New technique targets specific areas of cancer cells with different drugs

Jan. 6, 2014 — Researchers have developed a technique for creating nanoparticles that carry two different cancer-killing drugs into the body and deliver those drugs to separate parts of the cancer cell where they will be most effective. The technique was developed by researchers at North Carolina State University and the University of North Carolina at Chapel Hill.

"In testing on laboratory mice, our technique resulted in significant improvement in breast cancer tumor reduction as compared to conventional treatment techniques," says Dr. Zhen Gu, senior author of a paper on the research and an assistant professor in the joint biomedical engineering program at NC State and UNC-Chapel Hill.

"Cancer cells can develop resistance to chemotherapy drugs, but are less likely to develop resistance when multiple drugs are delivered simultaneously," Gu says. "However, different drugs target different parts of the cancer cell. For example, the protein drug TRAIL is most effective against the cell membrane, while doxorubicin (Dox) is most effective when delivered to the nucleus. We've come up with a sequential and site-specific delivery technique that first delivers TRAIL to cancer cell membranes and then penetrates the membrane to deliver Dox to the nucleus."

Gu's research team developed nanoparticles with an outer shell made of hyaluronic acid (HA) woven together with TRAIL. The HA interacts with receptors on cancer cell membranes, which "grab" the nanoparticle. Enzymes in the cancer cell environment break down the HA, releasing TRAIL onto the cell membrane and ultimately triggering cell death.

When the HA shell breaks down, it also reveals the core of the nanoparticle, which is made of Dox that is embedded with peptides that allow the core to penetrate into the cancer cell. The cancer cell encases the core in a protective bubble called an endosome, but the peptides on the core cause the endosome to begin breaking apart. This spills the Dox into the cell where it can penetrate the nucleus and trigger cell death.

"We designed this drug delivery vehicle using a 'programmed' strategy," says Tianyue Jiang, a lead author in Dr. Gu's lab. "Different drugs can be released at the right time in their right places," adds Dr. Ran Mo, a postdoctoral researcher in Gu's lab and the other lead author.

"This research is our first proof of concept, and we will continue to optimize the technique to make it even more efficient," Gu says. "The early results are very promising, and we think this could be scaled up for large-scale manufacturing."

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Avoiding specific region of brain during whole-brain radiotherapy prevents memory loss

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AppId is over the quota
Limiting the amount of radiation absorbed in the hippocampal portion of the brain during whole-brain radiotherapy (WBRT) for brain metastases preserves memory function in patients for up to six months after treatment, according to research presented at the American Society for Radiation Oncology's (ASTRO's) 55th Annual Meeting by researchers from the University of Wisconsin School of Medicine and Public Health, home of the UW Paul P. Carbone Comprehensive Cancer Center.

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Protecting specific area of the brain during radiation therapy substantially reduces memory loss

Sep. 23, 2013 — Protecting the stem cells that reside in and around the hippocampus -- a C-shaped area in the temporal lobe on both sides of the brain associated with the ability to form and store memories -- substantially reduces the rate of cancer patients' memory loss during whole-brain radiotherapy without a significant risk of recurrence in that area of the brain, a new study shows. Results of the Phase II clinical trial of patients with brain metastases are being presented today at the American Society for Radiation Oncology (ASTRO) annual meeting.

"Memory loss, especially short-term recall, is an important consideration for patients receiving whole-brain radiotherapy," says the study's co-principal investigator, Minesh P. Mehta, M.B., Ch.B., professor of radiation oncology at the University of Maryland School of Medicine. "We found that reducing the radiation dose to the stem-cell niches surrounding the hippocampus during treatment was clearly associated with memory preservation without an inordinate risk of relapse in that portion of the brain. The findings far exceeded our expectations."

Based on previous research, the predicted rate of cognitive decline at four months for patients receiving whole-brain radiation for brain metastases was 30 percent. Researchers designed the clinical trial so that a positive result would be a rate reduced by half, to 15 percent. The observed rate in the trial was actually 7 percent -- significantly better than the baseline rate of 30 percent. With a third fewer patients to evaluate, the rate of decline observed at six months was 2 percent, although comparable data from the historic control study were not available.

"These Phase II results, while not absolutely conclusive, offer very important insights which we hope to validate in a larger, randomized Phase III clinical trial," says Dr. Mehta, a radiation oncologist at the University of Maryland Marlene and Stewart Greenebaum Cancer Center who chairs the Radiation Therapy Oncology Group (RTOG) brain tumor committee. The RTOG, which managed the Phase II trial, also plans to manage the Phase III Study.

Co-principal investigator Vinai Gondi, M.D., will present the findings at the plenary session at the ASTRO annual meeting in Atlanta. He practices at Central DuPage Hospital Cancer Center in Warrenville, Ill.

E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and Dean of the University of Maryland School of Medicine, says, "Preserving neurocognitive function is extremely important in treating patients with brain metastases, and the results of this latest study on hippocampal-avoidance radiotherapy led by Dr. Mehta are very encouraging. This technique, if validated in a randomized clinical trial, will give physicians a significant new tool to help maintain patients' quality of life while aggressively treating their cancer."

Patients in the study, the majority of them with lung cancer that had spread to the brain, were treated with intensity-modulated radiation therapy (IMRT), which enabled doctors to shape the radiation beams to avoid the hippocampus. Researchers used a standardized cognitive function assessment -- the Hopkins Verbal Learning Test (HVLT) -- to measure patients' baseline memory, such as their ability to recall information immediately or after a delay, with follow-up at two, four and six months.

A total of 113 patients were recruited between 2011 and 2013; investigators were able to evaluate 42 patients at four months and 29 patients at six months. The median survival for the participants was 6.8 months. Three patients (4.5 percent) experienced progression of their disease in the hippocampal region, which was within the expected range.

Dr. Mehta says that the radiation affects cognitive function by damaging nerve cells as well as stem cells, which help to regenerate nerve cells that support memory formation. "These stem-cell niches are exquisitely sensitive to radiation and are involved in neurogenesis -- the process of generating new neurons, or nerve cells. Although we call it hippocampal-avoidance radiotherapy, we really are targeting the stem-cell niches in and around the hippocampus," Dr. Mehta says.

He notes that factors other than radiation may also contribute to cognitive decline in patients with brain metastases, including medicines to control seizures or swelling in the brain. The cancer itself may also have an effect.

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