New Nanoburrs Target Cardiovascular Disease, Could Potentially Eliminate Need for Arterial Stents in Some Patients Says MIT & Harvard Team

MIT and Harvard Nanoburr

Image Credit: MIT

Researchers at Massachusetts Institute of Technology (MIT) (Cambridge, MA) and Harvard Medical School have built targeted nanoparticles that can cling to artery walls and slowly release medicine, an advance that potentially provides an alternative to drug-releasing stents in some patients with cardiovascular disease.

The particles, dubbed "nanoburrs" because they are coated with tiny protein fragments that allow them to stick to target proteins, can be designed to release their drug payload over several days. They are one of the first such particles that can precisely home in on damaged vascular tissue, says Omid Farokhzad, associate professor at Harvard Medical School and an author of a paper describing the nanoparticles in the Jan. 18 issue of the Proceedings of the National Academy of Sciences.

Farokhzad and MIT Institute Professor Robert Langer, also an author of the paper, have previously developed nanoparticles that seek out and destroy tumors.

The nanoburrs are targeted to a specific structure, known as the basement membrane, which lines the arterial walls and is only exposed when those walls are damaged. Therefore, the nanoburrs could be used to deliver drugs to treat atherosclerosis and other inflammatory cardiovascular diseases. In the current study, the team used paclitaxel, a drug that inhibits cell division and helps prevent the growth of scar tissue that can clog arteries.

"This is a very exciting example of nanotechnology and cell targeting in action that I hope will have broad ramifications," says Langer.

The researchers hope the particles could become a complementary approach that can be used with vascular stents, which are the standard of care for most cases of clogged and damaged arteries, or in lieu of stents in areas not well suited to them, such as near a fork in the artery.

The particles, which are spheres 60 nanometers in diameter, consist of three layers: an inner core containing a complex of the drug and a polymer chain called PLA; a middle layer of soybean lecithin, a fatty material; and an outer coating of a polymer called PEG, which protects the particle as it travels through the bloodstream.

The drug can only be released when it detaches from the PLA polymer chain, which occurs gradually by a reaction called ester hydrolysis. The longer the polymer chain, the longer this process takes, so the researchers can control the timing of the drug's release by altering the chain length. So far, they have achieved drug release over 12 days, in tests in cultured cells.

In tests in rats, the researchers showed that the nanoburrs can be injected intravenously into the tail and still reach their intended target — damaged walls of the left carotid artery. The burrs bound to the damaged walls at twice the rate of nontargeted nanoparticles.

Because the particles can deliver drugs over a longer period of time, and can be injected intravenously, patients would not have to endure repeated and surgically invasive injections directly into the area that requires treatment, says Juliana Chan, a graduate student in Langer's lab and lead author of the paper.

How they did it: The researchers screened a library of short peptide sequences to find one that binds most effectively to molecules on the surface of the basement membrane. They used the most effective one, a seven-amino-acid sequence dubbed C11, to coat the outer layer of their nanoparticles.

Next steps: The team is testing the nanoburrs in rats over a two-week period to determine the most effective dose for treating damaged vascular tissue. The particles may also prove useful in delivering drugs to tumors.

"This technology could have broad applications across other important diseases, including cancer and inflammatory diseases where vascular permeability or vascular damage is commonly observed," says Farokhzad.

Source: "Spatiotemporal controlled delivery of nanoparticles to injured vasculature," Juliana Chan, Liangfang Zhang, Rong Tong, Debuyati Ghosh, Weiwei Gao, Grace Liao, Kai Yuet, David Gray, June-Wha Rhee, Jianjun Cheng, Gershon Golomb, Peter Libby, Robert Langer, Omid Farokhzad. Proceedings of the National Academy of Sciences, week of Jan. 18, 2010.

Contact: Jen Hirsch

jfhirsch@mit.edu

617-253-1682

Tera-Barrier Films Close to Commercializing Nanoparticle Protective Film for Plastic Electronics

Flexible electronics promise to form the basis for the next generation of electronic devices, and have already been applied in a range of prototypes and limited applications. This technology has made electronic paper, ultrathin flexible displays and low-cost solar cells a reality, but the resilience of these devices to practical environments, particularly moisture, has been an obstacle to commercial mass-production. Now, with a major investment by US-based Applied Materials, Tera-Barrier Films—a recent spin-off from A*STAR—is even closer to commercializing a revolutionary protective film for plastic electronics that meets all of the moisture-barrier requirements for future applications.

