Cellular Shuttles: Monocytes/Macrophages Exhibit Transendothelial Transport of Nanoparticles under Physiological Flow

Abstract

A major hurdle in the development of biomedical nanoparticles (NP) is understanding how they interact with complex biological systems and navigate biological barriers to arrive at pathological targets. It is becoming increasingly evident that merely controlling particle physicochemical properties may not be sufficient to mediate particle biodistribution in dynamic environments. Thus, researchers are increasingly turning toward more complex but likewise more physiological in vitro systems to study particle−-cell/particle−system interactions. An emerging paradigm is to utilize naturally migratory cells to act as so-called "Trojan horses" or cellular shuttles. We report here the use of monocytes/macrophages to transport NP across a confluent endothelial cell layer using a microfluidic in vitro model. With a custom-built flow chamber, we showed that physiological shear stress, when compared to low flow or static conditions, increased NP uptake by macrophages. We further provided a mathematical explanation for the effect of flow on NP uptake, namely that the physical exposure times of NP to cells is dictated by shear stress (i.e., flow rate) and results in increased particle uptake under flow. This study was extended to a multicellular, hydrodynamic in vitro model. Because monocytes are cells that naturally translocate across biological barriers, we utilized a monocyte/macrophage cell line as cellular NP transporters across an endothelial layer. In this exploratory study, we showed that monocyte/macrophage cells adhere to an endothelial layer and dynamically interact with the endothelial cells. The monocytes/macrophages took up NP and diapedesed across the endothelial layer with NP accumulating within the cellular uropod. These data illustrate that monocytes/macrophages may therefore act as active shuttles to deliver particles across endothelial barriers.

Increased Uptake of Silica Nanoparticles in Inflamed Macrophages but Not upon Co-Exposure to Micron-Sized Particles

“…Synthesis of SiO 2 particles (i.e., nanometer- and micrometer-sized particles) labeled with fluorescent dyes was performed following the Stöber method [ 32 ], as previously reported in the literature [ 33 ]. For 59-nm SiO 2 -BDP FL (i.e., BODIPY ® -fluorescein) particles, a mixture of 6.75 mL of water (Milli-Q), 104 mL of absolute ethanol (EtOH) (VWR, Dietikon, Switzerland), and 3.9 mL of 25% ammonium hydroxide (NH 4 OH) (Merck, Zug, Switzerland) were heated at 60 °C in a 500-mL rounded-bottom flask provided with a reflux system.…”

Emerging methods in therapeutics using multifunctional nanoparticles

“…Macrophages and monocytes as phagocytic cells can naturally internalize NPs and carry them to target sites that are otherwise largely inaccessible (Evans et al, ; Moore et al, ; Si, Shao, Shen, & Wang, ). For example, macrophages have been used for delivering various nanocarriers across BBB such as self‐assembled polyethyleneimine‐poly(ethylene glycol) catalase in a Parkinson's disease model (Batrakova et al, ), and gold‐silica nanoshells for photothermal therapy for glioma in vitro (Amani, Makkouk, & Sun, ) and in vivo (Madsen et al, ).…”

An Alternative Perspective towards Reducing the Risk of Engineered Nanomaterials to Human Health

“…Very few consider the notion that in the "whole body" in vivo approach all tissues/cells are at least impacted by dynamic flow-of either a liquid (i.e., liver) or air (i.e., lung). [50] In a study by Moore and colleagues, [51] it was reported that when cells were placed within a period of dynamic flow that their phenotype as well as transendothelial transport was significantly altered. It has also previously been noted that dynamic flow can change the maturation and differentiation status of cells in vitro.…”