Category Archives: NanoMedicine
Sequencing DNA base pairs — the individual molecules that make up DNA — is key for medical researchers working toward personalized medicine. Being able to isolate, study and sequence these DNA molecules would allow scientists to tailor diagnostic testing, therapies and treatments based on each patient’s individual genetic makeup.
But being able to isolate individual molecules like DNA base pairs, which are just two nanometers across — or about 1/50,000th the diameter of a human hair — is incredibly expensive and difficult to control. In addition, devising a way to trap DNA molecules in their natural aqueous environment further complicates things. Scientists have spent the past decade struggling to isolate and trap individual DNA molecules in an aqueous solution by trying to thread it through a tiny hole the size of DNA, called a “nanopore,” which is exceedingly difficult to make and control.
Now a team led by Yale University researchers has proven that isolating individual charged particles, like DNA molecules, is indeed possible using a method called “Paul trapping,” which uses oscillating electric fields to confine the particles to a space only nanometers in size. (The technique is named for Wolfgang Paul, who won the Nobel Prize for the discovery.) Until now, scientists have only been able to use Paul traps for particles in a vacuum, but the Yale team was able to confine a charged test particle — in this case, a polystyrene bead — to an accuracy of just 10 nanometers in aqueous solutions between quadruple microelectrodes that supplied the electric field.
Their device can be contained on a single chip and is simple and inexpensive to manufacture. “The idea would be that doctors could take a tiny drop of blood from patients and be able to run diagnostic tests on it right there in their office, instead of sending it away to a lab where testing can take days and is expensive,” said Weihua Guan, a Yale engineering graduate student who led the project.
Story Continues -> Particle Trap Paves Way for Personalized Medicine
Tiny, melanin-covered nanoparticles may protect bone marrow from the harmful effects of radiation therapy, according to scientists at Albert Einstein College of Medicine of Yeshiva University who successfully tested the strategy in mouse models. Infusing these particles into human patients may hold promise in the future.
The research is described in the current issue of the International Journal of Radiation Oncology, Biology and Physics.
Radiation therapy is used to kill cancer cells and shrink tumors. But because radiation also damages normal cells, doctors must limit the dose. Melanin, the naturally occurring pigment that gives skin and hair its color, helps shield the skin from the damaging effects of sunlight and has been shown to protect against radiation.
“A technique for shielding normal cells from radiation damage would allow doctors to administer higher doses of radiation to tumors, making the treatment more effective,” said Ekaterina Dadachova, Ph.D., associate professor of nuclear medicine and of microbiology & immunology and the Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research at Einstein, as well as senior author of the study.
In previously published research, Dr. Dadachova and colleagues showed that melanin protects against radiation by helping prevent the formation of free radicals, which cause DNA damage, and by scavenging the free radicals that do form.
“We wanted to devise a way to provide protective melanin to the bone marrow,” said Dr. Dadachova. “That’s where blood is formed, and the bone-marrow stem cells that produce blood cells are extremely susceptible to the damaging effects of radiation.”
Dr. Dadachova and her colleagues focused on packaging melanin in particles so small that they would not get trapped by the lungs, liver or spleen. They created “melanin nanoparticles” by coating tiny (20 nanometers in diameter) silica (sand) particles with several layers of melanin pigment that they synthesized in their laboratory.
The researchers found that these particles successfully lodged in bone marrow after being injected into mice. Then, in a series of experiments, they investigated whether their nanoparticles would protect the bone marrow of mice treated with two types of radiation.
In the first experiment, one group of mice was injected with nanoparticles and a second group was not. Three hours later, both groups were exposed to whole-body radiation. For the next 30 days, the researchers monitored the blood of the mice, looking for signs of bone marrow damage such as decreased numbers of white blood cells and platelets.
Compared with the control group, those receiving melanin nanoparticles before radiation exposure fared much better; their levels of white cells and platelets dropped much less precipitously. Ten days after irradiation, for example, platelet levels had fallen by only 10 percent in mice that had received nanoparticles compared with a 60 percent decline in untreated mice. Furthermore, levels of white blood cells and platelets returned to normal much more quickly than in the control mice.