 Fig. 1: A*STAR’s ultrahigh barrier film technology will significantly increase the life span of flexible electronic devices such as inorganic electroluminescent displays (pictured), expanding the practical applications of plastic electronics

.Credit: A*Star

Existing commercial protective films for plastic electronics provide a barrier to oxygen and water molecules, but due to unavoidable defects in the thin, flexible oxide films, these barriers still allow the diffusion of about 1/1,000th of a gram of water vapor per square meter each day at 90% relative humidity and 25 °C. Although low, this level of water penetration is 1,000 times higher than the level required for practical applications, and is sufficient to significantly shorten the lifetime of the organic materials at the heart of these devices. To minimize molecular diffusion, the protective films are constructed by stacking alternating layers of ultrathin inorganic (oxide) and organic films. This approach lengthens the diffusion path for invading molecules, but does not block the path completely.

Researchers at A*STAR’s Institute of Materials Research and Engineering (IMRE), led by Senthil Ramadas who is now chief technology officer of Tera-Barrier Films, took a different and innovative approach. Instead of stacking multiple layers to increase the film’s resistance to water molecule penetration, the researchers ‘plugged’ the defects in the barrier oxide layer with nanoparticles. Not only did they succeed in increasing the barrier property by more than 1,000 times, surpassing application requirements, they also reduced the number of layers required to just two—a considerable improvement in manufacturing and material efficiency. The new nano-engineered film has a barrier property of better than 10^–6 g/m²/day of water vapor at 90% relative humidity and 39 °C. The barrier stack consists of oxide layers and nanoparticulate layers that both seal the defects in the film and react with moisture and oxygen.

Fig. 2: Conventional protective films (top) slow the diffusion of oxygen and water molecules by lengthening the diffusion path. In the IMRE’s new ultrahigh barrier film, defects in the film are plugged with nanoparticles to more effectively block molecular diffusion.

 Credit: A*Star

Such are the prospects for this technology that Applied Materials, a global leader in nano-manufacturing technology, has made a major strategic investment in Tera-Barrier Films through its venture capital arm Applied Ventures. “We are pleased that our investment in Tera-Barrier will be used to support the commercialization of this breakthrough technology to enable a new generation of advanced devices,” said J. Christopher Moran, vice president of Applied Ventures, in a media release on August 25.

The performance of the ultrahigh barrier film technology has been validated by solar cell and flexible display manufacturers. “Tera-Barrier Films is in the process of securing product qualification and sample orders and has strong subcontract partnerships in place for scalable production of high performance barrier films,” says Mark Auch, who has been working on commercialization of this technology and who now acts as chief executive officer of Tera-Barrier Films. “The company maintains a growing portfolio of 29 patents in transparent gas barrier technology, encapsulation and gas permeation measurement systems, and works closely with flexible solar cell, printed electronics and display manufacturers to develop total barrier solutions for these applications,” says Ramadas, “the technology, know-how and patent portfolio generated from IMRE/A*STAR will provide Tera-Barrier Films with a competitive edge and enable us to offer a total barrier solution to customers.

Tera-Barrier Films Pte. Ltd was jointly founded by Senthil Ramadas and Mark Auch with the support of Exploit Technologies, the strategic marketing and commercialization arm of A*STAR. Tera-Barrier Films is a spin-off company from A*STAR’s Institute of Materials Research and Engineering.

Applied Ventures LLC, a subsidiary of Applied Materials Inc., invests in early stage technology companies with high growth potential that provide a window on technologies that advance or complement Applied Materials’ core expertise in nanomanufacturing technology.

A*STAR Affiliated Authors

1. Mark Auch, Institute of Materials Research and Engineering (IMRE)
2. Senthil Ramadas, Institute of Materials Research and Engineering (IMRE)

Microchannel-Magneto-Immunoassay Uses Luminescent Shells of Europium-Doped Gadolinium Nanoparticles

University of California, Davis Department of Mechanical and Aeronautical Engineering Professor Dosi Dosev, Vishal Talwar, Mikaela Nichkova and Ian Kennedy developed a microchannel-magneto-immunoassay.   A single microchannel is combined with external electromagnets for performing a fast immunoassay within a very small volume. Magnetic/luminescent Europium nanoparticles serve as carriers for the antibodies and as internal luminescent standard.

