P-Selectin-Targeting Nanoparticles Attack Tumors and Metastasis

July 7, 2016

Drug-encapsulating nanoparticles that target P-selectin in the tumor microenvironment shrank tumors and prolonged the lives of lab mice.

Drug-encapsulating nanoparticles that target P-selectin in the tumor microenvironment shrank tumors and prolonged the lives of lab mice, according to a study reported in Science Translational Medicine.

Because of P-selectin’s emerging role in tumor metastasis, the finding might represent a breakthrough in efforts to develop cancer treatments that target metastases, which is responsible for as many as 90% of cancer deaths. Using radiation, the researchers also found that they can induce P-selectin expression in tumors, facilitating tumor targeting by the nanotherapeutics.

“We found that the nanoparticles were more effective than the drugs normally were,” said senior study author Daniel A. Heller, PhD, of Memorial Sloan Kettering Cancer Center in New York, in a press release. “They allowed the administration of lower drug doses and they reduced side effects.”

“The ability to target drugs specifically to metastatic tumors would greatly improve their effectiveness,” noted lead study author Yosi Shamay, a member of Dr. Heller’s lab.

P-selectin is a cell adhesion molecule found on activated platelets and activated endothelial surfaces of blood vessels, where it helps to recruit immune cells. Endothelial selectins adhere to leukocytes rolling along the interior walls of vasculature and can usher them out of circulation, across vascular walls to areas of tissue damage.

But cancer can hijack that molecular machinery to spread to new tumor sites, previous studies have shown. P-selectin is expressed on the tumor cells’ outer surfaces in many, but not all, human cancers.

When they express selectin and selectin ligands like PSGL-1, primary tumor cells that are shed into the circulation can emulate leukocytes, adhering to intravascular P-selectin molecules, which then help them move into new tissues, where tumor cells proliferate to form metastatic tumors.

Cancer can also exploit P-selectin expression on platelets to form “immune complexes” and escape immune detection. “Hence, cancer cells can control vascular traffic by governing both the ‘roads’ (selectin expression on vascular endothelium) and the ‘passengers’ (rolling cancer cells and leukocytes),” explained PhD student Ranit Kedmi and Dan Peer, PhD, of the Laboratory of Precision NanoMedicine at Tel Aviv University in Israel, in a commentary that was published alongside the new study.

The research team used fucoidan polysaccharide from brown algae, which adheres to P-selectin, to create nanoparticles that carry encapsulated chemotherapy payloads and the MEK-inhibitor MEK162.

“The nanoparticles targeted the tumor microenvironment,” providing improved antitumor efficacy in mouse models, they reported.

The team also discovered that they can steer the nanoparticles to tumors using targeted, low-dose radiation therapy of target tumors because irradiation triggers P-selectin expression--even in tumors previously devoid of selectin.

“Radiation-guided drug delivery might allow us to target drugs to nearly any site in the body,” noted coauthor and radiation biologist Adriana Haimovitz-Friedman, PhD, of Memorial Sloan Kettering Cancer Center.

Combining the nanoparticles with low-dose radiotherapy “showed promising therapeutic results, enhancing drug accumulation in tumors and dramatically decreasing tumor volume” in mice with lung tumors, noted Kedmi and Dr. Peer in their commentary.

However, radiation-induced selectin expression “might also promote cancer aggression and encourage metastatic spread,” they cautioned.

Selectin therapy is like a “two-edged sword, which could result in either cancer eradication or cancer progression,” because selectins are involved in leukocyte trafficking, and tumor-infiltrating lymphocytes are key to the immune system’s antitumor response, they wrote.

“Damaging or blocking leukocytes’ trafficking could also impact lymphocyte circulation in general, and for T lymphocytes, in particular, this may hamper the antitumor immune response,” they explained.