Microarray Biochips for High-Throughput Drug Screening

Prashanth Asuri1, Moo-Yeal Lee1, Anand K. Ramasubramanian2, Michael Hogg1, Bilge Eker1, Sana Butt1, Jessica Ryan1, Sumitra Sukumaran3, Douglas S. Clark4, and Jonathan S. Dordick5. (1) Solidus Biosciences, Inc., 1223 Peoples Avenue, Troy, NY 12180, (2) UC - Berkeley, Dept of Chemical Engineering, Berkeley, CA 94720 - 1462, (3) Chemical & Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, (4) Chemical Engineering, University of California, Berkeley, Berkeley, CA 94720, (5) Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 4005 Center for Biotechnology, Troy, NY 12180

Combinatorial chemistry and advances in genomics and proteomics has resulted in a dramatic increase in the number of new chemical entities (NCEs) and screenable drug targets. Nevertheless, these advances have not translated into an increased number of new drug approvals, in part because of the high failure rate due to toxicity of the NCE or its metabolite(s). Thus, Solidus Biosciences, Inc. has developed microarray biochip platforms that can adequately mimic human metabolism and assess cell-specific toxicity of NCEs and their metabolites. Initial work has focused on the development of the Metabolizing Enzyme Toxicology Assay Chip (MetaChip) suitable for high-throughput analysis of drug metabolism and toxicity. Human cytochromes P450 are encapsulated in an array of alginate-gel spots on (MTMOS) treated glass slides, followed by the addition of a drug or prodrug to be tested, and the metabolites of the P450 reactions are screened in situ for cytotoxicity on a cell monolayer. To expand our 2D cell monolayer culture for cytotoxicity assays to a more physiologically relevant and robust three-dimensional (3D) cell culture for both cytotoxicity and growth inhibition assays, we have developed a miniaturized 3D cellular array chip (Datachip) that can be used for in vitro toxicological assessment of NCEs and their P450-generated metabolites. Various human cell lines were encapsulated and cultured in an array of alginate-gel drops spotted on poly(styrene-co-maleic anhydride) (PSMA) treated glass slides. We envisage that these novel technologies represents a promising, high-throughput microscale alternative to conventional in vitro multi-well plate platforms and creates new opportunities for rapid and inexpensive assessment of ADME/Tox at very early phases of drug development, thereby enabling unsuitable candidates to be eliminated from consideration much earlier in the drug discovery process.