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Quantum Dot Set to Launch its Bead-Based Gene Expression Assay Platform in Q1 2005

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Quantum Dot Corporation (QDC) is gearing up to enter the drug discovery arena as a tools provider, and if all goes according to plan, it will do so in the new year, QDC officials told Inside Bioassays last week.

The company has been fine-tuning and beta-testing a new platform for studying gene expression in cells for just over a year now, since it was first introduced at last September’s Society for Biomolecular Screening meeting.

The platform will pair QDC’s Qdot fluorescent semiconductor nanocrystal technology with an optical scanner from Panasonic called the Mosaic, which has been custom-made for reading the nanocrystals in microwell-plate applications. The full agreement, which the companies announced last year, is specifically between QDC, Matsushita Electric Industrial, and Matsushita Kotobuki Electronics. US electronics consumers more familiarly know the Matsushita name as Panasonic.

According to Mitch Gaver, QDC’s director of marketing, the new platform will be available early in the first quarter of next year. Panasonic is producing the instrumentation platform, which QDC will then bundle and market with its nanocrystals.

Also in on the deal is SC Biosciences, a subsidiary of Japanese trading company Sumitomo that specializes in providing assistance, sales, and marketing to foreign biotechnology companies, particularly in the area of drug discovery. SC Biosciences counts US companies CuraGen, Biotage, and Xenogen among its partners.

The Mosaic platform follows a recent trend in gene expression that falls somewhere in between gene microarrays and quantitative PCR. The technology is capable of measuring gene expression from cell lysates or fixed cells in 96-well plates, in a highly multiplexed fashion, and without the need for PCR, according to QDC.

“This allows screening of gene expression with a much higher throughput than qPCR, and on a much more cost-effective level than you can do with either qPCR or microarrays,” Steve Chamberlain, senior marketing manager at QDC, said. “We’ve developed a T7 amplification protocol that gives us sensitivity on the order of ten to the fourth copies detectable.

“More recently we’ve done studies looking at the total amount of RNA that we can put into a single round of T7 amplification and get reasonable gene expression information — even down to one nanogram — across hundreds of genes,” he added.

At the heart of the platform is the company’s core technology — Qdot semiconductor nanocrystals. The micron-scale particles made from layers of semiconductor metals demonstrate unique optical properties — long-lived fluorescence, tunability, and narrow emission bands — and thus have great potential in a variety of biological and medical applications, according to the company.

In molecular and cell biology, researchers have been using Qdots as they would traditional organic fluorescent dyes or genetically engineered fluorescent proteins — by attaching them to cellular products such as proteins in order to track their movements or measure their interactions.

The technology has been working — particularly in biochemical assays, such as those that measure protein-protein interactions — and to a lesser extent in live-cell applications. Scores of papers have now been published out of basic research laboratories on both applications, but scientists are still trying to work out how the nanocrystals might be used in high-throughput or high-content drug screening.

If the nanocrystals do have a major drawback, it’s their relatively large sizes — a little over 10 nanometers in diameter — as compared to cells, proteins, and other fluorescent dyes. This makes the dots sometimes cumbersome for biochemical assays, and downright difficult for live-cell assays.

For gene expression applications, this is not as much of an issue. The Qdots are packed inside beads, resulting in a variety of beads with “hundreds of distinct optical barcodes,” Chamberlain said, depending on what combination of Qdots was used. The beads are then attached to oligonucleotides, and the optical scanner can then detect and read the barcodes in a multiplexed fashion. According to Chamberlain, it offers the potential to measure the expression of anywhere between 100 and 150, and possibly up to 200 genes simultaneously.

“You can grow your cells in a 96-well format, treat them with whatever drugs or compounds you want, and we’re working with vendors now to integrate an automated lysis and amplification, or lysis and labeling protocol,” Chamberlain said. “We’ve also set the assay up to look at spliced variants … and you can have more than one oligo for each gene on each bead.”

We see this as less of a competitor and more of a downstream application to microarrays,” he added. “We don’t see it being used a lot for drug discovery, but we think pharmaceutical companies are going to come to realize that in a lot of disease processes, there are not simply single genes involved.”

The scanner is CCD-based and “basically takes pictures of each bead” inside of the wells, Gaver said. The system relies on epifluorescence imaging and a variety of bandpass filters optimized for the different optical emissions. Although a list price is not yet available, the system should be able to take advantage of the Qbeads’ unique optical qualities to keep the cost down. In fact, this point is the very crux of the system — because Qdots can all be excited by essentially one wavelength, this means that multiplexed imaging is possible with only the one laser line: 405 nm, according to Chamberlain.

Currently, Gaver said, QDC has “beta-testers of the instrument at several pharmaceutical companies and core labs,” although he was not at liberty to disclose which ones. The company has also developed software to enable Qbead encoding and generate an assay signal. “The objective to this point has been to make the data output in a format that is compatible with currently available packages; for example, Rosetta Resolver, GeneSpring [from Silicon Genetics], or [DecisionSite] from Spotfire,” Chamberlain said. “Our objective is not to write software to do data analysis.”

QDC can only hope its foray into the drug discovery market goes as swimmingly as have its efforts to enter the biomedical imaging field. Just last week, the company received a $2 million grant from the Advanced Technology Program at the National Institute of Standards and Technology, which it will use to further develop the nanocrystals for ocular and cancer imaging. Currently, the nanocrystals are also being used by several academic institutions and companies for live, small-animal imaging.

“Using quantum dots as labels was the thing we could get into the fastest, but probably has the smallest potential,” Gaver said. “The next phase is the Mosaic platform, which is a big market, but it took us a few years to develop. And long-term, the biggest market, and probably biggest risk, is long-term in vivo imaging.”

As far as live-cell assays go, Gaver said “there are a number of companies that are trying to get into that space, and we think that our labels are going to be used on those systems quite extensively.” He added that although this hasn’t happened yet, QDC has already worked with several cell-based assay instrumentation vendors to test the Qdots for long-term kinetic assays.

—BB

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