Novel strategy improves cancer cell uptake of nanoparticles

Posted: Jan 19th, 2012

Novel strategy improves cancer cell uptake of nanoparticles

(Nanowerk News) One of the promises of using nanoparticles to deliver potent anticancer agents to tumors is that it is easy to coat nanoparticles with tumor-targeting molecules that should increase the amount of drug that reaches a tumor while decreasing the amount of drug that hits healthy tissue. Taking this idea one step further, researchers at Harvard Medical School and the Massachusetts Institute of Technology have developed a strategy for identifying what could be called tumor uptake molecules for use on nanoparticles. This new class of tumor-targeting agents boosts the amount of drug-loaded nanoparticles that get into cancer cells.

Omid Farokhzad and Robert Langer, both members of the MIT-Harvard Center for Cancer Nanotechnology Excellence (CCNE), led this study. The researchers published their findings in the journal ACS Nano ("Engineering of Targeted Nanoparticles for Cancer Therapy Using Internalizing Aptamers Isolated by Cell-Uptake Selection").

The MIT-Harvard CCNE team focused their discovery efforts on molecules known as aptamers, which are small pieces of RNA or DNA that form three-dimensional shapes capable of binding tightly and specifically to designated targets. In most instances, aptamers are constructed to target a known biomolecule—a disease-associated protein, for example. In this case, the investigators took a different approach and instead targeted two biological properties—the ability to distinguish a prostate cancer cell from a normal prostate cell and the ability to get into the diseased cells. They performed this feat by starting with a huge pool of random RNA sequences and through an iterative process gradually enriched this pool for RNAs that targeted and entered prostate cancer cells. After 12 cycles of this enrichment process, the investigators identified a small number of aptamers that each displayed superior tumor targeting and uptake properties.

The researchers chose one of these aptamers and linked it to a polymer nanoparticle loaded with docetaxel, a potent anticancer agent. Experiments have so far shown that this construct has no effect on normal cells but is highly toxic to prostate cancer cells. The investigators are planning further studies in animal models of prostate cancer. They note that this approach is easily modified to finding targeting and uptake aptamers for any type of cancer cell.

Source: National Cancer Institute http://www.nanowerk.com/news/newsid=24007.php

Camden Professor Engineers E. coli to Produce Biodiesel

September 16, 2010

Desmond Lun is an associate professor of computer science at Rutgers-Camden.

CAMDEN — One mention of E. coli conjures images of sickness and food poisoning, but the malevolent bacteria may also be the key to the future of renewable energy.

Desmond Lun, an associate professor of computer science at Rutgers University–Camden, is researching how to alter the genetic makeup of E. coli to produce biodiesel fuel derived from fatty acids.

“If we can engineer biological organisms to produce biodiesel fuels, we’ll have a new way of storing and using energy,” Lun says.

Creating renewable energy by making fuels, like making ethanol out of corn, has been a common practice in trying to achieve sustainability.

However, Lun says, “It’s widely acknowledged that making fuel out of food sources is not very sustainable. It’s too expensive and it competes with our food sources.”

One alternative is to modify the E. coli microorganism to make it overproduce fatty acids, which are used to make biodiesel.

“Fatty acid molecules aren’t that different from a lot of fuel molecules,” says Lun, a Philadelphia resident. “Biodiesel is something that we can generate quite easily. E. coli has been used as a lab organism for more than 60 years and it’s well-studied. We know a lot about its genetics and how to manipulate it. We’ve got to make quite drastic changes to do it and it requires major intervention.”

That’s where Lun’s computer science expertise comes in. Lun builds computational models of the E. coli organisms to determine what would happen if changes are made. Those changes could include removing enzymes to enhance fatty acid production.

The E. coli microorganism can be modified to make it overproduce fatty acids.

“We call it synthetic biology,” he says. “It’s sort of the next stage of genetic engineering. Instead of making small changes to specific genes, we’re really modifying large sections of genome. We’re putting in entirely new traits rather than modifying existing traits.”

Lun explains, “The unique aspect of my work is this emphasis on computational modeling as a way of guiding it. Even these simple bacteria are immensely complex. Computational modeling can offer a way to speed up the process and make it a faster, better process.”

Fatty acid production in the altered bacteria would be enhanced, paving the way for biofuel development.

Lun is collaborating with researchers from Harvard University on his E. coli project.

He teaches computational and integrative biology and biological networks at the Camden Campus of Rutgers, The State University of New Jersey.

Lun received bachelor's degrees in mathematics and computer engineering from the University of Melbourne, Australia. He received his master’s in electrical engineering and doctorate in computer science from MIT.

Media Contact: Ed Moorhouse
856-225-6759
E-mail: ejmoor@camden.rutgers.edu

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Conquering cancer with implants? Bioengineered vaccines and magnetic nanodiscs show promise

Nov 29, 2009 01:01 PM in Health & Medicine | Post a comment

By Katherine Harmon

Rather than surgically removingtumors, what if doctors could simply implant new tools in our bodies to do the work internally? One team of researchers has been able to vanquish tumors in mice by implanting bioengineered disks filled with tumor-specific antigens, and another has developed magnetized nanodiscs to induce cancer cells destroy themselves.

Numerous cancer vaccines have shown promise in animal models only to later fail to generate results in humans. But an implant-based approach may hold the key, according to a team of immunologists and bioengineers at Harvard University. They designed a tiny polymer disk saturated with dendritic cells and antigens specifically tuned to go after tumor cells. The results, published online November 25 in Science Translational Medicine, show "the power of applying engineering approaches to immunology," David Mooney, a professor of bioengineering ant Harvard's School of Engineering and Applied Sciences, said in a prepared statement.