A second experiment assessed not only bone-marrow protection but whether the nanoparticles might have the undesirable effect of infiltrating and protecting tumors being targeted with radiation. Two groups of mice were injected with melanoma cells that formed melanoma tumors. After one group of mice was injected with melanin nanoparticles, both groups received an experimental radiation treatment designed by Dr. Dadachova and her colleagues specifically for treating melanoma.
This treatment uses a radiation-emitting isotope “piggybacked” onto an antibody that binds to melanin. When injected into the bloodstream, the antibodies latch onto the free melanin particles released by cells within melanoma tumors. Their isotopes then emit radiation that kills nearby melanoma tumor cells.
Following the second experiment, the melanoma tumors shrank significantly and to the same extent in both groups of mice — indicating that the melanized nanoparticles did not interfere with the radiation therapy’s effectiveness. And once again, the melanized nanoparticles prevented radiation-induced bone-marrow damage: between the third and seventh day after the antibody-isotope radiation therapy was administered, mice injected with nanoparticles experienced a drop in white cells that was significantly less than occurred in mice not pre-treated with nanoparticles.
“The ability to protect the bone marrow will allow physicians to use more extensive cancer-killing radiation therapies and this will hopefully translate into greater tumor response rates,” said Arturo Casadevall, M.D., Ph.D., professor of medicine and of microbiology & immunology, the Leo and Julia Forchheimer Chair in Microbiology & Immunology, and a co-author of the study.
Some nanoparticles could still be found in bone marrow 24 hours after their injection, which shouldn’t pose a problem. “Since the nanoparticles are rapidly removed by phagocytic cells, they’re unlikely to damage the bone marrow,” said Dr. Dadachova. “We didn’t detect any side effects associated with administering the particles.”
“These results are encouraging for other potential applications of melanin, including radioprotection of other radiation-sensitive tissues, such as the gastrointestinal tract,” noted Andrew Schweitzer, M.D., formerly a Howard Hughes Medical Institute fellow at Einstein and lead author of the study.
Clinical trials testing whether melanized nanoparticles might protect cancer patients undergoing radiation therapy could begin in two to three years, Dr. Dadachova predicted. She also noted that melanized nanoparticles might also have other applications, such as protecting workers charged with cleaning up nuclear accidents, protecting astronauts against radiation exposure in space, or even protecting people following a nuclear attack.
- Andrew D. Schweitzer, Ekaterina Revskaya, Peter Chu, Valeria Pazo, Matthew Friedman, Joshua D. Nosanchuk, Sean Cahill, Susana Frases, Arturo Casadevall, Ekaterina Dadachova. Melanin-Covered Nanoparticles for Protection of Bone Marrow During Radiation Therapy of Cancer. International Journal of Radiation OncologyBiologyPhysics, 2010; DOI: 10.1016/j.ijrobp.2010.02.020
3D illustration of the knee. Damaged cartilage can lead to joint pain and loss of physical function and eventually to osteoarthritis. (Credit: iStockphoto/Sebastian Kaulitzki)
Northwestern University researchers are the first to design a bioactive nanomaterial that promotes the growth of new cartilage in vivo and without the use of expensive growth factors. Minimally invasive, the therapy activates the bone marrow stem cells and produces natural cartilage. No conventional therapy can do this.
The results will be published online the week of Feb. 1 by the Proceedings of the National Academy of Sciences (PNAS).
“Unlike bone, cartilage does not grow back, and therefore clinical strategies to regenerate this tissue are of great interest,” said Samuel I. Stupp, senior author, Board of Trustees Professor of Chemistry, Materials Science and Engineering, and Medicine, and director of the Institute for BioNanotechnology in Medicine. Countless people — amateur athletes, professional athletes and people whose joints have just worn out — learn this all too well when they bring their bad knees, shoulders and elbows to an orthopaedic surgeon.
