"Our finding points to a novel mechanism of nanoparticle targeting to disease, and opens up a whole new area of research in cell-based delivery of nanotherapeutics," says team member Bryan Ronain Smith. "It is important because one of biggest obstacles confronting nanomedicine today is that nanoparticle delivery to desired disease sites is inefficient."

Our approach could in principle be used to treat all types of solid tumours since Ly-6Chi immune cells naturally enter cancerous tissue and deposit their nanoparticle load there, rather like a Trojan horse, he adds.

Ly-6Chi monocytes take up nanotubes

The Stanford researchers, led by Sanjiv Sam Gambhir, say that they were surprised by their discovery. While looking at how single-walled carbon nanotubes (SWCNTs) target tumours in live mice using a special type of "intravital" microscope (that can image and video nanoparticles interacting with cells), they observed that the mice cells "gobbled up" nanotubes circulating in the bloodstream.

"Taking some blood samples and analysing these, we were intrigued to find that of all the many different types of cells in blood, only the Ly-6Chi monocytes took up nanotubes to any considerable degree," Smith told our sister site nanotechweb.org. "As mentioned, Ly-6Chi monocytes are naturally attracted to cancer cells and 'ferry' the nanoparticles into a tumour site."

And that is not all: the team also found that targeting ligands called RGD peptides conjugated to the nanotubes significantly enhance the number of SWCNT-loaded monocytes reaching a tumour. Although the mechanisms behind this increased uptake are rather uncertain at present, the experiments suggest that the RGD peptides attached to the SWCNT may remain on the monocytes' surface after they are taken up the nanotubes.

Manipulating monocytes

"RGD peptides can strongly bind to blood vessels in tumours, so it turns out that the RGD-nanotube loaded monocytes seem to target the tumour in a sort of molecular address system that allows them to bind selectively to blood vessels via the RGD," explains Smith. "This is an interesting finding in itself, because, once they are bound, the monocytes tend to actively 'crawl out' of the blood vessels and into the tumour itself. The result implies that cells can, in a sense, be programmed to increase traffic to a particular site."

According to the researchers, the discovery could be used as a tool to diagnose and treat diseases in which Ly-6Chi monocytes are directly implicated. These include cancer, heart disease and diabetes, to name but three. "While under normal conditions, these monocytes are good, under disease conditions, they can make the pathology even worse," explains Smith. "One example is when they become so-called tumour-associated macrophages in cancer and accelerate tumour growth. We could thus imagine exploiting our discovery to directly manipulate monocytes to become disease-fighting rather than disease-promoting."

While the studies are still in their early stage, the fact that nanotubes are inherently attracted to the monocyte subset opens up the field of immune cell targeting by nanoparticles, says the team. "Our findings could ultimately be used for specific tracking, manipulating or treating immune cells," adds Smith, "and our future work will investigate these possibilities more thoroughly."

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