The principal is the same as a vaccine: prompt the immune system to attack invading cells. However, unlike previously tested injected cancer vaccines, cells from the disk are less prone to die before they can get the job done.

The 8.5-millimeter biodegradable disk can be "inserted anywhere under the skin—much like the implantable contraceptives that can be placed in a woman's arm," Mooney said. "The implants activate an immune response that destroys tumor cells." When the disks were implanted in mice with melanoma, the treatment led to remission and longer lives in "a substantial portion of the population," the authors reported.

Another trick to zapping cancer cells may lie in nano-scale magnets. Previous studies have investigated the use of magnetic fields to kill cancer cells via hyperthermia, but they required a lot more power than the new method and proved to have some dangerous side effects.

A new study, published November 29 in Nature Materials, reports promise in a scaled-down version of this idea to tackle tumors. "Nanomagnetic materials offer exciting avenues for probing cell mechanics and…advancing cancer therapies," the paper authors wrote. Using nanodiscs (about 60 nanometers thick) made of iron and nickel, researchers based in the Argonne National Laboratory in Illinois and the University of Chicago Pritzker School of Medicine have created a so-called "magnetic vortex" in the magnetic alloy with the magnetic charge arranged in concentric circles. "Integration of magnetic materials with biological molecules and therapeutics creates hybrid materials with advanced properties," the authors noted in the paper.

By introducing an alternating magnetic field, researchers made the discs oscillate, thereby damaging the membranes of cancer cells in the lab and causing the cells to die. The researchers needed only a frequency of "a few tens of hertz applied for only 10 minutes" to "achieve cancer-cell destruction in vitro," they wrote. With this approach they rely on neither heat nor mechanical assault, but rather on the oscillation "which triggers the programmed cell-death pathway" via an ionic electrical signal, the authors explained. Thus, "the total energy necessary to accomplish cell death is minute."

While these innovative implant technologies are being tested in the lab, however, cancer continues to be one of the leading causes of death in the U.S. (second only to heart disease), killing more than half a million people last year.

Image of polymer matrix (next to dime for size comparison) courtesy of InCytu, Inc.

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Miniaturised scanner zooms in on disease

13:15 08 July 2008

A handheld nuclear magnetic resonance (NMR) scanner that can diagnose diseases and identify pathogens has been built by scientists in the US.

The revolutionary scanner is many times smaller than conventional NMR spectroscopy machines, which require huge magnets to create the powerful magnetic fields necessary to make them work.

Nuclear magnetic resonance spectroscopy works by lining up nuclei in a sample using a powerful magnetic field and then zapping them with radio waves that cause them to wobble, or precess.

This precession induces currents in a nearby coil which can be used to determine the chemical structure of the molecules that contain the nuclei. The same process is used in magnetic resonance imaging machines to make non-invasive images of human bodies. The new device does not produce images, however.

Weaker fields

In conventional NMR spectroscopy machines, powerful fields are necessary to line up individual nuclei.

However, Ralph Weissleder at Harvard Medical School in Cambridge, Massachusetts, US, and colleagues have found that magnetic nanoparticles generate a much larger signal than single nuclei, and can thus be detected using the weaker fields from small permanent magnets.

The trick that Weissleder and colleagues have perfected is to coat these nanoparticles with molecules that bind to specific biomolecules, or bacteria and viruses.

This binding process causes the nanoparticles to clump together, producing a measurable change in the signal they produce. In this way, the team says it can identify a large variety of biological targets.

The team has squeezed the electronics that detect and interpret the signals onto a chip just 2 millimetres square (pdf format).

Small and sensitive

What's more, the researchers have also designed a microfluidics network that shuttles the samples around and concentrates them in volumes of just five millionths of a litre (5 microlitres) – some 60 times less than conventional systems.

"The smaller the system, the better the sensitivity in terms of absolute amount of sample that can be detected," says Hakho Lee, lead author on the research.

The prototype device has eight tiny coils, each of which can monitor nanoparticles sensitive to different biomolecules. Future devices could employ many more such coils.

The result is a prototype machine that is 800 times more sensitive than standard NMR scanners used in many laboratories, says Weissleder.

The team put the prototype through its paces, showing that it is sensitive enough to detect just 10 bacteria in a given sample. By loading each of the eight microcoils with different nanoparticles, the system could distinguish between simulated blood samples representing healthy individuals, those with cancer, and those with diabetes, by looking for eight different biomarker molecules.

Multiple applications

"The biggest advantage is that we don't need sample preparation or purification steps," Lee says. The nanoparticles are simply added to whatever samples are present. "This method could provide an easy and fast way to diagnose almost any kind of disease, such as bacterial infection or cancers in point-of-care settings – right next to the patient or in developing countries."

The device could also be used to test for water purity or even applied to gaseous samples, to search for airborne pathogens or pollutants.

Other researchers are impressed with the work. "If you came to my lab you would see that our spectrometers occupy whole rooms, and we are always struggling with sensitivity in NMR experiments," says Dusan Uhrin, an NMR spectroscopist at the University of Edinburgh.

"They have been able to improve the sensitivity such that they can detect just a few bacteria. It's quite remarkable that they can detect down to that limit," he says.

Weissleder has filed a patent for the design and started a company called T2 Biosystems to market the devices.

Journal reference: Nature Medicine (DOI: 10.1038/nm.1711)

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T2 Biosystems

United States Patent Application 20060269965