Damaged cartilage can lead to joint pain and loss of physical function and eventually to osteoarthritis, a disorder with an estimated economic impact approaching $65 billion in the United States. With an aging and increasingly active population, this is expected to grow.
“Cartilage does not regenerate in adults. Once you are fully grown you have all the cartilage you’ll ever have,” said first author Ramille N. Shah, assistant professor of materials science and engineering at the McCormick School of Engineering and Applied Science and assistant professor of orthopaedic surgery at the Feinberg School of Medicine. Shah is also a resident faculty member at the Institute for BioNanotechnology in Medicine.
Type II collagen is the major protein in articular cartilage, the smooth, white connective tissue that covers the ends of bones where they come together to form joints.
“Our material of nanoscopic fibers stimulates stem cells present in bone marrow to produce cartilage containing type II collagen and repair the damaged joint,” Shah said. “A procedure called microfracture is the most common technique currently used by doctors, but it tends to produce a cartilage having predominantly type I collagen which is more like scar tissue.”
The Northwestern gel is injected as a liquid to the area of the damaged joint, where it then self-assembles and forms a solid. This extracellular matrix, which mimics what cells usually see, binds by molecular design one of the most important growth factors for the repair and regeneration of cartilage. By keeping the growth factor concentrated and localized, the cartilage cells have the opportunity to regenerate.
Together with Nirav A. Shah, a sports medicine orthopaedic surgeon and former orthopaedic resident at Northwestern, the researchers implanted their nanofiber gel in an animal model with cartilage defects.
The animals were treated with microfracture, where tiny holes are made in the bone beneath the damaged cartilage to create a new blood supply to stimulate the growth of new cartilage. The researchers tested various combinations: microfracture alone; microfracture and the nanofiber gel with growth factor added; and microfracture and the nanofiber gel without growth factor added.
They found their technique produced much better results than the microfracture procedure alone and, more importantly, found that addition of the expensive growth factor was not required to get the best results. Instead, because of the molecular design of the gel material, growth factor already present in the body is enough to regenerate cartilage.
The matrix only needed to be present for a month to produce cartilage growth. The matrix, based on self-assembling molecules known as peptide amphiphiles, biodegrades into nutrients and is replaced by natural cartilage.
The National Institutes of Health and the company Nanotope supported the research.
Adapted from materials provided by Northwestern University.
- Samuel Stupp, Ramille Shah, Nirav Shah, Marc M. Del Rosario Lim, Caleb Hsieh and Gordon Nuber. Supramolecular Design of Self-assembling Nanofibers for Cartilage Regeneration. Proceedings of the National Academy of Sciences, Feb 1, 2010
Rapidly expanding nanobubbles blasted through arterial plaque in a 2009 study. Gold nanoparticles were sprayed on the plaque (from left) and illuminated with a laser from above. (Credit: Image courtesy of Rice University)
Using lasers and nanoparticles, scientists at Rice University have discovered a new technique for singling out individual diseased cells and destroying them with tiny explosions. The scientists used lasers to make “nanobubbles” by zapping gold nanoparticles inside cells. In tests on cancer cells, they found they could tune the lasers to create either small, bright bubbles that were visible but harmless or large bubbles that burst the cells.
“Single-cell targeting is one of the most touted advantages of nanomedicine, and our approach delivers on that promise with a localized effect inside an individual cell,” said Rice physicist Dmitri Lapotko, the lead researcher on the project. “The idea is to spot and treat unhealthy cells early, before a disease progresses to the point of making people extremely ill.”
Adapted from materials provided by Rice University.
By Emily Singer
Nanoparticles designed to mimic the clotting capability of blood platelets have been shown to quickly reduce bleeding in rodents with severed arteries. The synthetic particles, which stick to the body’s own platelets, stanch bleeding more effectively than a clotting drug currently used to stem uncontrolled blood loss. “We’re helping to form the clot,” says Erin Lavik, a bioengineer at Case Western University in Cleveland, who led the research.
