In a set of studies in mice bearing human tumors, nanoparticles designed to bind to a protein called P-selectin successfully delivered both chemotherapy drugs and targeted therapies to tumor blood vessels. Targeting the blood vessels improved the delivery of drugs to tumor tissue, causing the tumors to shrink and improving how long the mice lived.
A tumor’s blood vessels can serve as a barrier to engineered drug-delivery systems like nanoparticles, which may not be able to cross the blood vessel wall. However, the same blood vessels may express proteins—such as P-selectin—that researchers can potentially exploit, by engineering their nanoparticles to recognize and latch onto those proteins, which enables them to reach the tumor.
What makes P-selectin different from other nanoparticle targets, the research team that led the study showed, is that it can be “turned on” in the blood vessels of tumors that do not normally express it by exposing the tumors to certain stressful conditions—in these experiments, a low dose of focused radiation.
This ability to trigger the expression of P-selectin in a tumor that normally lacks the protein, they wrote, suggests that the nanoparticle may be useful against a wide range of cancer types.
Turning on the Target
Blood vessels in some tumors naturally express P-selectin on their surfaces, providing a target for nanoparticles. In the study, a research team led by Daniel Heller, Ph.D., of Memorial Sloan Kettering Cancer Center, engineered drug-carrying nanoparticles made of a sugar-based compound called fucoidan, which is derived from algae and binds to P-selectin.
The research team then confirmed P-selectin expression in the blood vessels of a variety of tumor types, including lung, ovarian, and breast cancer, and lymphoma. In laboratory experiments, their fucoidan nanoparticles latched onto tumor blood vessel cells that normally expressed P-selectin while control nanoparticles composed of a different compound did not. The same was true for tumor blood vessel cells that were induced to express P-selectin by exposure to radiation.
In additional laboratory experiments using layers of tissue, the targeted nanoparticles were also able to work their way through blood vessel cells into adjacent tumor tissue.
Based on these findings, the researchers tested the fucoidan and control nanoparticles in a mouse model of lung cancer that expressed P-selectin on its blood vessels. Three days after injecting the mice with the nanoparticles, the researchers found the concentration of targeted nanoparticles within tumors to be four times that of the control, non-targeted nanoparticles. The targeted nanoparticles were also more likely to be found in tumor tissue (as opposed to normal tissue) than the non-targeted nanoparticles.
The researchers then conducted experiments using a mouse model of lung cancer that does not normally express P-selectin on its blood vessels. The researchers exposed a tumor in each mouse to stress using a low dose of radiation. Twenty-four hours after exposure, a substantial amount of P-selectin was found in the tumor blood vessels.
When the researchers injected these mice with nanoparticles 4 hours after they received the radiation, they found accumulations of the nanoparticles in tumor tissue similar to those seen in tumors that naturally express P-selectin. In many of the mice, the tumors disappeared completely and did not return over the 100-day course of the study.
Although it requires an additional step compared with other methods for targeting nanoparticles to tumors, activating a targeted protein before administering the nanoparticles “is a very clever approach to gaining more control in the nanoparticle delivery,” said Piotr Grodzinski, Ph.D., director of NCI’s Office of Cancer Nanotechnology Research.
Unexpectedly, the researchers also found that other tumors in the mice also began to express P-selectin—and had their growth inhibited by the nanoparticles—even though they had not been irradiated directly. This phenomenon is likely triggered by the immune system, explained Dr. Heller, and suggests that the approach may be effective for treating metastatic tumors.
“We may be able to irradiate one site and get some sort of effect in other [distant] tumors,” he said.
“In contemporary [cancer] treatment, you may use different therapeutic strategies for primary and metastatic tumors in the same patient," said Dr. Grodzinski. "What people are trying to do with nanoparticles in general is to see if the same strategy can [be used to] treat both."
Targeting Distant Disease, Preventing Off-Target Effects
In proof-of-concept studies using two models of aggressive metastatic cancers that naturally express P-selectin, mice given the targeted nanoparticle containing doxorubicin lived significantly longer (mean of 70 days) than mice given a control nanoparticle that did not target P-selectin (39 days) or mice that received no treatment (32 days). The drug was also substantially more effective when it was delivered with the nanoparticle than when it was simply infused into the blood stream, explained Dr. Heller.
“When we gave one dose of doxorubicin to the mice, nothing happened,” said Dr. Heller. However, just one-sixth of that dose delivered in the nanoparticle shrank tumors and extended survival time. When they increased the amount of doxorubicin delivered in the nanoparticle, they saw tumors completely disappear in about half the mice after a single dose.
The researchers also tried filling their nanoparticles with a targeted therapy called a MEK inhibitor, which blocks a molecular pathway in the body that is important to many cancers but is also active in normal skin. Many patients taking MEK inhibitors have had to discontinue the drugs or have their doses reduced because of side effects, such as a severe, painful skin rash.
When encapsulated in the nanoparticle, the drug inhibited the MEK pathway in tumors but not in the mice’s skin. “We expect that we might see something similar in humans, where we avoid the toxicity but get prolonged inhibition of the target, which increases the effectiveness of the drug,” said Dr. Heller.
His team is currently performing follow-up studies with other targeted therapies, and they would like to learn more about the P-selectin expression in distant tumors that they saw in their radiation studies.
“Quite a lot of work needs to be done before we can test [the nanoparticles] in a phase I trial,” said Dr. Heller, “but we’re definitely excited about it.”