Quantum Dots Targeting Multiplexed Bioassays

New technology has potential to create a variety of multiplexed diagnostic tests

CEO SUMMARY: Here’s another exciting new technology which promises to expand the capabilities of diagnostic testing while lowering laboratory costs. Based on research originally done during the 1970’s, quantum dots™ are nanometer-sized semiconductors with unique properties. Quantum Dot Corporation wants to use an “Intel Inside” strategy with diagnostic partners to launch new assays.

DIAGNOSTIC TESTING technology may soon get a boost from Qdot™ nanocrystals, a new technology offered by Quantum Dot Corporation of Palo Alto, California.

“Quantum dots (Qdots) are nanometer-sized crystals made of semiconductor material such as cadmium selenide,” stated Bala S. Manian, co-founder of Quantum Dot Corporation (QDC). “These crystals light up like molecular-sized LEDs and make it possible to detect biological materials ranging from DNA to proteins.”

Manian’s company believes that quantum dots can play a useful role across the entire spectrum of bioassay applications. “Qdots are water soluble and will attach to cells, proteins, and nucleic acids,” he noted. “They make excellent tags and multiplexing agents for all types of bioassays.”

Founded in November 1998, QDC is moving rapidly to engage its technology across all types of bioassay applications. “During 1999, we signed our first agreement with one of the major diagnostic companies,” said Joel Martin, Ph.D., President and CEO at QDC. “A public announcement about this agreement is expected sometime in April.”

Martin is confident that Qdots will find rapid acceptance in a wide variety of bioassay applications. He predicts at least one additional agreement with a major diagnostics company will be signed by year’s end. Agreements with pharmaceutical and research companies are also expected.

Martin’s confidence is based upon the performance of Qdots in lab trials conducted at QDC. “Virtually every application of Qdots to different bioassays has worked extremely well on the first attempt,” explained Martin. “There is sharpness of color and better detection limits. Now we are moving beyond ‘proof of principle’ efforts to further refine the performance of Qdots.”

Variety Of Problems

Quantum dots solve a variety of problems that plague fluorescent dye markers. First, quantum dots will not photo-bleach under the light source.

Second, existing fluorescent dye markers generate a broad color emission spectra which overlap and make it difficult to simultaneously detect a number of markers. In contrast, quantum dots produce sharp colors at specific wavelengths. This makes them ideal for multiplexed assays.

Third, fluorescent dye markers will photo-degrade in the specimen over time. This causes problems if the specimen needs to be retested at a future date. Qdots remain photo-stable over long periods of time.

“Another benefit of quantum dots is the fact that a single light source is all that’s required to light them up,” stated Manian. “This eliminates the need for a blue laser to excite blue dyes, a red laser to excite red dyes, and so forth. Instead, a single, inexpensive ultraviolet or even a blue LED will light up all quantum dots.”

Business Strategy

“Our business strategy is to be like ‘Intel Inside’, where Qdots are the engine that powers our partners’ products,” explained Manian. “We intend to carefully chose our partners and collaborate in the development of diagnostic tests built upon Qdots.”

“I would like to emphasize that our technology is available to all comers, on the right terms,”? added Martin. “However, we will closely participate with our partners to add value. We want to share in the profits generated by the use of Qdots in various applications, including diagnostic testing.”

QDC’s “Intel Inside” business approach is different from that of Luminex Corporation of Austin, Texas. Luminex would like to position its LabMap™ multiplex test platform as an open technology system for use in diagnostics, pharmaceutical research, and other purposes. Luminex wants to emulate how the open technology of the IBM-compatible PC and Microsoft Windows formed the technology backbone for the personal computer industry. (See TDR, December 21, 1998.)

“Our business strategy is to be like ‘Intel Inside’, where Qdots are the engine that powers our partners’ products.”

“We expect quantum dots to find a ready application in diagnostic testing,” said Manian. “This technology can be adapted to existing laboratory instruments, minimizing the need for special equipment and training. It also can support reduced sample sizes and less expensive reagents.”

Quantum dots were discovered at Bell Laboratories and later developed for biological applications by researchers at Lawrence Livermore National Laboratory, Massachusetts Institute of Technology, and the University of Melbourne. QDC has licensed all major biological patents held by developers. This gives QDC an unchallenged position for developing the quantum dot technology.

QDC was formed in November 1998, by Martin and Manian, two veteran entrepreneurs. It obtained first-round venture capital funding of $7.5 million in January 1999.

Within the diagnostics category of bioassays, QDC has a specific objective. “Together with our diagnostic partners, we would like to accomplish two things with Qdots,” noted Martin.

Start With Approved Tests

“First, we want to start with approved assays and combine them into multiplexed assays which can be moved from expensive, sophisticated lab instruments and performed on smaller, less expensive lab instruments,”? he said. “This would generate superior results, from multiplexed assays, at lower cost.

“Second, we believe that a huge reagent business will spring from our Qdot technology,” continued Martin. “For example, ELISA-like assays can substitute Qdots for the enzymes. Analyte A is the color red, Analyte B is orange, and so forth.”

E-Commerce Is Wild Card

Lab executives and pathologists who investigate quantum dot technology will find that it is simple and robust. It is poised to demonstrate its effectiveness in a number of diagnostic applications.

There seems to be no major hurdle preventing Qdots from entering the marketplace for laboratory testing. Since Quantum Dot Corporation already has one agreement with a major diagnostics company, it would be reasonable to expect that assays built around Qdots will be available within the next 12 to 18 months.

Both Quantum Dot Corporation and Luminex demonstrate that there are technologies, not based in genetic or molecular science, which can lower the cost of diagnostic testing while improving the quality of results.

Many Potential Uses For Quantum Dots

Executives at Quantum Dot Corporation expect Qdots to find applications in research, drug discovery, diagnostics, and genetic analysis. The list below shows the wide range of potential applications:

  • Genotyping
  • Whole blood assays
  • Multiplexed diagnostics
  • RNA expression analysis
  • Fluorescence microscopy
  • High throughput screening
  • Multi-color flow cytometry
  • Immunoassays

Selected References & Publications
1. Alivisatos, AP, Nanocrystals: Building blocks for modern materials design, Endeavour 21, 56 (1997).
2. Alivisatos, AP, Perspectives on the Physical Chemistry of Semiconductor Nanocrystals, J. Phys. Chem 100, 13226 (1996).
3. Alivisatos, AP, Semiconductor Clusters, Nanocrystals, and Quantum Dots, Science 271, 933 (1996).
4. Bruchez, MP et. al., Semiconductor Nanocrystals as Fluorescent Biological Labels, Science 281, 2013 (1998).
5. Chan, WC et. al., Quantum Dot Bioconjugates for Ultrasensitive Nonisotopic Detection, Science 281, 2016 (1998).
6. Colvin, VL et. al., Light-Emitting Diodes Made From Cadmium Selenide Nanocrystals And A Semiconducting Polymer, Nature 370, 354 (1994).
7. Empedocles SA et al, Three Dimensional Orientation Measurements of Symmetric Single Chromophores using Polarization Microscopy, Nature 399, 126 (1999).
8. Empedocles, SAet al, Photoluminescence Spectroscopy of Single CdSe Nanocrystallite Quantum Dots, Phys. Rev. Lett. 77(18), 3873-3876 (1996).

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