Nanoparticles can be cancer killers

Nanoparticles known as Cornell dots, or C dots, have shown great promise as a therapeutic tool in the detection and treatment of cancer.

Now, the ultrasmall particles – developed more than a dozen years ago by Ulrich Wiesner, the Spencer T. Olin Professor of Engineering – have shown they can do something even better: kill cancer cells without attaching a cytotoxic drug.

A study led by Michelle Bradbury, director of intraoperative imaging at Memorial Sloan Kettering Cancer Center and associate professor of radiology at Weill Cornell Medicine, and Michael Overholtzer, cell biologist at MSKCC, in collaboration with Wiesner has thrown a surprising twist into the decadelong quest to bring C dots out of the lab and into use as a clinical therapy.

“In fact,” Bradbury said, “this is the first time we have shown that the particle has intrinsic therapeutic properties.”

Wiesner’s fluorescent silica particles, as small as 5 nanometers in diameter, were originally designed to be used as diagnostic tools, attaching to cancer cells and lighting up to show a surgeon where the tumor cells are. Potential uses also included drug delivery and environmental sensing. A first-in-human clinical trial by the Food and Drug Administration, led by Bradbury, deemed the particles safe for humans.

In further testing of the particles over the last five years – including the last 13 months as a member of the Centers of Cancer Nanotechnology Excellence, a National Cancer Institute initiative established in August 2015 – Bradbury, Overholtzer, Wiesner and their collaborators made this major, unexpected finding.

When incubated with cancer cells at high doses – and, importantly, with cancer cells in a state of nutrient deprivation – Wiesner’s peptide-coated C dots show the ability to adsorb iron from the environment and deliver this into cancer cells. The peptide, called alpha-MSH, was developed by Thomas Quinn, professor of biochemistry at the University of Missouri.

This process triggers ferroptosis, a necrotic form of cell death involving plasma membrane rupture – different from the typical cell fragmentation found during a more commonly observed form of cell death called apoptosis.

“The original purpose for studying the dots in cells was to see how well larger concentrations would be tolerated without altering cellular function,” Overholtzer said. “While high concentrations were well-tolerated under normal conditions, we wanted to also know how cancer cells under stress might respond.”

To the group’s surprise, in 24 to 48 hours after the cancer cells were exposed to the dots, there was a “wave of destruction” throughout the entire cell culture, Wiesner said. Tumors also shrank when mice were administered multiple high dose injections without any adverse reactions, said Bradbury, co-director with Wiesner of the MSKCC-Cornell Center for Translation of Cancer Nanomedicines.

In the ongoing fight against a disease that kills millions worldwide annually – cancer has taken several in Wiesner’s family, making this also a personal crusade for him. Having another weapon can only help, Wiesner said.

“We’ve found another tool that people have not thought about at all so far,” he said. “This has changed our way of thinking about nanoparticles and what they could potentially do.”

Future work will focus on utilizing these particles in combination with other standard therapies for a given tumor type, Bradbury said, with the hope of further enhancing efficacy before testing in humans.

Researchers will also look to tailor the particle to target specific cancers. “It’s a matter of designing the particles with different attachments on them, so they’ll bind to the particular cancer we’re after,” Overholtzer said.

Source: Cornell University



Particles carry more drugs hold potential for targeted cancer therapy

Nanoparticles offer a promising way to deliver cancer drugs in a targeted fashion, helping to kill tumors while sparing healthy tissue. However, most nanoparticles that have been developed so far are limited to carrying only one or two drugs.

MIT chemists have now shown that they can package three or more drugs into a novel type of nanoparticle, allowing them to design custom combination therapies for cancer. In tests in mice, the researchers showed that the particles could successfully deliver three chemotherapy drugs and shrink tumors.

In the same study, which appears in the Sept. 14 issue of the Journal of the American Chemical Society, the researchers also showed that when drugs are delivered by nanoparticles, they don’t necessarily work by the same DNA-damaging mechanism as when delivered in their traditional form.

That is significant because most scientists usually assume that nanoparticle drugs are working the same way as the original drugs, says Jeremiah Johnson, the Firmenich Career Development Associate Professor of Chemistry and the senior author of the paper. Even if the nanoparticle version of the drug still kills cancer cells, it’s important to know the underlying mechanism of action when choosing combination therapies and seeking regulatory approval of new drugs, he says.

Using a method developed by Hemann’s lab, the researchers then investigated how their nanoparticle drugs affect cells. The technique measures cancer drugs’ effects on eight genes that are involved in the programmed cell death often triggered by cancer drugs. This allows scientists to classify the drugs based on which clusters of genes they affect.

The researchers found that nanoparticle-delivered camptothecin and doxorubicin worked just as expected. However, cisplatin did not. Cisplatin normally acts by linking adjacent strands of DNA, causing damage that is nearly impossible for the cell to repair. When delivered in nanoparticle form, the researchers found that cisplatin acts more like a different platinum-based drug known as oxaliplatin. This drug also kills cells, but by a different mechanism: It binds to DNA but induces a different pattern of DNA damage.

