEADS’ growth rate and motility in an NP size‐dependent manner. These findings will contribute to the development of scalable and repeatable bacteria–NP biohybrids for applications in drug delivery and beyond. An interactive preprint version of the article can be found here: https://www.authorea.com/doi/full/10.22541/au.163100509.93917936.
Highlights
Biohybrid or cell-mediated drug delivery cancer therapy
The NP attachment density is critical to the efficacy of bacteriabased drug delivery systems, as it determines the amount of
We first investigated the effect of mixing method, assembly volume, and assembly period, as depicted in Table 1, on the formation of antibody–biotin–streptavidin NanoBEADS (ABS NanoBEADS) using 165 Æ 11 nm diameter NPs
Summary
The NP attachment density is critical to the efficacy of bacteriabased drug delivery systems, as it determines the amount of. Assembly volume had no statistically significant effect on the average NP attachment density of ABS NanoBEADS constructed using a vortex mixer, except for the significantly decreased NPs attachment density in the 60 min assembly period, when the volume increased from 100 to 800 μL (p < 0.01). For all the assembly periods tested with the 800 μL volume, the Belly Dancer and the end-over-end mixer resulted in similar or higher average NPs areal density than the vortex mixer (Figure 2a). The vortex mixer resulted in the lowest count of NanoBEADS with attachment density higher than 10 NPs μmÀ2 cell area and the highest count of bacteria with no NP attachment (Figure 2b–d). Upon increasing the assembly time to 90 min, more NanoBEADS with attachment density lower than 10 NPs μmÀ2 were observed (Figure 2c,d), resulting in an overall decrease in average attachment density (Figure 2a). The viability of the bacteria was not affected by the attached NPs in either of the two variants (Figure S1, Supporting Information)
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