A nano-sized drug capsule designed to seek-and-destroy malignant cells shows signs of being able to significantly shrink ovarian cancer tumors. The researchers behind the novel drug, Mansoor Amiji at Northeastern University and MIT’s Robert Langer, say the secret is in the packaging: a pH-sensitive nanoparticle that encapsulates the therapeutics, delivering them directly to cancer sites in mice and suppressing tumor growth. The researchers reported their success in the journal Cancer Chemotherapy and Pharmacology.
“The main challenge in ovarian cancer treatment is lack of selectivity for tumor cells versus normal cells,” says Amiji, a pharmaceutical scientist and the study’s principal investigator. “Many approaches have devastating side effects, attacking a lot of normal cells like hair follicle and gastrointestinal cells.” Ovarian cancer is a tempting target for the technology because it is particularly difficult to treat and often has a high relapse rate, Amiji says, but the nanoparticle system could be applicable to other forms of cancer.
To avoid such side effects and hone drug delivery, Amiji and his colleagues looked for ways to exploit key characteristics of tumor cells. The environment around most tumors is acidic, having lower pH levels than the rest of the body. Levels are even more acidic inside tumors due to lack of blood and lactic acid buildup. They deduced that a pH-sensitive drug package could thus selectively target the tumor cells.
The drug-carrying vessel needs to be small enough to pass through a tumor’s membrane and yet resilient enough to not be broken down by the body’s immune cells before reaching the tumor site. So the researchers engineered a nanoparticle out of pH-sensitive, biodegradable polymers. Much like a suitcase which could only be opened with a specific combination, this vessel could only be “unlocked” in the presence of low pH levels exhibited by tumor cells. Once unlocked, the vessel dissolves, releasing its drug contents specifically to cancer cells.
Other existing cancer therapies employ similar nano vessels for drug delivery. The most common are liposomes: naturally-derived, spherical vesicles that package drugs, carrying them across tumor membranes into cancer cells. However, these drug carriers run the risk of getting taken up by macrophages before getting to the tumor. Other potential drug carriers more resistant to the body’s natural defenses have been shown to have toxic side effects. Amiji and his colleagues hoped their nanoparticle would not only decrease toxicity, but also boost drug efficiency by more effectively evading the body’s immune system.
Live animal models put the theory and design to the test. The team packed their pH-sensitive nanoparticle with paclitaxel – a widely used cancer drug – and injected it into mice with ovarian cancer tumors. Other mice received injections of the same drug package minus pH sensitivity, while yet others received the drug alone (without a nanoparticle shell). Each group received only one dose of their respective treatments. A control group received no treatment at all.
Four weeks after the injections, mice with pH-sensitive treatments had tumors half as big as those treated with paclitaxel alone, and were slightly smaller than tumors treated with nano-packaged paclitaxel that was not pH-sensitive, suggesting a more effective delivery system. These same mice exhibited no measurable side effects: blood cell counts and body weight remained unchanged, and few mice were lethargic during treatment.
Expert observers are impressed, not only by the ability of the nano drugs to shrink tumors but also by its potential to seek out early-stage tumors. “This could have an impact in the overall treatment of cancer patients, not just for therapy but for diagnosis too,” says Kattesh Katti, a researcher at the University of Missouri-Columbia who works with nanoparticles in cancer therapy.
But others are skeptical of pH as a viable marker for cancer cells. Denis Wirtz, associate director of the Institute for Nanobiotechnology at Johns Hopkins University, warns that sites of infection are also highly acidic, and could potentially throw pH-sensitive cancer drugs off their course. “It’s not always the most specific way to do it,” Wirtz says. “For viral infections, you can have drastic pH changes that have nothing to do with cancer.”
Wirtz suggests another approach: map the molecules on a tumor’s surface, design peptides that can recognize those tumor molecules, then coat a drug-carrying nanoparticle with the tumor-targeted peptides.
That kind of research may be down the line, suggests Amiji, adding that an advantage in working with a polymer-based nanoparticle is that its surface can be easily modified.
Meanwhile, Amiji’s lab is also tackling the problem of drug resistance. Over 50 percent of women with ovarian cancer relapse after any given treatment. It’s a statistic that spurred the team to experiment with multiple drugs, encapsulating several drugs into a single nanoparticle, and controlling when each drug is released.
“If you think about it, we have luggage,” says Amiji. “So the contents inside that package really are up to the creativity of the scientist.”