The researchers hypothesize that after cisplatin is released from the nanoparticle, via a reaction that kicks off a group known as a carboxylate, the carboxylate group then reattaches in a way that makes the drug act more like oxaliplatin. Many other researchers attach cisplatin to nanoparticles the same way, so Johnson suspects this could be a more widespread issue.

Source: Massachusetts Institute of Technology



Cheap paper strips for cancer testing at home

Chemists at The Ohio State University are developing paper strips that detect diseases including cancer and malaria—for a cost of 50 cents per strip.

The idea, explained Abraham Badu-Tawiah, is that people could apply a drop of blood to the paper at home and mail it to a laboratory on a regular basis—and see a doctor only if the test comes out positive. The researchers found that the tests were accurate even a month after the blood sample was taken, proving they could work for people living in remote areas.

The assistant professor of chemistry and biochemistry at Ohio State conceived of the papers as a way to get cheap malaria diagnoses into the hands of people in rural Africa and southeast Asia, where the disease kills hundreds of thousands of people and infects hundreds of millions every year.

But in the Journal of the American Chemical Society, he and his colleagues report that the test can be tailored to detect any disease for which the human body produces antibodies, including ovarian cancer and cancer of the large intestine.

The patent-pending technology could bring disease diagnosis to people who need it most—those who don’t have regular access to a doctor or can’t afford regular in-person visits, Badu-Tawiah said.

“We want to empower people. If you care at all about your health and you have reason to worry about a condition, then you don’t want to wait until you get sick to go to the hospital. You could test yourself as often as you want,” he said.

The technology resembles today’s “lab on a chip” diagnostics, but instead of plastic, the “chip” is made from sheets of plain white paper stuck together with two-sided adhesive tape and run through a typical ink jet printer.

Instead of regular ink, however, the researchers use wax ink to trace the outline of channels and reservoirs on the paper. The wax penetrates the paper and forms a waterproof barrier to capture the blood sample and keep it between layers. One 8.5-by-11-inch sheet of paper can hold dozens of individual tests that can then be cut apart into strips, each a little larger than a postage stamp.

“To get tested, all a person would have to do is put a drop of blood on the paper strip, fold it in half, put it in an envelope and mail it,” Badu-Tawiah said.

The technology works differently than other paper-based medical diagnostics like home pregnancy tests, which are coated with enzymes or gold nanoparticles to make the paper change color. Instead, the paper contains small synthetic chemical probes that carry a positive charge. It’s these “ionic” probes that allow ultra-sensitive detection by a handheld mass spectrometer.

“Enzymes are picky. They have to be kept at just the right temperature and they can’t be stored dry or exposed to light,” Badu-Tawiah said. “But the ionic probes are hardy. They are not affected by light, temperature, humidity—even the heat in Africa can’t do anything to them. So you can mail one of these strips to a hospital and know that it will be readable when it gets there.”

The chemists designed ionic probes to tag specific antibodies that extract the disease biomarker from the blood and onto the paper chip. Once they are extracted, the chemicals stay unchanged until the paper is dipped in an ammonia solution at the laboratory. There, someone peels the paper layers apart and holds them in front of a mass spectrometer, which detects the presence of the probes based on their atomic characteristics—and, by extension, the presence of biomarkers in an infected person’s blood.

Badu-Tawiah and postdoctoral researchers Suming Chen and Qiongqiong Wan successfully demonstrated that they could detect protein biomarkers from the most common malaria parasite, Plasmodium falciparum, which is most prevalent in Africa.

They also successfully detected the protein biomarker for ovarian cancer, known as cancer antigen 125, and the carcinoembryonic antigen, which is a marker for cancer of the large intestine, among other cancers.

They worked with former doctoral student Yang Song in the lab of colleague Vicki Wysocki, professor of chemistry and biochemistry, to study how the probes stick to the antibodies with a high-resolution mass spectrometer. Wysocki is the Ohio Eminent Scholar of Macromolecular Structure and Function and director of the Campus Chemical Instrument Center at Ohio State.

After confirming that their tests worked, Badu-Tawiah and his team stored the strips away and re-tested them every few days to see if the signal detected by the mass spectrometer would fade over time. It didn’t. The signal was just as strong after 30 days as on day one, meaning that the disease proteins were stable and detectable even after a month.

Since the antibody strips survive more than long enough to reach a lab by mail, they could open up a whole new world of medical care for people in rural communities—even in the United States, Badu-Tawiah said. Even for people living in the city, testing themselves at home would save money compared to going to the doctor.

In the US, he said, the tests would be ideal for people who have a family history of cancer or have successfully undergone cancer treatment. Instead of waiting to visit a doctor every six months to confirm that they are still in remission, they could test themselves from home more frequently.

In the case of malaria, the human and financial costs are high, especially in Africa.

Malaria is a mosquito-borne disease caused by parasites. The infection starts with flulike symptoms that can develop into kidney failure or other complications. The Centers for Disease Control and Prevention estimates that there were 214 million cases of malaria worldwide in 2015, and 438,000 people died—mostly children in Africa.

“In Africa, malaria is so common that whenever you get feverish, the first thing you think is, ‘Oh, it’s probably malaria,’” Badu-Tawiah said.