If successful in further tests, researchers hope the nanoparticles could one day be injected soon after a traumatic injury by paramedics, or in the battlefield. Early safety tests are promising, but developing safe blood-clotting treatments has been a challenge. “There’s a balance between the two edges of the sword–bleeding too much and clotting too much,” says Mortimer Poncz, a physician at the University of Pennsylvania Medical School, in Philadelphia, who was not involved in the research. “You don’t want to stop bleeding in the leg but die of a heart attack or have stroke.”
Uncontrolled bleeding is a major cause of trauma-related death. Existing methods of stemming blood loss are largely limited to treating open wounds or for use in the operating room. None have proven effective in stanching internal bleeding prior to arrival in a hospital.
After a traumatic injury, the body launches its own clotting cascade by activating platelets. These disc-shaped blood cells transform into spiky, sticky cells that adhere to each other and to molecules at the injury site, forming a blood clot. Physicians can already enhance the clotting process with drugs or materials that incorporate molecules in the clotting cascade. One such drug is NovoSeven, a synthetic protein derived from a human gene. But this drug is enormously expensive, costing $10,000 to $30,000, and some trauma surgeons question its effectiveness.
Attempts to mimic platelets themselves have so far been unsuccessful. Scientists have engineered red blood cells and blood-specific proteins to bind to platelets, “but those particles can build up in capillary beds, increasing the potential for [dangerous blood clots],” says Lavik.
Lavik and collaborator James Bertram, a graduate student at Yale, have now developed a nanoparticle small enough to flow through capillaries unfettered. It also has a platelet’s specific stickiness. The particle is about a third of the size of a normal platelet.
Each particle has a polymer core that’s coated with polyethylene glycol (PEG)–a water-soluble molecule that keeps them from sticking to each other or to the blood vessels. The PEG molecules are also topped with a peptide sequence that binds to activated platelets. “People had previously shown that activated platelets bind to [this sequence], so we optimized the chemistry to expose the molecule, presenting them to activated platelets,” says Lavik, who was recognized by Technology Review as a TR35 Young Innovator in 2003.
Story Continues – http://www.technologyreview.com/biomedicine/24238/?a=f
Johns Hopkins biomedical engineers, working with colleagues in Korea, have produced a laboratory chip with nanoscopic grooves and ridges capable of growing cardiac tissue that more closely resembles natural heart muscle. Surprisingly, heart cells cultured in this way used a “nanosense” to collect instructions for growth and function solely from the physical patterns on the nanotextured chip and did not require any special chemical cues to steer the tissue development in distinct ways.
The scientists say this tool could be used to design new therapies or diagnostic tests for cardiac disease.
The device and experiments using it were described online in the Early Edition of Proceedings of the National Academy of Sciences. The work, a collaboration with Seoul National University, represents an important advance for researchers who grow cells in the lab to learn more about cardiac disorders and possible remedies.
“Heart muscle cells grown on the smooth surface of a Petri dish, would possess some, but never all, of the same physiological characteristics of an actual heart in a living organism,” said Andre Levchenko, a Johns Hopkins associate professor of biomedical engineering at the Whiting School of Engineering. “That’s because heart muscle cells — cardiomyocytes — take cues from the highly structured extracellular matrix or ECM, which is a scaffold made of fibers that supports all tissue growth in mammals. These cues from the ECM influence tissue structure and function, but when you grow cells on a smooth surface in the lab, the physical signals can be missing. To address this, we developed a chip whose surface and softness mimic the ECM. The result was lab-grown heart tissue that more closely resembles the real thing.”
Levchenko added that when he and his colleagues examined the natural heart tissue taken from a living animal, “we immediately noticed that the cell layer closest to the extracellular matrix grew in a highly elongated and linear fashion. The cells orient with the direction of the fibers in the matrix, which suggests that ECM fibers give structural or functional instructions to the myocardium, a general term for the heart muscle.” These instructions, Levchenko said, are delivered on the nanoscale — activity at the scale of one-billionth of a meter and a thousand times smaller than the width of a human hair.
