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At ACT Conference, Companies Plug Technologies for Solving the New Cellular Delivery Bottleneck

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SAN DIEGO — IBC’s Assays and Cellular Targets meeting enabled members of the high-content screening, biochemical assay, and drug development communities to have highly focused discussions and presentations about the latest developments in these booming fields.

The conference, held here last week, was divided into four tracks, or “mini-conferences,” each with a specific focus-area: cell-based assays, assay development, ion channels, and GPCRs.

The focus, though, was clearly on methods and instrumentation for screening live cells, and one theme constantly came to the forefront: As high-content and cell-based assays continue to gain popularity for drug screening, a two-pronged bottleneck is developing at the level of preparing cells for large-scale studies.

The first part of the bottleneck is maintaining the sheer volume of cultured cells to keep up with the increasing speed with which they are used. While this conundrum is far from solved, companies and researchers are making strides — for example, UK-based biotech The Automation Partnership markets several products and services to increases automation of cell culture. (See Inside Bioassays, 5/11/2004)

The second part of the bottleneck is the lack of reliable and efficient methods for delivering into cells the necessary molecules — such as nucleic acids, proteins, and small-molecule compounds — to prepare for and conduct assays. And unlike the cell culture bottleneck, the current school of thought is that delivery issues have not been sufficiently addressed.

“There is potential for it, but there had been no large-scale success for incorporating reagents into cells,” said Lansing Taylor, co-founder and former director of Cellomics, and founder and current CEO of biotech startup Cellumen, during a keynote presentation at ACT. “Sample preparation is now the main stumbling block.”

Not surprisingly, several companies are attempting to tackle the delivery bottleneck. Two such companies — Excellin Life Sciences and Cyntellect — presented posters at ACT describing their efforts in this area.

Laura Mazzola, Excellin’s CEO, presented a poster entitled “Universal Molecular Delivery into Cells,” which described her company’s ElectroInjection technology, and was co-recipient of the best cell-based assay poster as voted by conference attendees.

ElectroInjection is a variation on traditional electroporation. Although it works via the same physical phenomenon — the application of voltage — Excellin’s platform is much gentler to cells than traditional methods, Mazzola said.

As opposed to traditional electroporation, in which voltage is applied directly to individual cells, the ElectroInjection technique applies voltage to scores of cells being grown on a porous substance within an electrical field. The design is such that a much smaller electrical field, on the order of millivolts, is applied to the cells in the presence of the molecule that needs to be delivered.

The advantage, according to Mazzola, is that a great deal more of the cells remain viable than in traditional electroporation — about 95 percent viability as compared to less than 50 percent. Both methods are among the quickest available, with each typically taking less than a minute.

At the same time, Mazzola said, the technique demonstrates greater efficiency and speed than lipofection, the most commonly used method for molecular delivery. According to the Excellin scientific poster, ElectroInjection’s efficacy rate is greater than 90 percent, while lipofection’s is less than 80 percent. Furthermore, lipofection can take anywhere from a half-day to a day to complete.

“And when people say that a method has an 80-percent success rate, that’s often only referring to 80 percent of the live cells,” Mazzola added.

Excellin, which is based in Menlo Park, Calif., is incorporating the technology into a bench top instrument called CellPort-SE, which the company expects to be commercially available in the fourth quarter of next year, Mazzola said. The instrument is to eventually be combined with a 96-well version of the porous substrate, designed to even further increase the method’s throughput.

Laser Power

Meanwhile, San Diego-based Cyntellect is developing platforms that will use a laser-based technology called LEAP (Laser-Enabled Analysis and Processing), that the company says combines a highly efficient molecular delivery method with a plethora of other tools, such as high-throughput cell purification and imaging.

A Cyntellect representative was presenting a poster at ACT on LEAP’s usefulness as a cell transfection tool. Although Inside Bioassays was unable to catch up with the representative at the conference, Jim Linton, Cyntellect’s chief business officer, last week discussed this and several other applications.

“We see two major bottlenecks in this area: preparation of cells and delivery of biomolecules,” Linton said. “People are trying to get mostly siRNA into cells for assays, but also ions, proteins, small molecules, and even quantum dots. But if you can’t get it into the cell, then you can’t do anything.

“In response to this, we’ve set out to perform broad, non-toxic delivery into many cell types,” Linton added, “and to do it in such a way that you can get a pure population of cells.”

LEAP enables this by training a laser onto adherent or suspended cells via digital micromirrors. Under the control of proprietary optics and object recognition software, the system can image cells “10 to 100 times faster than any other platform,” Linton said. The laser’s power can be adjusted so that when a laser hits a cell, it can kill it, or it can punch a small, non-lethal hole in them to allow them to uptake small molecules.

The advantage of combining these two applications is that it allows for a complete assay preparation system on one platform, Linton said.

“We can culture cells, and then eliminate the ones that aren’t interesting,” he said, thus obtaining a pure population. Those remaining cells can then be assayed on the same platform by subsequently delivering nucleic acids, and then small molecule compounds via opto-injection.

Linton said that the company also sees applications in biopharmaceutical production and diagnostics, as researchers could quickly and efficiently eliminate all but the highest expressing cells in a particular culture.

But he added the company is probably most excited about the opto-injection capabilities. “We really think it could change the whole paradigm of molecular delivery,” he said.

Cyntellect is quickly gaining support for both the cell purification and opto-injection applications. Just last week, coincidental with the ACT conference, Cyntellect announced the publication of a scientific paper describing LEAP’s efficacy as a cell purification tool in the October issue of Cytometry.

In addition, Linton said, the company has publicly disclosed partnerships with the University of Texas at Galveston and Eli Lilly to test LEAP for several applications, as well as several undisclosed agreements — one of which it expects to announce this week.

The company does not yet have a commercialized product, but Linton said that the LEAP platform, as well as a lower-cost bench top version called HOP, are expected to be available early to mid-next year.

— BB

 

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