While the prototype test strips at Ohio State cost about 50 cents each to produce, those costs would likely go down with mass production, he said. The greatest cost of using the strips would fall to urban medical facilities, which would have to purchase mass spectrometers to read the results. Model portable instruments can cost $100,000 but less expensive handheld mass specs are under development.

Still, Badu-Tawiah pointed out, an initial investment in mass specs would be more than offset by the potential boon to Africa’s economy. UNICEF estimates that malaria costs the continent $12 billion in lost worker productivity every year.

In the United States, where mass spectrometers are more common, the cost savings would come in the form of reduced insurance use and fewer out-of-pocket expenses from going to the doctor less often.

“Although this approach requires an initial investment, we believe the low-cost paper-based consumable devices will make it sustainable,” Badu-Tawiah said. “We can set one small instrument at a grocery store, then sell the paper strips for just 50 cents per test. The same for Africa, and perhaps much cheaper there.”

The university will license the technology to a medical diagnostics company for further development, and Badu-Tawiah hopes to be able to test the strips in a clinical setting within three years. In the meantime, he and his colleagues are working to make the tests more sensitive, so that people could eventually use them non-invasively, with saliva or urine as the test material instead of blood.

Full story can be found from The Ohio State University website.

Nanobubbles Generated by Pulsed Laser Identify & Destroy Cancer Cells

Innovative technology developed by NIH-funded researchers has been able to find and facilitate the killing of cancer cells in mice without harming the nearby healthy tissue. A treatment using this technology in humans could reduce the rate of cancer recurrence or metastasis.

Cancer cells that cannot be removed by surgeons often cause tumors to return or metastasize. In a study published in Nature Nanotechnology in February, Dmitri Lapotko, Ph.D., and his team at Rice University (currently with Masimo Corporation, CA) describe a new way to combat these leftover cancer cells. In this new approach, tiny gold particles have cancer-specific antibodies attached to their surface, which enable the particles to be engulfed in high concentrations and cluster only in cancer cells. These gold clusters, when exposed to a short broad laser pulse, heat and evaporate surrounding liquid, producing a “plasmonic nanobubble.” This nanobubble produces an “acoustic pop” which reveals the cancer cell and then causes an explosion that destroys it from the inside out.

Researchers have examined gold nanoparticles for treating cancer in the past, but the particles lacked specificity; they were unable to differentiate between healthy cells and cancer cells. Lapotko and his team are combatting this problem by combining the use of antibody-coated gold particles with the generation of nanobubbles created with a short laser pulse.

Gold particles can be injected prior to a surgery so they can travel to and cluster in cancer cells. After a tumor is removed in surgery, the laser (near-infrared) pulse is low energy, which can travel safely through a centimeter of tissue, is applied. The laser pulse only causes the nanobubble-induced damage in the remaining cancer cells with gold particles and are the only ones destroyed. This unique approach might be able to reduce the amount of unintended damage done to the patient, especially if the tumor is located in a sensitive area such as the brain, head and neck, breast, or prostate.

“This is a creative and novel approach that combines an understanding of the basic biophysics of heat transfer with the exquisite specificity and chemistry of the targeting antibodies,” said Rosemarie Hunziker, Director of the program for Tissue Engineering at NIBIB. “It could become a powerful tool in our arsenal to fight cancer.”

When surgeons injected these gold particles into mice with cancer before surgery, the initial results were impressive. While 80% of the mice in the operated group that did not receive the gold particle treatment died due to tumors that recurred within 10 days after surgery, none of the mice that received the additional nanobubble treatment regrew tumors in the following two months.

Detailed information can be found from NIBIB website.

Nanoparticles as new drug-delivery approach to hold potential for treating obesity

Researchers at MIT and Brigham and Women’s Hospital have developed nanoparticles that can deliver antiobesity drugs directly to fat tissue. Overweight mice treated with these nanoparticles lost 10 percent of their body weight over 25 days, without showing any negative side effects.

The drugs work by transforming white adipose tissue, which is made of fat-storing cells, into brown adipose tissue, which burns fat. The drugs also stimulate the growth of new blood vessels in fat tissue, which positively reinforces the nanoparticle targeting and aids in the white-to-brown transformation.

These drugs, which are not FDA-approved to treat obesity, are not new, but the research team developed a new way to deliver them so that they accumulate in fatty tissues, helping to avoid unwanted side effects in other parts of the body.

“The advantage here is now you have a way of targeting it to a particular area and not giving the body systemic effects. You can get the positive effects that you’d want in terms of antiobesity but not the negative ones that sometimes occur,” says Robert Langer, the David H. Koch Institute Professor at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research.

More than one-third of Americans are considered to be obese, and last year obesity overtook smoking as the top preventable cause of cancer death in the United States, with 20 percent of the 600,000 cancer deaths attributed to obesity.

Langer and Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s Hospital, are the senior authors of the study, which appears in the Proceedings of the National Academy of Sciences the week of May 2. The paper’s lead authors are former MIT postdoc Yuan Xue and former BWH postdoc Xiaoyang Xu.

More information can be found from MIT website following this link.