Killing cancer the simple way

The nanocar­riers in a mix­ture of can­cerous and healthy cells

Tar­geted drug delivery is a hot topic these days. Chemotherapy, for example, blindly kills any­thing in its path — these drugs don’t dis­tin­guish between healthy cells and can­cerous cells; they just kill cells. Period.

Pro­fessor Vladimir Torchilin and his bud­dies at the Center for Cancer Nan­otech­nology Excel­lence are devel­oping nanoscale drug delivery tech­nolo­gies, which I like to think of as micro­scopic Trojan horses. Very basi­cally, the out­side is cov­ered with pro­teins that make it tumor friendly while the inside con­tains a deadly pay­load that is unleashed after the cancer cell wel­comes it through its gates. Healthy cells don’t rec­og­nize the sur­face pro­teins and thus don’t get the chance to be exposed to the drug.

This is a great idea of course, but as you might imaging, making micro­scopic Trojan horses, or nanocar­riers, as they’re called, can be rather chal­lenging. At this year’s RISE:2012 con­fer­ence I met a grad­uate stu­dent in Torchilin’s lab, Tao Wang, who has devel­oped a simple, straight­for­ward approach that could take tar­geted drug delivery from “hot topic” to “hot practice.”

Get­ting the sur­face pro­teins onto these nanocar­riers is often costly and chem­i­cally com­pli­cated (how’s that for allit­er­a­tion!?) Wang’s approach over­comes these problem by let­ting biology do all the hard work.

Bac­te­rio­phages are viruses that infect bac­te­rial cells by lodging them­selves in the cell mem­brane and depositing genetic mate­rial inside which messes up the bacterium’s stan­dard oper­ating pro­ce­dures, so to speak. A process called “phage dis­play” devel­oped ‘80s allows sci­en­tists to tag the ends of bac­te­rio­phages with var­ious pro­tein fragments.

There’s a con­ve­nient sim­i­larity between bac­te­rial cell mem­branes and nanocar­riers: they are both made out of lipids, which are hydrophobic (water hating) mol­e­cules. Bac­te­rio­phage pro­teinss are also hydrophobic, which is what allows them to buddy up to the bac­te­rial cell mem­brane. The pro­tein frag­ments tagged to its end, how­ever, is hydrophilic, which means it will want to hang out on the out­side of any lipid mem­brane it finds itself near.

Do you see where this is going yet? The group sifted through a huge library of protein-​​tagged bac­te­rio­phages until they found one that was rec­og­nized by breast cancer cells. Then they mixed the phage-​​derived pro­tein with a the nanocar­rier con­taining a drug that kills breast cancer cells. The bac­te­rio­phage lodged itself inside the nanocarrier’s lipid mem­brane, as if it were a bac­te­rial mem­brane, with the pro­tein frag­ment dan­gling on the out­side. Then they mixed these little guys with can­cerous and non can­cerous cells in a test tube and found that they attacked cancer cells and bypassed healthy cells.

A foregin gene inserted into the bac­te­rio­phage (left) tags it with a pro­tein frag­ment, which is rec­og­nized by recep­tors on the sur­face of a cancer cell but not a healthy cell. The tagged bac­te­rio­phage spon­ta­neously nes­tles into the lipid mem­brane of the drug-​​containing nanocar­rier (right).

All this work was pub­lished in a paper in 2010 in the journal Nanomed­i­cine. Wang’s poster at RISE:2012 illus­trated some of the work she’s been doing since then, using this tech­nique to cure cancer in mice.

First she had to give the mice cancer, which I’m sure wasn’t good for the moral com­pass, but then she had the sat­is­fac­tion of knowing that her drugs actu­ally helped them.

When she gave them the drug inside a nanocar­rier that didn’t have the bac­te­rio­phage fusion pro­tein incor­po­rated, they showed very little reduc­tion in tumor size.

But when she deliv­ered the drug via bacteriophage-​​nanocarriers new tumor growth slowed down and existing tumor size reduced sig­nif­i­cantly. The mice main­tained healthy body weights and “showed no signs of discomfort.”