Nanomedicine strives to deliver targeted medical therapies at the molecular scale while dealing with the challenges of biocompatibility and toxicity of nanomaterials.Nanomedicine is an emerging field whose definition is still evolving," says Richard Fisher, project team leader of the Nanomedicine Roadmap Initiative at the National Institutes of Health (NIH), Bethesda, Md. Currently, the definition of this nascent field refers to finding cures for diseases through targeted medical intervention at the molecular level.
To encourage and accelerate research in nanomedicine, the NIH has developed a novel program, the NIH Nanomedicine Roadmap Initiative, to fund several Nanomedicine Development Centers. These centers will focus on learning about the physical properties of molecules and supermolecular complexes within cells at an unprecedented level of detail. "Once this information is gathered, scientists can begin to engineer new structures," says Fisher.
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"Like any new drug, nanomedicine technology will have to undergo the rigorous testing necessary for human applications," says Paras Prasad, executive director at Buffalo Univ.'s Institute for Lasers, Photonics, and Biophotonics. |
The first step in the Nanomedicine Roadmap Initiative involved the release of a RFA (Request for Application) in May 2004, soliciting applications for financial support for nanomedicine centers. Three or four such facilities are expected to be established with the $6 million allocated for FY2005. One or more of these centers will focus on the biocompatibility and toxicity of nanomaterials, two significant challenges in the application of nanotechnology to medicine. However, Fisher believes that "nanomedicine is adopting a forward-thinking view of these potential problems by addressing the issues upfront."
Artificial cellular parts
The designation of biocompatibility as a major challenge to nanotherapy is shared by James Baker, director of the Center for Biologic Nanotechnology at the Univ. of Michigan (U-M) Medical School, Ann Arbor. "Nanotechnology has real potential to impact medicine, but people need to be very circumspect and understand that a lot of nanomaterials will create problems in biological systems. Biocompatibility is the ultimate issue, and researchers need to evaluate it early on, not just in tissue culture and cells, but in living organisms," says Baker.
The U-M team is leading a research effort into nanotherapeutics and nanoimaging agents that will eventually lead to artificial parts for cells. "We're trying to make artificial materials that can actually go into cells and replace defective materials to cure diseases. We want to treat a disease like cancer to make cancer cells turn off and die or treat a genetic disorder to make the cells function normally," says Baker.
The nanoparticle therapeutics that Baker's group is studying are not only targeted drugs that deliver to cancer cells, but also contain imaging agents. Thus, the delivery of the drug to the tumor cells can be monitored along with the tumor's response.
Still in animal studies, researchers at the center hope to test this technology in humans in two years.
Targeted micro/nano bursts
As important as biocompatibility is the problem of nanomaterials' toxicity, which is being addressed by a collaboration between Ill.-based researchers at Argonne National Laboratory (ANL) and the Univ. of Chicago. This alliance has led to the development of a technique that uses the injection of magnetic nanospheres for drug delivery or detoxification. Capable of being metabolized in the body without any side effects, these non-toxic, biodegradable, 200- to 1,000-nm spherical polymers can encapsulate a medication or have their surface coated with receptors that bind to toxins. Since they contain tiny nanocrystalline iron particles, magnetic guidance can be used by researchers to bring the nanospheres from point A to B. As a result, "you can accumulate and trap the nanospheres in the area of interest, then use a signal like radio frequency to open them up and release the medication," says Axel Rosengart, associate professor of neurology and surgery at the Univ. of Chicago Hospitals.
Rosengart uses this micro/nano burst technology to perform in vitro stroke studies. He has been successful in encapsulating the appropriate concentration of tissue plasminogen activator (TPA), a drug that dissolves blood clots, within the nanospheres. In the next phase, he plans to investigate how the TPA release occurs, the nanospheres' effect on clot lysis, and the degree of efficiency of the encapsulation. Rosengart and his team are also concentrating on another major issue-monodispersity -by designing and fabricating nanospheres that have the same size and diameter.
When the nanospheres are used for detoxification, they circulate through the body, allowing toxins to bind to the receptors on their surface. After circulating for an hour, "an extracorporeal magnetic filter is tapped into a suitable artery or vein and the blood is bypassed through this filter," says Michael Kaminski, a scientist at ANL. This filter magnetically holds the nanospheres carrying the toxins, while the clean blood is returned into the body without exposure to the environment. "No large dialysis machines are needed and the system should be completely portable," says Kaminski. So far, filters capable of trapping more than 70% of the nanospheres in a single pass have been designed.
