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Topic Name: MIT develops thin-film 'micro pharmacy' may be used to deliver drugs for cancer, epilepsy, diabetes and other diseases

Category: Nanobiotechnology

Research persons: Paula Hammond

Location: Massachusetts Institute of Technology, United States

Details

A new thin-film coating developed at Massachusetts Institute of Technology can deliver controlled drug doses to specific targets in the body following implantation, essentially serving as a “micro pharmacy.”

The film could eventually be used to deliver drugs for cancer, epilepsy, diabetes and other diseases. It is among the first drug-delivery coatings that can be remotely activated by applying a small electric field.

“You can mete out what is needed, exactly when it's needed, in a systematic fashion,” said Paula Hammond, the Bayer Professor of Chemical Engineering and senior author of a paper on the work appearing in the Feb. 11 issue of the Proceedings of the National Academy of Sciences.

The film, which is typically about 150 nanometers (billionths of a meter) thick, can be implanted in specific parts of the body.

The films are made from alternating layers of two materials: a negatively charged pigment and a positively charged drug molecule, or a neutral drug wrapped in a positively charged molecule.

The pigment, called Prussian Blue, sandwiches the drug molecules and holds them in place. (Part of the reason the researchers chose to work with Prussian Blue is that the FDA has already found it safe for use in humans.)

When an electrical potential is applied to the film, the Prussian Blue loses its negative charge, which causes the film to disintegrate, releasing the drugs. The amount of drug delivered and the timing of the dose can be precisely controlled by turning the voltage on and off.

The electrical signal can be remotely administered (for example, by a physician) using radio signals or other techniques that have already been developed for other biomedical devices.

The films can carry discrete packets of drugs that can be released separately, which could be especially beneficial for chemotherapy. The research team is now working on loading the films with different cancer drugs.

Eventually, devices could be designed that can automatically deliver drugs after sensing that they're needed. For example, they could release chemotherapy agents if a tumor starts to regrow, or deliver insulin if a diabetic patient has high blood sugar.

“You could eventually have a signaling system with biosensors coupled with the drug delivery component,” said Daniel Schmidt, a graduate student in chemical engineering and one of the lead authors of the paper.

Other lead authors are recent MIT PhD recipients Kris Wood, now a postdoctoral associate at the Broad Institute of MIT and Harvard, and Nicole Zacharia, now a postdoctoral associate at the University of Toronto.

Because the films are built layer by layer, it is easy to control their composition. They can be coated onto a surface of any size or shape, which offers more design flexibility than other drug-delivery devices that have to be microfabricated.

“The drawback to microfabricated devices is that it's hard to coat the drug over a large surface area or over an area that is not planar,” said Wood.

Another advantage to the films is that they are easy to mass-produce using a variety of techniques, said Hammond. These thin-film systems can be directly applied or patterned onto 3D surfaces such as medical implants.

Note for Prussian Blue
Prussian blue is a dark blue pigment used in paints and formerly in blueprints. Prussian blue was discovered by accident by painter Heinrich Diesbach and Johann Konrad Dippel in Berlin in 1704-5, which is why it is also known as Berlin blue. (Diesbach was attempting to create a paint with a red hue.) It has several different chemical names, these being iron(III) ferrocyanide, ferric ferrocyanide, iron(III) hexacyanoferrate(II), and ferric hexacyanoferrate. Commonly and conveniently it is simply called "PB."
Prussian Blue was the first modern dye to be synthesized and was the result of an accident. The chemist and paint maker Heinrich Diesbach and alchemist Johann Konrad Dippel had intended to prepare a red lake pigment. Due to a contaminated source of potash, they obtained the blue instead.
The pigment is significant as the first stable and lightfast blue to be widely used. European painters previously used a number of pigments such as indigo and smalt which tended to fade, and the extremely expensive ultramarine. Japanese painters and woodblock print artists likewise did not have access to a long-lasting blue pigment until they began to import Prussian blue from Europe, though cobalt blue had been used extensively by Chinese artists in blue and white porcelains for centuries prior.
Despite being one of the oldest known synthetic compounds, the composition of PB was uncertain until recently. The precise identification of PB was complicated by three factors: (i) PB is extremely insoluble but also tends to form colloids, (ii) traditional syntheses tend to afford impure compositions, and (iii) even pure PB is structurally complex, defying routine crystallographic analysis.

