Giving Cancer the Old One-Two

Countless anti-cancer compounds have failed in development because of problems related to specificity. Previous research has suggested nanoparticles as a potential means of delivering anti-cancer drugs directly to the tumor site, but targeting is still difficult because of the vascular barrier surrounding most solid tumors. Now, researchers from the Memorial Sloan Kettering Cancer Center in New York, USA, believe they can target the cancer vascular specifically. How? By zapping cells with radiation to trigger P-selectin expression in tumor blood vessels, and then using fucoidan-based nanoparticles to deliver drugs to the target (1). Daniel Heller, co-author of the paper, tells us more.

Why is it so difficult to combat cancer?

Most cancer drugs have a two-in-one specificity problem: the drugs often don’t act specifically on the tumors and don’t localize specifically to tumors. Many drug companies are focusing on the first type of specificity – how do we make a drug toxic only to a tumor? One difficulty with this approach is that almost every effective compound has some sort of off-target effect, which often limits the dosage and prevents the drug from substantially affecting the tumor. Our thinking is that if we can’t depend on a drug to be specific enough by itself, then we should improve its specificity by targeting it physically to the tumor site.

What is the story behind your research?

We first developed our fucoidan-based nanoparticles to target P-selectin, which is spontaneously expressed in tumor blood vessels (without radiation). We knew that fucoidan binds to P-selectin so we decided to make a nanoparticle for drug delivery out of it. Using fucoidan also avoids the complication of synthesizing a nanoparticle with an antibody bound to it.

After obtaining some interesting results showing that the nanoparticle can target tumors that express P-selectin spontaneously, we started talking to Adriana “Ady” Haimovitz-Friedman, a radiation biologist whose lab happens to be two doors down from ours. Ady knew the work of Dennis Hallahan, who showed that P-selectin can be induced in tumors via low doses of radiotherapy.

We worked with Ady to determine whether this process could help to guide nanoparticles to the tumor site. And the answer was, “yes”: introducing nanoparticles shortly after irradiating a tumor with just a single, low dose of radiation can result in strikingly efficient anti-tumor efficacy.

What are the benefits of targeting drugs in this way?

New “targeted” therapeutics and precision medicines, like MEK inhibitors, can be used with our nanoparticles to significantly reduce their side effects. Not only did we show that the nanoparticles allowed for much greater doses of chemotherapeutic drugs to be delivered to the tumor site, but we also showed (in collaboration with José Baselga’s lab) that the pharmacokinetics, pharmacodynamics, toxicity, and efficacy of a drug can be drastically improved by physically targeting the drugs to the tumor. For example, tumor-targeted nanoparticles can localize MEK inhibitor in the tumor site, resulting in prolonged inhibition of pERK (which promotes cancer cell proliferation). MEK inhibitors have been known to cause serious dermatologic side effects, but our work showed that the drug doesn’t reach or affect the skin when it is administered using the nanoparticles. This pharmacodynamics approach to studying nanoparticle drugs is a new step in nano-drug development.

Next, we plan to partner with others (including drug companies) to develop new nano-precision therapies based on drugs in need of improvement.