During the past few years, new and innovative developments of nanospheres and nanoparticles for drug delivery systems and life science applications have been reported [1-2]. This new technology has raised a great deal of attention from both scientists and investors, since it promises several new low-cost therapeutic treatments and diagnostics which are non-invasive, highly sensitive and precise. An important issue, particularly in human therapeutic treatments that require in-depth understanding before investing in the nanoparticle-based companies, is the capability of controlling the size distribution of nanospheres and nanoparticles.

One critical criteria, for example, is based upon the fact that the smallest blood vessels, the capillaries, are approximately 8 microns in diameter and hence no more than 1000 particles per ml over 2 microns in an intravenous injection 

is recommended to prevent clotting [3]. The nanoparticles should be designed such that they are stable enough to withstand the harsh conditions of the bloodstream or are not filtered out by the kidneys as they are considered to be foreign to the body. In this report, we provide some insight on new potential products and advanced applications based upon nanospheres and nanoparticles.

Non-Invasive Stroke Therapy: According to the American Society of Cardiovascular & Interventional Radiology, more than 500,000 people suffer strokes every year and stroke is the third leading cause of death. Currently, catheter-based brain interventions, including invasive catheter placement into the brain artery and intravenous injection of the tissue plasminogen activator (t-PA) to the clot site, is the only FDA-approved clot-busting therapy for treating strokes.

Research scientists at Argonne National Laboratory are in the conceptual development stage of a non-invasive acute stroke treatment based on nanotechnology using magnetically guided encapsulated nanoparticles [4]. The drug delivery concept consists of injecting a small dose of "designer" magnetic particles, containing active t-PA into the vein, which are then magnetically guided and trapped at the blood clot site by an externally applied magnetic field. The drug is then released from the particle matrix using focused ultrasonics.  

The particle matrix, which is a mixture of non-toxic biodegradable magnetic metal oxide nanophases (i.e. Fe₃O₄ or γ -Fe₂O₃) and active t-PA, is packed in biodegradable poly(lactic acid) (PLA) nanospheres having sizes ranging from 100 nm to several microns. PLA nanospheres are encapsulated with poly(ethylene glycol) (PEG) to provide protection against interaction with the patient's immune system. White blood cells can attack the nanoparticles and reduce their circulating life in the blood stream.

For years, biotech companies, such as Enzon Pharmaceuticals (NASDAQ : ENZN), Maxygen (NASDAQ : MAXY) and venture-backed Novocell, Inc., have developed PEG technology (pegylation). Pegylation can involve the attachment of PEG to therapeutic proteins or small molecules, such as cancer chemotherapy agents and antibiotics, or PEG encapsulation of individual cells and cell clusters.

Nanoparticle DNA Probe: The widely used DNA probe, using techniques such as the fluorophore-enhanced polymerase chain reaction (PCR) and a gene chip microarray to identify a segment of unknown DNA strands, has a wide range of applications in life sciences, medicine, bio-defense and genomic research. In 2003 alone, Affymetrix (NASDAQ : AFFX), one of the leading manufacturers of gene chips, sold over $300 million of its GeneChip system and other products directly to customers, including Schering AG (NYSE ADR : SHR), Amgen (NASDAQ: AMGN), and Roche.

Nanotech start-ups such as Northbrook, IL-based Nanosphere, Inc., is developing a nano-scale DNA probe using gold nanoparticles, having sizes as small as 13nm in diameter. These nanoparticles are attached with hundreds of complementary DNA sequences designed to capture specific genomic targets from a clinical sample. Captured DNA strands are isolated and analyzed using Nanosphere's proprietary molecular detection system and data analysis software. Because the probe is at nano-scale, its sensitivity could reach a level of 10,000 times greater than the current fluorophore-enhanced PCR technique.

In the past two years, Nanosphere, Inc. received third-round financing for a total of $15 million from Lurie Investments, NextGen Partners LLC, Kyoto, Japan-based Takara Bio Inc. and a $2.5 million U.S. Government contract for the identification of biological toxins.

Nano-Scale Cancer Treatments: With a goal of reducing the unpleasant side effects for patients that are associated with chemotherapeutic treatments, government, academia and industry are developing several alternative, safe and effective cancer therapies including anti-angiogenesis and novel non-invasive thermotherapies such as Nanoshell optical therapeutics [5] and the Targeted Nano- Therapeutics™ (TNT™) system.

Research scientists at a Houston, Texas-based Nanospectra Biosciences Inc. and Rice University are in early-stage development of novel "Nanoshell" optical therapeutics. This unique therapy employs "Nanoshells", having sizes ~ 100nm, made of silica nanospheres coated with an ultra-thin gold layer. The "Nanoshells" are conjugated with antibodies so that they seek out and bind themselves to the cancer cells when the solution is intravenously injected to the cancer patient. Near-infrared light (laser) is applied externally to the diseased cells bound with the "Nanoshells" through the tissue. 

A solid-state interaction between gold and laser generates heat at the "Nanoshells" which in turn destroys the cancer cells. Nanospectra Biosciences just received $3 million funding from the U.S. Government to develop nanoshells for breast cancer treatment.

Based upon similar thermotherapeutic approaches, Triton BioSystems, Inc., a Chelmsford, MA-based venture-backed company, is developing non-invasive targeted therapeutics that also use heat to treat late-stage breast, lung, colon, pancreatic and prostate cancers. The Triton BioSystems Targeted Nano-Therapeutics™ (TNT™) System is an injectable product that uses nanoscale magnetic spheres made of a special formulated material that when activated by external magnetic energy, generates localized heat and destroys cancer cells. 

According to, Mr. Samuel Straface, Triton BioSyStems CEO, at temperatures exceeding 42°C, cancer cells which are more sensitive to heat than normal cells, are destroyed [6]. Since the spheres are so small, the heating is very local and does not harm the healthy vital tissues or organs nearby, unlike chemotherapy or radiation. The company is in pre-clinical development and in 2006, is anticipated to begin human clinical trials.

REFERENCES

[1] M.R. Kumar, J Pharm Pharmaceut Sci, 3(2):234-258, 2000.
[2] S. Rudershausen, et al , European Cells and Materials Vol. 3. Suppl. 2, 2002: 81-83.
[3] Limit Test For Particulate Matter. British Pharmacoepia 1993, Volume 2, Appendix X111. London, HMSO. 
[4] M.D. Kaminski, et al, Using Nanoscale Technology to Help Stroke Victims: Prototype Nanoparticles for Future Magnetically Guided, Targeted Tissue Plasminogen Activator Stroke Therapy, Argonne News, April 23, 2004.
[5] C. Loo, et al, Technol Cancer Res Treat. 2004 Feb;3(1):33-40.
[6] Nanoparticle News, December 2002.