Levchenko and his Korean colleagues, working with Deok-Ho Kim, a biomedical engineering doctoral student from Levchenko’s lab and the lead author of the PNAS article, developed a two-dimensional hydrogel surface simulating the rigidity, size and shape of the fibers found throughout a natural ECM network. This bio-friendly surface made of nontoxic polyethylene glycol displays an array of long ridges resembling the folded pattern of corrugated cardboard. The ridged hydrogel sits upon a glass slide about the size of a U.S. dollar coin. The team made a variety of chips with ridge widths spanning from 150 to 800 nanometers, groove widths ranging from 50 to 800 nanometers, and ridge heights varying from 200 to 500 nanometers. This allowed researchers to control the surface texture over more than five orders of magnitude of length.
“We were pleased to find that within just two days, the cells became longer and grew along the ridges on the surface of the slide,” said Kim. Furthermore, the researchers found improved coupling between adjacent cells, an arrangement that more closely resembled the architecture found in natural layers of heart muscle tissue. Cells grown on smooth, unpatterned hydrogels, however, remained smaller and less organized with poorer cell-to-cell coupling between layers. “It was very exciting to observe engineered heart cells behave on a tiny chip in two dimensions like they would in the native heart in three dimensions,” Kim said.
Collaborating with Leslie Tung, a professor of biomedical engineering at the Johns Hopkins School of Medicine, the researchers found that, after a few more days of growth, cells on the nanopatterned surface began to conduct electric waves and contract strongly in a specific direction, as intact heart muscle would. “Perhaps most surprisingly, these tissue functions and the structure of the engineered heart tissue could be controlled by simply altering the nanoscale properties of the scaffold. That shows us that heart cells have an acute ‘nanosense,’” Levchenko said.
“This nanoscale sensitivity was due to the ability of cells to deform in sticking to the crevices in the nanotextured surface and probably not because of the presence of any molecular cue,” Levchenko said. “These results show that the ECM serves as a powerful cue for cell growth, as well as a supporting structure, and that it can control heart cell function on the nanoscale separately in different parts of this vital organ. By mimicking this ECM property, we could start designing better engineered heart tissue.”
Looking ahead, Levchenko anticipates that engineering surfaces with similar nanoscale features in three dimensions, instead of just two, could provide an even more potent way to control the structure and function of cultured cardiac tissue.
In addition to Kim, Levchenko and Tung, other authors on this paper are postdoctoral fellow Elizabeth A. Lipke, doctoral student Raymond Cheong, and doctoral student Susan Edmonds Thompson, all from the Johns Hopkins School of Medicine Department of Biomedical Engineering; assistant director Michael Delannoy from the Johns Hopkins School of Medicine Microscope Facility Center; and Pilnam Kim and Kahp-Yang Suh from Seoul National University.
Both Tung and Levchenko are affiliated faculty members of Johns Hopkins Institute for NanoBioTechnology. Thompson is a member of INBT’s Integrative Graduate Education and Research Traineeship in nanobiotechnology. Funding for this research was provided by the National Institutes of Health and the American Heart Association.
Adapted from materials provided by Johns Hopkins University.
The novel particles could last longer in the blood.
By Lauren Gravitz
Since the 1950s, researchers have been trying to mimic the abilities of red blood cells. These flexible discs carry oxygen throughout the body, squeezing through the smallest capillaries to do so. But the physical characteristics of red blood cells, including their doubly concave shape, have made them difficult to copy with precision.
In research published Monday in the Proceedings of the National Academy of Sciences, a group specializing in drug delivery has found a way to create biodegradable, biocompatible particles with the size, shape, and flexibility of red blood cells. The group believes these artificial cells might be particularly effective not just for carrying oxygen but also as therapeutic and imaging agents.
