W560:Ward:Improved Dose-Response Analyses Using Direct Titration with Picoliter Dispense

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Ken Ward, Michael Day, Christie Dudenhoefer, Jeff Nielsen, Heather Paris, Kevin F. Peters, Debora Thomas and Joshua Yu

Hewlett-Packard Company USA

Serial dilution is routinely used for dose-response analyses, for secondary screening, SAR, ADMET and drug-drug interaction studies among others. This sequential process with its associated problems such as carry-over, compounded errors and compound wastage among others, is easily avoided by using HP picoliter dispense technology.

With HP technology, direct dilutions are accomplished at your bench top by dispensing the proper number of picoliter droplets into each well, to independently generate each required dose using non-contact dispense. This also means that any dose can be placed in any well on the plate, rendering complicated experiments to be simple to both design and execute.

Direct dilution digital technology is now being used at five beta test sites around the world in both large and small pharma. In collaboration with HP researchers, results have been generated which demonstrate the advantages of the technology. Four major scientific benefits for IC50 and EC50 determination precision and accuracy will be shown. First, a three-fold reduction in replicate precision from an SAR campaign. Second, improvement due to randomization of plate designs to reduce edge effects. Next, the advantage of greater Hill slopes through elimination of serial dilution carryover. And finally, precision improvements due to using very finely-spaced doses compared to standard serial dilutions.

In addition, the complicated workflows for serial dilution involving intermediate dilutions and plate replication, are radically simplified with direct dilution. Furthermore, these titrations can readily be performed by biologists at the bench top, reducing critical time-to-results for dose-response studies. Less compound is required for these direct dilutions than for standard serial dilutions, due to both the lack of intermediate dilution and the lower dead volume of this dispense technology. Using picoliter droplets ensures that a wide dynamic range is generated between a single drop dose and the dose needed to reach the DMSO limit of any assay.

HP digital dispense can be used directly into cell based assay-ready plates, or into dry or wet plates for enzymatic assays. This new methodology will be demonstrated to have numerous benefits to pharmaceutical research, particularly emphasizing streamlined workflows and improved scientific results.

(Poster looks fantastic in PowerPoint, it's destroyed in the jpg conversion)

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