Improving Cisplatin with Nanoparticles

One of the first chemotherapy drugs given to patients diagnosed with cancer — especially lung, ovarian, or breast cancer — is cisplatin, a platinum-containing compound that binds to tumor cells' DNA. Cisplatin does a good job of killing those tumor cells, but it can also seriously damage the kidneys, which receive high doses of cisplatin because they filter the blood.

Now a team of scientists at the Harvard-MIT Division of Health Sciences and Technology (HST) has come up with a new way to package cisplatin into nanoparticles that are too big to enter the kidneys. Tumors in mice treated with the new cisplatin nanoparticle shrank to half the size of those treated with traditional cisplatin, with minimal side effects. The new compound could spare patients the usual side effects and allow doctors to administer higher doses of the drug, says Shiladitya Sengupta, leader of the research team, which published its findings in the Proceedings of the National Academy of Sciences.

Doctors began using cisplatin to treat cancer in the 1970s. Early on, doctors recognized that it harmed the kidneys, and cancer researchers began looking for alternatives. In the past few decades, the FDA has approved two less-toxic derivatives of cisplatin: carboplatin and oxaliplatin. However, those drugs don't kill tumor cells as successfully as cisplatin.

Cisplatin's effectiveness lies in how easily it releases its platinum molecule, freeing it to cross-link DNA strands, which in turn disrupts cell division and forces the cell to undergo suicide. Carboplatin and oxaliplatin are less effective (but less toxic) than cisplatin because they hold on to their platinum atoms more tightly.

Dr. Sengupta and his colleagues took a new approach to making cisplatin safer: stringing cisplatin molecules together into a nanoparticle that is too large to get into the kidneys. (It has been shown that the kidneys cannot absorb particles larger than five nanometers). His team designed a polymer that binds to cisplatin, arranging the molecules like beads on a string. The string then winds itself into a nanoparticle about 100 nanometers long — much too large to fit into the kidneys. However, the particles can still reach tumor cells because tumors are surrounded by "leaky" blood vessels, which have 500-nanometer pores.

Their first nanoparticle proved less effective than cisplatin, so they tweaked the polymer to make it hold a little less tightly to platinum, and ended up with a molecule with a tumor-killing power similar to cisplatin's. However, because its side effects are minimal, the nanoparticle can be delivered in higher doses.

The investigators demonstrated that the nanoparticles outperformed cisplatin in mice engineered to develop ovarian cancer. The researchers also showed it to be effective against lung and breast tumor cells grown in the lab. Once the tumor cells die, the immune system clears platinum from the body.

The MIT researchers are now working on new variants of the nanoparticles that would be easier to manufacture. They are also making plans to test the nanoparticles in clinical trials, which Dr. Sengupta hopes will get underway within the next two years. The polymer used for the nanoparticle backbone is similar to malic acid, a natural product of cellular metabolism, so Dr. Sengupta is optimistic that it will prove safe in humans.

This work is detailed in a paper titled, "Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy." An abstract of this paper is available at the journal's Web site.

Source: National Cancer Institute; August 20, 2010

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