The standard approach to cancer therapy today is to mix and match chemotherapy drugs in order to attack tumors in multiple ways. Now, two separate teams of investigators have demonstrated that using nanoparticles to deliver multiple drugs simultaneously can produce a synergistic effect that boosts the cell-killing ability of both drugs.

In one study, a team of investigators at Northwestern University has shown that they can combine two powerful but extremely toxic anticancer agents - cisplatin and doxorubicin – in one polymer nanoparticle, producing a substantial boost in their ability of the combination to destroy tumors. In addition, the two-in-one nanoparticle reduces the amount of both drugs needed to kill cancer cells, which presumably would reduce the toxic side effects associated with these drugs.

SonBinh Nguyen and Thomas O’Halloran led this study, which was published in the Journal of the American Chemical Society. Dr. O’Halloran is the co-principal investigator of one of 12 Cancer Nanotechnology Platform Partnerships funded by the National Cancer Institute Alliance for Nanotechnology in Cancer. He is also a member of the Northwestern University Center for Cancer Nanotechnology Excellence (CCNE), which is also part of the Alliance for Nanotechnology in Cancer.

Though originally designed to carry arsenic trioxide to solid tumors, the nanoparticles used in this study are proving to be quite versatile in their ability to ferry a wide range of cargos to malignancies. In this study, the investigators wanted to see if delivering two drugs in one nanoparticle offered any advantages of delivering them without the nanoparticle or in separate nanoparticles. The nanoparticles, which the researchers call nanobins, are made by encasing a liposome inside a pH-responsive polymer cage. In this case, doxorubicin is entrapped within the liposome’s core, while cisplatin was entrapped in the polymer cage.

In an initial set of experiments, the investigators determined that a 5 to 1 ratio of cisplatin to doxorubicin was the most effective at treating ovarian tumors when the two drugs were combined in the same nanoparticle. When the two drugs were administered at this ratio but with each in its own nanoparticle, the combination was not only less effective at killing malignant cells, but the two drugs appeared to be interfering with each other, a phenomenon often observed in clinical practice. Administering the two drugs in the same nanoparticle ensures that the drugs are hitting their intracellular targets at the same time, which is what likely leads to the synergism observed in this study.

Meanwhile, Mansoor Amiji and Zhenfeng Duan, co-principle investigators of the Cancer Nanotechnology Platform Partnership at Northeastern University, have shown that a different type of polymer nanoparticle can also deliver two anticancer agents simultaneously and as a result can kill cancer cells that have become resistant to drug therapy. In this case, the researchers synthesized biocompatible polymer nanoparticles that entrapped paclitaxel and lonidamine and that targeted the epidermal growth factor receptor (EGFR) that is overexpressed on highly aggressive tumors. When added to tumor cells growing in culture, the nanoparticle containing both drugs was far more effective at killing the drug-resistance cells than when the two drugs were co-administered in separate nanoparticles. The investigators reported their findings in the journal Molecular Pharmaceutics.

In a separate set of experiments, the results of which were published in the journal Angewandte Chemie International Edition, Drs. Nguyen and O’Halloran, joined by Thomas Meade, another member of the Northwestern CCNE, demonstrated that nanobins can also co-deliver a therapeutic and magnetic resonance imaging agent to tumors. In this study, the researchers loaded the anticancer agent gemcitabine into the nanobin’s core and added a gadolinium magnetic resonance contrast agent to the nanobin’s surface. When added to mouse tumor cells, the nanobins were taken up rapidly and the nanobins were clearly visible in magnetic resonance images. In addition, the nanoparticles released their gemcitabine payload once the nanobins were taken up by the cultured cells.

You can teach an old drug new chemotherapy tricks. Northwestern University researchers took a drug therapy proven for blood cancers but ineffective against solid tumors, packaged it with nanotechnology and got it to combat an aggressive type of breast cancer prevalent in young women, particularly young African-American women.