“People have made over a thousand different polymers of different sizes for drug delivery. But if you look at them all together, they represent the synthetic world; the particles are nice and spherical,” says Samir Mitragotri, a chemical engineer at the University of California at Santa Barbara, who led the new work. “If you look at the biological world, nature uses all kinds of particles for delivering its own goods. Bacteria, cells, viruses are all designed to perform very specific delivery functions.”
To create the synthetic cells, Mitragotri, along with researchers at the University of Michigan, start with spherical particles made of a common polymer called poly(lactic-co-glycolic acid (PLGA), a compound known for its biocompatible and biodegradable properties. They expose the spheres to rubbing alcohol, which causes them to deflate and collapse into the dimpled shape of a red blood cell. The hard PLGA particle acts as a mold, around which the researchers can deposit layer after layer of proteins. They crosslink the proteins to get them to hold to the PLGA, then dissolve the rigid inner structure. The result is a soft, flexible protein shell the size and shape of a red blood cell. The researchers can also vary the protein coatings depending, for example adding hemoglobin, which could carry oxygen.
So far, Mitragotri has shown that the particles are flexible enough to compress and flow through capillary-sized tubes, and can be infused with drugs at just about every stage of the process. His group has also encapsulated iron-oxide nanoparticles in the synthetic cells, creating a potential contrast agent for MRIs. “One can imagine putting these particles into the blood and using them to visualize blood flow,” Mitragotri says.
“Overall, I’ve never seen anything like it. Both the concept and the fabrication methods they developed are very interesting,” says Ali Khademhosseini, a biomedical engineer at the Harvard-MIT Division of Health Sciences and Technology. “There’s an increasing appreciation about how the shape of particles is important for a variety of different things, like the hydrodynamics of particles inside fluid, or how different biological entities interact with them.”
Such flexible, potentially long-lasting particles hold great potential for drug delivery. But Mitragotri has not yet looked to see whether the synthetic cells can stand up to the most difficult test: remaining in circulation. Proving that the particles remain in the bloodstream and do not prompt an immune attack is a critical step that will require testing in animals.
“Back in 1966, I made similar [particles] that can change in shape and in size,” says artificial blood researcher Thomas Chang from McGill University in Quebec, Canada. Those cells, he says, could also squeeze through capillary tubes and were about the same size as red blood cells. The problem was that even synthetic cells one-eighth of the size of regular blood cells were purged from the blood within 30 seconds. (By the 1970s, researchers found that artificial blood particles work best at 200 nanometers or less–30 times smaller than red blood cells.) “The main thing is to show that they remain in circulation,” Chang says.
Even the most advanced synthetic particles get cleared out of the blood incredibly rapidly. “The longest circulating nanoparticle ever lasted about 24 hours, so there’s a need for developing an approach to something that can circulate in the bloodstream for a long period of time,” says Jeffrey Karp, a Harvard-MIT professor of health science and technology. But the new research could be a big step in that direction, he says, if the body keeps the synthetic cells circulating for as long as two to three months, like real red blood cells. Karp says that the production methods that Mitragotri and his colleagues used could be scaled up without much difficulty.
Assuming that the cells stand up to the circulatory test of time, “I would think that anybody who’s trying to use a nanoparticle-like system for delivery or for imaging would have good reason to go with these particles,” says Daniel Pack, a drug-delivery researcher at the University of Illinois at Urbana-Champaign.
Mitragotri says that the next step will be animal testing. He also wants to look into other ways to mimic nature’s delivery methods. “We started with red blood cells, but there are many others I can think of that might be of interest, like viruses and bacteria,” he says. “You have your synthetic world on one side, and your biological world on the other, and we want to bridge the gap as best we can between these two extremes.”
Microscopic magnetic particles have been used to bring stem cells to sites of cardiovascular injury in a new method designed to increase the capacity of cells to repair damaged tissue, UCL scientists have announced.
