Professor Glen Kwon receives new NIH grant for research targeting triple-negative breast cancer
By Jill Sakai
Despite numerous advances in cancer treatment in recent decades, even the most advanced drugs continue to face a basic challenge: how to get those drugs right where they’re needed while minimizing unwanted side effects. That challenge is growing with the increasing use of combination therapies that require a patient to receive multiple drugs as part of a single treatment plan.
“Combination therapy plays a central role in the treatment of cancer,” says Glen Kwon, professor and Jens T. Carstensen Distinguished Chair in Pharmaceutical Sciences at the University of Wisconsin–Madison School of Pharmacy. But typically, each drug is given separately, with the hope that each will independently reach and affect the cancer. “We are asking, what happens if you deliver them together into the tumor? Can we get synergy, or greater than additive activity?”
Kwon has spent most of his career developing nanotechnology solutions for drug delivery. Now, with a new $1.3 million translational research grant from the National Institutes of Health, Kwon’s group is developing a novel application using nanoparticles to deliver precise combinations of drugs to breast tumors. They are targeting triple-negative breast cancer, which is notoriously difficult to treat.
“Nanomedicine is expanding the repertoire of these molecules,” Kwon says. “We can reformulate highly potent yet toxic drugs, like paclitaxel, and put two or more different anticancer drugs in the same nanoparticle to deliver them together into the tumor.”
The advance offers a simple, fast way to administer multiple drugs simultaneously with the potential for enhanced efficacy and lower toxicity compared with current treatment strategies, Kwon says. “The goal is to use the nanoparticles to get multiple drugs at the tumor at the same time in hopes of getting synergistic activity.”
Many potent cancer drugs are poorly water soluble and are therefore not readily absorbed through the gut. Although some medications are produced in tablet or capsule formulations for ease of administration, they may require higher doses to achieve sufficient anticancer activity.
“The goal is to use the nanoparticles to get multiple drugs at the tumor at the same time in hopes of getting synergistic activity.”
Other drugs are given through intravenous injections, which can improve solubility but may require harsh solvents. The common chemotherapy agent paclitaxel, for example, is dissolved in a solution of ethanol and a surfactant — effective for delivering the medication, Kwon says, but hard on a patient’s body. Such formulations also distribute throughout the body, which can harm healthy tissues and cause side effects.
Kwon’s team is developing an alternative delivery strategy using a polymeric nanotechnology. They create non-toxic polymers that have a water-soluble polyethylene glycol molecule on one end and fat-soluble polylactic acid on the other. When placed in water, the polymers self-assemble into a little “bubble” called a micelle.
“The core is made up of the polylactic acid and the shell is polyethylene glycol,” Kwon says. “We can load poorly water-soluble drugs into the core of this polymeric micelle, and then we can inject it.”
The hydrophilic shell allows the micelles to be dissolved in water for injection, while sheltering the solubilized drug molecules within the hydrophobic core until they reach their target. The micelles travel through the bloodstream to the tumor where, thanks to the leaky nature of tumor blood vessels, they will infiltrate the tumor tissue and release the drugs right where they are needed. The polymers themselves are biodegradable and clear easily from the body.
This safer solubilization method means that a larger percentage of the injected drug is likely to reach the cancer. This should reduce toxic side effects in other body tissues and may allow the use of lower dosages. And by putting two or more different drugs in the same nanoparticle, they can deliver combination therapies in precise ratios selected for optimal activity.
Old drug, new tricks
Kwon’s team has already reported promising early preclinical results with three-drug loaded micelles, in work pursued through his start-up company, Co-D Therapeutics. But the new grant will support a novel twist: Rather than load the micelles with active drug molecules, the researchers will pack the particles with prodrugs — modified molecules that require a simple chemical reaction to convert to an active drug form.
Prodrugs are often made to enhance the pharmaceutical properties of a drug, Kwon says. The paclitaxel prodrug is made by adding an oligolactic acid chain, which makes the molecule more compatible with the micelle and thereby delays its release from the nanoparticle. That’s important because paclitaxel acts on cancer cells when the cells are in a specific stage of their growth cycle, called the G2/M phase. At any given time, only a fraction of the cells in a tumor are in that vulnerable phase. A fast-release drug will only affect the relatively low proportion of susceptible cells. Delayed release prolongs the exposure time, increasing the number of cells that will enter the vulnerable phase of their cell cycle while the drug is present.
“Delayed release increases and prolongs tumor exposure,” Kwon says. “The paclitaxel can act on more of the cells and, in this way, gain potency.”
Typically, physicians have relied on multi-hour infusions of chemotherapy drugs to expose a larger percentage of tumor cells. With delayed release prodrugs, such infusions could be replaced with a single injection, which would be far easier on patients. In fact, blood plasma levels of paclitaxel over time following a single prodrug injection look very similar to those resulting from a 24-hour infusion of the unmodified drug, Kwon says.
“Delayed release increases and prolongs tumor exposure. The paclitaxel can act on more of the cells and, in this way, gain potency.”
The delayed release properties may also enhance the cancer-fighting activity of paclitaxel and its combinations when the drugs are co-loaded in the nanoparticles. Kwon and one of his former PhD students, Tony Tam (PhD ’17), created micelles containing prodrugs of paclitaxel and two targeted anticancer agents, rapamycin and selumetinib, work that was patented in 2019.
With the new funding, Kwon’s group will be able to analyze the pharmacokinetics of the novel prodrugs alone and in combination and look for synergistic ratios of the different agents. Then they will deliver those ratio-balanced combination treatments via nanoparticles in animal models. In preliminary studies done in collaboration with Suzanne Ponik in the School of Medicine and Public Health, the delayed release prodrugs have shown enhanced efficacy and reduced toxicity in mouse models of triple-negative breast cancer.
Prodrug-loaded nanoparticles could be used to deliver a wide variety of drug combinations, making the system adaptable to many different diseases and treatments, Kwon says. One of the aims of the new grant is scaling up the manufacturing process to the level needed for clinical use.
“The long-term goal of this work is to move this nanomedicine-based treatment closer to the clinic and help expand the repertoire of molecules available to help patients with hard-to-treat diseases,” Kwon says. “I think the reality is that to fight triple-negative breast cancer, it’s going to take innovative, multimodal therapies that are relatively easy to implement, not too onerous for clinicians, and safe and effective for patients.”