Thursday, August 30, 2012
One result of the side effects of cancer treatments is that patients often can't tolerate or survive a combination of different drugs at the same time—which can limit a doctor's ability to knock out the disease. The head of a Boston-area biotech called Cerulean Pharma thinks the solution is nanoparticle-delivered drugs, which have fewer and less severe side effects. They could make it easier for doctors to mount a multipronged attack on tumors and kill the cells before they can develop a resistance to any one compound.
Cancer cells can develop resistance to individual drugs very quickly, says Oliver Fetzer, CEO of Cerulean. And he points to recent studies showing that different cells within the same tumor can have different genetic mutations. In some cases, that means that a drug that kills cancer cells in one part of a tumor may not work in other parts. This tumor diversity suggests that it would be best to hit cancer cells with multiple drugs at once to make it extremely difficult for the tumor to develop resistance to all therapies.
Nanoparticles could help achieve this goal. The nanoparticles developed by Cerulean are too big to get out of blood vessels and into healthy tissue, but they are the right size to get into tumors because the blood vessels that grow around cancer tissue have pores or gaps that aren't found in healthy tissue. "These nanoparticles find their way into the tumor through the leaky [blood vessels], so they can't really escape out of your normal bloodstream in the healthy tissue," says Fetzer. Once inside the tumor tissue, cancer cells take them in.
Cerulean's nanoparticle acts like time-release packaging—instead of dumping all the cancer drug into the tumor at one time, the nanoparticle slowly breaks down and releases the drug bit by bit. A feature of Cerulean's technology is that the nanoparticle and the drug are connected by a chemical bond. While drugs in other nanoparticles used in delivery are held by polymer meshes or inside a fatty capsule, drugs in Cerulean's nanoparticles are tethered by a chemical link. The drug is released as the chemical bond is broken, a process partly controlled by an unknown enzyme in the body. That rate of release can be tuned using different linkers, says Fetzer.
Data from early clinical trials of Cerulean's lead compound—a nanoparticle containing a drug called Camptothecin that is too toxic to be administered on its own—suggests it is well-tolerated. Patients in the trial experienced fewer and milder side effects than do patients given available drugs.
Another player in the nanoparticle-delivery space, BIND Biosciences, adds a layer of specificity to its delivery by affixing targeting molecules to the outside of its nanoparticles (see "Fine-tuning Nanotech to Target Cancer"). The targeting molecules recognize proteins on the outside of cancer cells and so help bring the nanopharmaceutical to its desired location.
Fetzer says that while there may be applications where the targeting is helpful, his company does not think it is necessary. "When we look at the data we've generated with untargeted particles, we haven't seen the need to add another layer of complexity."
The company expects to have results from its human trials of its lead compound in treating lung cancers by the end of the 2012. It recently began testing the effectiveness of the same compound in ovarian cancer patients. To begin to explore the possibility of combining nanoparticle-based cancer drugs with other therapies, Cerulean is also enrolling patients with kidney cancer in a phase I trial that will combine the company's lead compound with bevacizumab, a commercially available cancer drug used in a variety of cancers.