Like a mini SWAT team, microscopic particles of a platinum-based chemotherapy drug could be deployed within a tumor to unleash a forceful three-pronged attack on cancer with minimal collateral damage to healthy tissue—that's the way this early research reported at the American Association of Physicists in Medicine (AAPM) was described.
“Nanoparticles of platinum-based drugs, at Food and Drug Association-approved doses, can be employed in a strategic new way to substantially boost standard cancer radiotherapy treatment, with significantly fewer side effects and at no additional inconvenience to patients,” said Wilfred Ngwa, PhD, an instructor in radiation oncology at Brigham & Women's Hospital, Dana Farber Cancer Institute, and Harvard Medical School. “If successfully developed, the new strategy could significantly increase survival and quality of life for cancer patients—for example, lung and prostate cancer patients.”
Nanoparticles as drug-delivery systems enable unique approaches for cancer treatment. Over the last two decades, a large number of nanoparticle delivery systems have been developed for cancer therapy, including organic and inorganic materials. Many liposomal polymer-drug conjugates and micellar formulations are part of the state of the art in the clinic, and an even greater number of nanoparticle platforms are currently in preclinical development.
More recently developed nanoparticles are demonstrating the potential sophistication of these delivery systems by incorporating multifunctional capabilities and targeting strategies in an effort to increase the efficacy of these systems against the most difficult cancer challenges, including drug resistance and metastatic disease.
Several such engineered drugs are in clinical practice, including liposomal doxorubicin and albumin conjugate paclitaxel. Carrier-mediated paclitaxel has already shown significant efficacy in taxane-resistant cancers, an approach highly relevant in prostate cancer, where taxanes are the treatment of choice.
Research at Harvard Medical School has shown that nanoparticles could be used during radiation treatment to increase damage to the tumor's blood vessels, as well as the cells that cause cancer to recur, while also delivering chemotherapy with fewer side effects.
The study by Ngwa and colleagues builds on research showing that nanoparticles (100 million of which could fit on the head of a pin) made of precious metals such as platinum and gold can increase the dose and accuracy of radiation therapy.
Another study presented at the meeting suggests that shell-shaped hollow gold nanoparticles can enable the same cancer-killing benefits of standard radiation therapy but at much lower doses than typically used.
Currently, physicians routinely insert rice grain-sized implants into tumors to guide radiation therapy by marking the location of the cancer and to direct irradiation. The Harvard researchers along with collaborators at Northeastern University are developing their own “smart” implants by coating them with a polymer film containing nanoparticles of platinum-based cisplatin.
That approach uses FDA-approved concentrations of cisplatin nanoparticles released from the smart implant. The theory is that once the smart implant is placed inside the tumor, the nanoparticles could be released to attack the cancer by disrupting its blood vessels, as well as damaging the cancer cell's DNA via chemotherapy and a highly targeted, enhanced dose of radiation.
“The nanoparticles could be programmed to deliver a sustainable one-two-three punch to the cancer where it hurts the tumor the most,” said Ngwa. “The first punch is to use nanoparticles to disrupt tumor blood vessels. The second is to boost radiation dose to high-risk tumor cells, and the third is chemotherapy delivered with fewer side effects.”
The major advantage, he said, is to allow nanoparticles to deliver chemotherapy directly to the cancer cell: “Tumor blood vessels receive twice the radiation dose over standard radiation therapy with fewer side effects. Over the past two years, we have seen enormous positive customizing of radiation therapy. We anticipate this could provide huge benefits, including helping prevent cancer recurrence, and significantly increasing survival and quality of life for cancer patients.”
The research to date is still at an early stage, with the platinum-based nanoparticles tested only in mice. Ngwa says he is looking for funding to start a human clinical trial.
“Based on the promising results, we believe that our new approach presents enormous possibilities for customizing and significantly improving radiation therapy,” he said. If successfully developed, the new method could be employed at virtually no additional inconvenience to patients to enhance treatment of lung and prostate cancers, among others.”
‘Could Be Used as Part of Brachytherapy’
Asked for his opinion, Ken Westover MD, Assistant Professor of Radiation Oncology and Biochemistry at the University of Texas Southwestern Medical Center, said, “Eventually, the potential for nanoparticles is to potentiate how effective radiation therapy might be, or to open possibilities for delivery of drugs considered classically more systemic agents. The key challenge is targeting and delivery to the appropriate location.
“The Boston group's idea is interesting to use platinum to physically target a tumor. That could be used for delivery as part of brachytherapy—that is, to place the material where it is supposed to go.”
Nanoparticles also carry the potential for targeted and time-release drugs, Westover noted. A potent dose of drugs could be delivered to a specific area, but engineered to release over a planned period to ensure maximum effectiveness and the patient's safety.
Hollow Gold Nanoparticles Produce Same Biological Effect at Much Lower RT Doses
Also at the meeting, other researchers at UT Southwestern reported on the concept of injecting shell-shaped hollow gold nanoparticles directly into tumors to enhance the effects of radiation. While still microscopic, the hollow nanoparticles are about 10 times the size of standard solid nanoparticles.
“The advantage of hollow nanoparticles is they have short-range effects. We can deliver the same amount of gold with much larger surface area for an enhancement of therapy,” said Weihua Mao, PhD, Assistant Professor in the Department of Radiation Oncology.
As he put it, when radiation treatment strikes gold nanoparticles, they create an avalanche of electrons near the tumor cells, making the radiation more lethal to the cancer. Making the nanoparticles larger increases the amount of surface area and, therefore, their ability to boost radiation to kill tumor cells. Using a clonogenic assay, he and his colleagues found that hollow gold nanoparticles produced the same biological treatment effect at much lower doses of radiation.
“This preliminary research suggests that gold nanoparticles can boost the cancer-killing power of the radiation so that much lower doses of radiation can be used to achieve the same effect,” Mao said. “It's safer and better for the patient to be exposed to less radiation, so this therapy holds promise.”
The team has conducted in vivo studies in breast cancer cells and irradiated small animals with gold nanoparticles. “When we add nanoparticles, we see a significantly improved killing effect,” he said.
Westover commented: “Gold has been used in patients for a long time, and it may get to clinic more quickly, depending on the formulation.
“Platinum and gold give good contrast on computed tomography scans. If there was some way to deliver these nanoparticles to targets, we might have more confidence in targeting, which would open the door to stereotactic therapy.”
He said he considered nanoparticle research to be exciting because it might enable stereotactic procedures and enhance radiation response. It also could be an opportunity for surgeons to use in lieu of surgical clips to highlight margins.
“Better targeting than traditional radiation therapy could enhance the effects. We will see how this will be used over the next 10 years.”