A common strategy for treating tumors is combining two or more drugs, which has the effect of decreasing toxicity and increasing the synergistic effects between the drugs. However, the efficacy of this kind of cocktail treatment suffers when the drugs require access to different parts of the cell, a bit like fighting a battle by depositing all your archers on the same spot as your infantrymen. By making use of nanoparticle-based carriers, researchers at North Carolina State University are able to transport multiple drugs into cancerous cells optimally and precisely, in maneuvers that any field commander would be proud of.
Their research has focused on multiple scenarios of drugs, including those targeted for gene therapy or chemotherapy, but all rely on the same nanoscale drug delivery mechanism or “nanodepot." In it, an outer gel shell surrounds a liposomal core, each layer bearing a different drug. The shell and core are collectively known as “Gelipo."
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In their tests, Gelipo’s outer layer was laced both with a cancer drug, TRAIL, that requires delivery to the outer membrane of the cancerous cell, and with an additional chemical, HA. Hidden inside is yet another drug, Dox, targeted for the cell’s nucleus and attached to peptides. Hold onto those terms, because HA and the peptides are about to manipulate the cell’s natural mechanisms against itself.
A diagram of the process of Gelipo's targeted delivery of two different drugs to the cell membrane and nucleus
As Gelipo approaches the cell, anti-HA enzymes naturally present in the cell’s exterior latch onto the HA and begin to break down the gel layer, releasing the first drug. This drug is then free to bind to receptors in the tumor cell’s membrane, triggering programmed cell death.
But Gelipo’s progress doesn’t stop there. As its outer layer is breaking down, the tumor cell encapsulates Gelipo’s contents into what would be a defensive sphere (see the diagram below), unwittingly transporting the second drug into the cell, Trojan-horse-style. However, the peptides attached to the second drug allow passage through this defensive membrane, where the second drug is free to bind with its target.
Though this exploitation of biochemical and cellular pathways, the Gelipo-TRAIL-Dox combo accumulated more than the controls in the affected tumor tissue and had a greater cytotoxicity. The synergistic effects of using two drugs was controlled by comparing Gelipo with just one drug, Dox. Below are mice with tumors treated with saline, just Dox, Gelipo and Dox, and finally, Gelipo with both drugs.
Tumor size in mice, left to right, with treatment with saline, just Dox, Gelipo-Dox, and Gelipo-TRAIL-Dox
The team describes this experiment as proof-of-concept and has further refinements to make on the technique, but expects that the process can be scaled up for manufacturing. A paper on the research was recently published in the journal Advanced Functional Materials.
Source: NCSUView gallery - 3 images