That drug is arsenic trioxide, long part of the arsenal of ancient Chinese medicine and recently adopted by Western oncologists for a type of leukemia. The cancer is triple negative breast cancer, which often doesn’t respond well to traditional chemotherapy and can’t be treated by potentially life-saving targeted therapies. Women with triple negative breast cancer have a high risk of the cancer metastasizing and poor survival rates.

Prior to the new research, arsenic hadn’t been effective in solid tumors. After the drug was injected into the bloodstream, it was excreted too rapidly to work. The concentration of arsenic couldn’t be increased, because it was then too toxic.

A new arsenic nanoparticle — designed to slip undetected through the bloodstream until it arrives at the tumor and delivers its poisonous cargo — solved all that. The nanoparticle, called a nanobin, was injected into mice with triple negative breast tumors. Nanobins loaded with arsenic reduced tumor growth in mice, while the non-encapsulated arsenic had no effect on tumor growth. The arsenic nanobins blocked tumor growth by causing the cancer cells to die by a process known as apoptosis.

The nanobin consists of nanoparticulate arsenic trioxide encapsulated in a tiny fat vessel (a liposome) and coated with a second layer of a cloaking chemical that prolongs the life of the nanobin and prevents scavenger cells from seeing it. The nanobin technology limits the exposure of normal tissue to the toxic drug as it passes through the bloodstream. When the nanobin gets absorbed by the abnormal, leaky blood vessels of the tumor, the nanoparticles of arsenic are released and trapped inside the tumor cells.

“The anti-tumor effects of the arsenic nanobins against clinically aggressive triple negative breast tumors in mice are extremely encouraging,” said Vince Cryns, associate professor of medicine and an endocrinologist at Northwestern Medicine and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “There’s an urgent need to develop new therapies for poor prognosis triple negative breast cancer.”

Cryns and Tom O’Halloran, director of the Chemistry of Life Processes Institute at Northwestern, are senior authors of a paper on the research, which will be published July 15 in Clinical Cancer Research and featured on the journal cover. Richard Ahn, a student in the medical scientists training program at Northwestern, is lead author.

“Everyone said you can’t use arsenic for solid tumors,” said O’Halloran, also associate director of basic sciences at the Lurie Cancer Center. “That’s because they didn’t deliver it the right way. This new technology delivered the drug directly to the tumor, maintained its stability and shielded normal cells from the toxicity. That’s huge.”

The nanoparticle technology has great potential for other existing cancer drugs that have been shelved because they are too toxic or excreted too rapidly, Cryns noted. “We can potentially make those drugs more effective against solid tumors by increasing their delivery to the tumor and by shielding normal cells from their toxicity,” he said. “This nanotechnology platform has the potential to expand our arsenal of chemotherapy drugs to treat cancer.”

“Working with both professors O’Halloran and Cryns has enabled us to develop the nanobins and hopefully create a new platform for the effective treatment of triple negative breast cancer,” Ahn said. “Having both a basic science mentor and breast cancer mentor is ideal training for me as a future physician-scientist.”

Looking ahead, the challenge now is to refine and improve the technology. “How do we make it more toxic to cancer cells and less toxic to healthy cells?” asked Cryns, also the director of SUCCEED, a Northwestern Medicine program to improve the quality of life for breast cancer survivors.

Northwestern scientists are working on decorating the nanobins with antibodies that recognize markers on tumor cells to increase the drug’s uptake by the tumor.  They also want to put two or more drugs into the same nanobin and deliver them together to the tumor.

“Once you fine-tune this, you could use what would otherwise be a lethal or highly toxic dose of the drug, because a good deal of it will be directly released in the tumor,” O’Halloran said.

The research was supported by the National Cancer Institute-funded Northwestern University Center of Cancer Nanotechnology Excellence. Northwestern has one of seven such centers in the United States.

- Marla Paul

by Jennifer Cline, Science in Society

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