Technical Highlight - March 2013
Short description: Membranes of white blood cells are harnessed to improve drug-delivery vehicles.
Organisms have layers of defenses against foreign attackers. But when the attack comes from within, as with cancer, clever tools are needed to evade these defenses. Hiding drugs within nanoparticles—such as nanoporous silicon (NPS)-based vehicles—has been investigated, but there is room for improvement.
To make the nanoparticles appear friendly to cells, Tasciotti and colleagues camouflaged them to resemble the organism's own white blood cells, or leukocytes. Purified negatively charged membranes and lipids effectively covered positively charged NPS, to form “leukolike vectors” (LLVs). More than half of the membranes remained bound after 24 hours in vitro. Compared to NPS particles, LLVs were protected from opsonization (tagging by antibodies or other factors that promote subsequent phagocytosis), which clears foreign objects from an organism.
Next, any vehicle injected into the bloodstream must negotiate endothelial cells lining blood vessels. With their native-cell camouflage, LLVs could pass undetected at this checkpoint. Endothelium treated with bare NPS formed filopodia, eventually expunging these particles in vesicles, but treatment with LLVs had no noticeable effect.
Finally, the vehicle must deliver the cargo to the target. LLVs contain the adhesion molecule lymphocyte function-associated antigen 1, which allows leukocytes to bind cell receptors that are upregulated in response to inflammation. True to form, LLVs exhibited twofold greater binding to inflamed versus normal endothelium, whereas NPS particles bound equally in both conditions. LLVs also have an edge in traversing the endothelium to reach cells causing the inflammation, which the researchers showed using an in vitro-reconstructed endothelial monolayer system. Only ∼30% of NPS particles could go past inflamed endothelium, whereas ∼70% of LLVs did so. When cancer cells were placed beyond the endothelial monolayer, application of a drug alone or drug-containing NPS mainly killed surface endothelial cells, whereas drug-containing LLVs decreased underlying tumor viability ∼57% and caused marginal endothelial damage.
Thus, under cover of leukocyte membranes, LLVs speak the 'cell-cell language' well enough to negotiate cell defenses en route to the target. In a proof-of-concept experiment in mice, LLVs were not found sequestered in the liver up to 40 minutes after administration, while their accumulation at tumors could be observed. With further development, LLVs may enable delivery of chemotherapeutics to cancer cells.
A. Parodi et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions.
Nat. Nanotechnol. 8, 61-68 (2013). doi:10.1038/nnano.2012.212