Kaminski estimates that this technology will be ready for FDA testing and public use by 2006 and envisions it having a broad impact. "It could greatly affect the treatment for autoimmune diseases, reduce complications from cardiac arrest, and remove biological/chemical/radiological toxins."
Multiple guidance with controlled release
Also working on the delivery and controlled release of a drug is Challa Kumar, group leader of the nanofabrication group at the Center for Advanced Microstructures and Devices at Louisiana State Univ. (LSU), Baton Rouge. Working with Carola Leuschner, assistant professor at the Pennington Biomedical Research Center, Baton Rouge, Kumar is developing a single-unit system that provides both site-specificity and controlled drug delivery to treat cancer and their metastases. Comprised of magnetic-core polymer-shell nanoparticles, magnetically modulated controlled delivery and release vehicles are embedded with lytic peptide conjugates and feature peptide hormone ligands on the surface.
These ligands have "the capability of triple guidance, provided by two ligand-receptor interactions through peptide hormone ligands with their corresponding receptors on cancer cells, and the third one by an external magnetic field," says Kumar. An oscillating magnetic field is used to control the release of the drug at the site of the tumors. This multiple guidance "is expected to increase site specificity and provide controlled release with no effect on gonads, preventing infertility in patients," says Kumar.
The LSU drug delivery vehicles are also versatile, with only minor structural modifications required to allow the administering of other medications and the treatment of various diseases. The ability to deliver compounds with poor stability is also an advantage since they would be protected within the polymeric shell.
Smart nanoclinic
Researchers at the Institute for Lasers, Photonics, and Biophotonics at the Univ. at Buffalo, N.Y., are also using an external magnetic field to activate nanoparticles-nanoclinics -for diagnostics and targeted drug delivery at the cellular level. Consisting of a thin silica bubble, the nanoclinic has the ability to target a specific cell type or tissue site because of the presence of carrier groups -which are often peptides, but could be a sugar, or folic acid- on its surface.
While activated by a magnetic field, these diagnostic and therapeutic agents can also be activated by light when the nanoparticles' ferromagnetic core is replaced with a photosensitizer for use in photodynamic therapy. "The nanoencapsulation process enables these sensitizers to become water soluble, so they are more biocompatible for therapeutic applications," says Paras Prasad, executive director of the institute.
Foundation work on the magnetic nanoclinic has been patented and licensed to Nanobiotix, Paris, France.
e-Mosquito
Drug delivery applications combined with blood sampling and analysis are the focus of a team of researchers at the Univ. of Calgary, Alberta, Canada. Inspired by a mosquito's extraction of blood, Martin Mintchev and Karan Kaler, professors in the Electrical and Computer Engineering Dept., and Giorgio Gattiker, doctoral student, are developing the ELECTRONIC MOSQUITO (e-Mosquito)-a semi-invasive, automated microsystem for blood work and delivery of medication.
The battery-operated e-Mosquito is composed of a MEMS-based microactuator and an embedded micro-
needle. The microneedle penetrates the skin as painlessly as a mosquito bite to remove a static blood sample for analysis. The sample is then housed in a compartment containing an electrochemical microsensor. Microelectronics are used for signal amplification and conditioning, analog-to-digital conversion, and wireless transfer. An array of single-use, e-Mosquito cells with a 5-mm2 area forms a disposable patch, which can be attached to the skin's surface through an adhesive antiseptic layer. A matrix of 180 of these individually actuated e-Mosquito cells on a 3- x 3-cm patch could supply blood sampling every hour for a week.
So far, "three MEMS prototype chips have been fabricated to study different parts of the e-Mosquito system," says Gattiker. The Canadian scientists expect the e-Mosquito to become mainstream technology in the next five to 10 years, where it could find application in "any medical situation requiring close blood monitoring and/or automated drug delivery," says Gattiker.
--Danielle Sidawi
Argonne National Laboratory, 630-252-5580, www.anl.gov
Louisiana State Univ., Center for Advanced Microstructures and Devices, 225-578-8887, www.camd.lsu.edu
National Institutes of Health, 301-496-4000, www.nih.gov
Pennington Biomedical Research Center, 225-763-2500, www.pbrc.edu
The Univ. of Chicago Hospitals, 773-702-1000, www.uchospitals.edu
Univ. at Buffalo, The Institute for Lasers, Photonics, and Biophotonics, 716-645-2680, ext. 2105, www.photonics.buffalo.edu
Univ. of Calgary, 403-220-5110, www.ucalgary.ca
Univ. of Michigan, Center for Biologic Nanotechnology, 734-764-2777, http://nano.med.umich.edu