Note for Electric Field
In physics, the space surrounding an electric charge or in the presence of a time-varying magnetic field has a property called an electric field (that can also be equated to electric flux density). This electric field exerts a force on other electrically charged objects. The concept of electric field was introduced by Michael Faraday.
The electric field is a vector field with SI units of newtons per coulomb (N C−1) or, equivalently, volts per meter (V m−1). The strength of the field at a given point is defined as the force that would be exerted on a positive test charge of +1 coulomb placed at that point; the direction of the field is given by the direction of that force. Electric fields contain electrical energy with energy density proportional to the square of the field intensity. The electric field is to charge as gravitational acceleration is to mass and force density is to volume.
A moving charge has not just an electric field but also a magnetic field, and in general the electric and magnetic fields are not completely separate phenomena; what one observer perceives as an electric field, another observer in a different frame of reference perceives as a mixture of electric and magnetic fields. For this reason, one speaks of "electromagnetism" or "electromagnetic fields." In quantum mechanics, disturbances in the electromagnetic fields are called photons, and the energy of photons is quantized.

Note for Chemotherapy
Chemotherapy, in its most general sense, refers to treatment of disease by chemicals that kill cells, specifically those of micro-organisms or cancer. In popular usage, it usually refers to antineoplastic drugs used to treat cancer or the combination of these drugs into a standardized treatment regimen.
In its non-oncological use, the term may also refer to antibiotics (antibacterial chemotherapy). In that sense, the first modern chemotherapeutic agent was Paul Ehrlich's arsphenamine, an arsenic compound discovered in 1909 and used to treat syphilis. This was later followed by sulfonamides discovered by Domagk and penicillin discovered by Alexander Fleming.
Other uses of cytostatic chemotherapy agents (including the ones mentioned below) are the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis and the suppression of transplant rejections (see immunosuppression and DMARDs).
The first drug used for cancer chemotherapy, however, dates back to the early 20th century, though it was not originally intended for that purpose. Mustard gas was used as a chemical warfare agent during World War I and was studied further during World War II. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in the 1940s, several patients with advanced lymphomas (cancers of certain white blood cells) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. That experience led researchers to look for other substances that might have similar effects against cancer. As a result, many other drugs have been developed to treat cancer, and drug development since then has exploded into a multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply.

Note for Microfabrication
Microfabrication or micromanufacturing are the terms to describe processes of fabrication of miniature structures, of sizes measured in microns and smaller. Historically the earliest micromanufacturing was used for semiconductor devices in integrated circuit fabrication and these processes have been covered by the term "semiconductor device fabrication," "semiconductor manufacturing," etc. Practical advances in microelectromechanical systems (MEMS) and other nanotechnology, where the technologies from IC fabrication are being re-used, adapted or extended have led to the extension of the scope and techniques of microfabrication.
Miniaturization of various devices presents challenges in many areas of science and engineering: physics, chemistry, material science, computer science, ultra-precision engineering, fabrication processes, and equipment design. It is also giving rise to various kinds of interdisciplinary research.
The major concepts and principles of micromanufacturing are laser technology, microlithography, micromechatronics, micromachining and microfinishing (nanofinishing).
Microfabricated devices include:
Fabrication of integrated circuits (“microchips”) (see semiconductor manufacturing) 
Microelectromechanical systems (MEMS), MOEMS, microfluidic devices (ink jet print heads) 
Laser diodes 
Flat Panel Displays (see AMLCD and Thin Film Transistor) 
Sensors (micro-sensors) (biosensors, nanosensors,) 
Nanotubes, fuel cells

Stefani Wrightman, a 2006 MIT graduate, and Brian Andaya, a recent graduate of the University of Rochester and summer intern at the MIT Materials Processing Center, are also authors on the paper. The research was funded by the National Science Foundation, the Office of Naval Research and MIT's Institute for Soldier Nanotechnologies.

In figure 1, A sample of Prussian blue

In figure 2, From left, Broad Institute postdoctoral associate Kris Wood, Bayer Professor of Chemical Engineering Paula Hammond and chemical engineering graduate student Dan Schmidt show the thin film they have developed. The film releases drugs and other chemical agents upon application of a small electrical field.