The cross disciplinary research, published in The Journal of the American College of Cardiology: Cardiovascular Interventions, demonstrates a technique where endothelial progenitor cells – a type of stem cell shown to be important in vascular healing processes – have been magnetically tagged with a tiny iron-containing clinical agent, then successfully targeted to a site of arterial injury using a magnet positioned outside the body.
Following magnetic targeting, there was a five-fold increase in cell localisation at a site of vascular injury in rats. The team also demonstrated a six-fold increase in cell capture in an in vitro flow system (where microscopic particles are suspended in a stream of fluid and examined to see how they behave).
Although magnetic fields have been used to guide cellular therapies, this is the first time cells have been targeted using a method directly applicable to clinical practice. The technique uses an FDA (U.S. Food and Drug Administration) approved agent that is already used to monitor cells in humans using MRI (magnetic resonance imaging).
Dr Mark Lythgoe, UCL Centre for Advanced Biomedical Imaging, the senior author on the study, said: “Because the material we used in this method is already FDA approved we could see this technology being applied in human clinical trials within 3-5 years. It’s feasible that heart attacks and other vascular injuries could eventually be treated using regular injections of magnetised stem cells. The technology could be adapted to localise cells in other organs and provide a useful tool for the systemic injection of all manner of cell therapies. And it’s not just limited to cells – by focusing tagged antibodies or viruses using this method, cancerous tumours could be much more specifically targeted”
Panagiotis Kyrtatos, also from the UCL Centre for Advanced Biomedical Imaging and lead researcher of the study, added: “This research tackles one of the most critical challenges in the biomedical sciences today: ensuring the effective delivery and retention of cellular therapies to specific targets within the body.
“Cell therapies could greatly benefit from nano-magnetic techniques which concentrate cells where they are needed most. The nano-magnets not only assist with the targeting, but with the aid of MRI also allow us to observe how the cells behave once they’re injected.”
This work was supported by public and charitable funding from the UCL Institute of Child Health (Child Health Research Appeal Trust), The British Heart Foundation, the Alexander S. Onassis Public Benefit Foundation and the Biotechnology and Biological Sciences Research Council (BBSRC).
- Panagiotis G. Kyrtatos, Pauliina Lehtolainen, Manfred Junemann-Ramirez, Ana Garcia-Prieto, Anthony N. Price, John F. Martin, David G. Gadian, Quentin A. Pankhurst, Mark F. Lythgoe. Magnetic Tagging Increases Delivery of Circulating Progenitors in Vascular Injury. JACC Cardiovascular Interventions, 2009; 2 (8): 794 DOI: 10.1016/j.jcin.2009.05.014
Adapted from materials provided by University College London
Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC) have uncovered what happens to biomimetic nanoparticles when they enter human cells. They found that the important proteins that make up the outer layer of these nanoparticles are degraded by an enzyme called cathepsin L. Scientists now have to take this phenomenon into account and overcome this process to ensure the exciting field of nanomedicine can progress.
The research is published September 22, 2009 in ACS Nano.
Dr Raphaël Lévy, a BBSRC David Phillips Fellow at the University of Liverpool and lead researcher on the project said: “We’ve known for some time that nanoparticles are taken into cells and there have been experiments done to establish their final destinations, but we didn’t know until now what state they are in by the time they get there.”
In most biological applications, nanoparticles are coated with a layer of molecules, often proteins, which determine the use of nanoparticles when they enter cells. The researchers have confirmed, in a wide range of cells, that nanoparticles are taken into a region called the endosome, where this essential coating is degraded by cathepsin L.
Dr Violaine Sée, also a BBSRC David Phillips Fellow at the University of Liverpool, and joint corresponding author, added: “One of the promising applications of nanoparticles in medicine is to use them as a method to deliver therapeutic protein molecules inside cells. For these biological therapies to be effective the proteins have to be maintained with high integrity and unfortunately we have seen this compromised by the degrading action of cathepsin L.”
The design of any intracellular nanodevice must now take into account the possibility of cathepsin L degradation and either bypass the endosome area all together or have some built-in inhibition of the enzyme.