According to U.S. Patent Application 20090227044, the immunoreaction is accelerated by applying alternating magnetic field by means of the external electromagnets, thus inducing oscillation of the particles and achieving better diffusion during the incubation steps. Using the electromagnets the particles are held into the channel for washing and luminescence detection steps. The luminescence of the particles serves as an internal calibration for the assay and helps to avoid experimental error from particle loss.

An immunoassay is a biochemical test that measures the concentration of a substance in a biological liquid, typically serum or urine, using the reaction of an antibody or antibodies to its antigen. The assay takes advantage of the specific binding of an antibody to its antigen. Monoclonal antibodies are often used as they only usually bind to one site of a particular molecule, and therefore provide a more specific and accurate test, which is less easily confused by the presence of other molecules. The antibodies picked must have a high affinity for the antigen (if there is antigen available, a very high proportion of it must bind to the antibody).

Europium containing nanoparticles have been used previously as labels for time-resolved bioassays. The research team found that natural or untreated Eu2O3 particles are insoluble in water but are easily dissolved by acid during activation and conjugation, losing their desirable optical properties. Coating the particles by silanization protected the particle from being dissolved by acid, and provided useful functional groups for biological conjugation. Passive absorption of proteins is an alternative for surface functionalization that they also recently explored.

The derivatized nanoparticle compositions retain the optical properties of the native particles and enable the efficient and low-cost use of these nanoparticles to label and optionally separate or purify biological and other materials.  The luminescence of the particles serves as an internal calibration for the assay and helps to avoid experimental error from particle loss

The assay device consists of using a single microchannel combined with external electromagnets for performing a fast immunoassay within a very small volume. Magnetic/luminescent nanoparticles provide an internal luminescent standard. A binding reaction is accelerated by applying an alternating magnetic field by alternately energizing electromagnets external to a microchannel, thus inducing oscillation and/or agitation of the particles and achieving better diffusion during incubation. Using the electromagnets, the particles are held in the channel for washing and luminescence detection steps. The luminescence of the particles serves as an internal calibration for the assay and helps to avoid experimental error from particle loss.

Also described is the synthesis and the properties of magnetic/luminescent core/shell particles, including magnetic cores of iron oxide doped with cobalt and neodymium (NdCoFe2O3) that are encapsulated in luminescent shells of europium-doped gadolinium oxide (EuGd2O3). Cobalt and neodymium were shown to improve the magnetic properties of iron oxides. In addition, doping of Eu ions into the Gd2O3 matrix gives unique luminescent properties. The manufacturing methods employ flame spray pyrolysis as a cost-effective, high throughput and versatile synthesis method, allowing a variety of doped materials to be obtained.

Nanoparticles Control Underground Water Flow during Oil Recovery Operations

 Baker Hughes Inc researchers Tianping Huang, James B Crews and Michael H. Johnson created methods for using non-aqueous fluids containing certain nanoparticles to selectively inhibit or shut-off the flow of water in underground formations but not inhibit the flow of oil or gas during hydrocarbon recovery operations.  The non-aqueous carrier fluids containing nano-sized particles in high concentration are effective for zone isolation and flow control in water shutoff applications for subterranean formations.

The nanoparticles interact with water and solidify it to inhibit its flow, but do not have the same effect on hydrocarbons and thus selectively assist the production of hydrocarbons while suppressing water.  Suitable nanoparticles include alkaline earth metal oxides, alkaline earth metal hydroxides, alkali metal oxides, alkali metal hydroxides, transition metal oxides, transition metal hydroxides, post-transition metal oxides, post-transition metal hydroxides, piezoelectric crystals, and/or pyroelectric crystals which are detailed in U.S. Patent Application 2009028670. 

Certain subterranean oil producing wells are formed or completed in formations which contain both oil-producing zones and water-producing zones. Unwanted water production is a major problem in maximizing the hydrocarbon production potential of these wells. Tremendous costs may be incurred from separating and disposing of large amounts of produced water, inhibiting the corrosion of pipe used in drilling and replacing tubular equipment downhole, and surface equipment maintenance. Shutting off unwanted water production is a necessary condition to maintaining a productive field. While there is a wide array of treatments available to solve these problems, they all suffer from a number of difficulties, including, but not necessarily limited to, surface mixing and handling problems, etc.

Traditional water shut-off technology with chemicals uses sodium silicate solutions and crosslinked polymers. The silicate solution is typically not compatible with formation waters, since sodium silicate reacts with calcium chloride instantly to generate gel .  Thus there remains a need to find a chemical system that will simplify the pumping schedule and permit deep penetration into the formation to shut off the water channels in an effective manner and keep oil flow channels open.