Image-Based High-Content Analysis, Stem Cells and Nanomedicines: A Novel Strategy for Drug Discovery - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 272

for risk assessment of the cancer-inducing potential of a new drug,
which is required by regulatory agencies for drug approval. The
image-based high-content analysis of micronuclei has been shown
to have good correlation with in vivo micronucleus assays [63].
Since hepatotoxicity is one of the major reasons for drug
non-approval, the development of an assay predictive of drug-
induced liver toxicity has been considered imperative. Individual
conventional assays in animals have not been reliable in predicting
human hepatotoxicity. However, when cellular assays are used
in combination, as it is possible using the HCS approach, the
level of hepatotoxicity prediction is improved for these assays
(e.g., mitochondrial activity, glutathione and cell proliferation).
Furthermore, the predictive value can be dramatically increased in
HCS assays that use human hepatocyte cell lines. Thus, the assessment
of multiple pre-lethal hepatotoxic eff ects of a potential drug on
individual live cells, including mitochondrial toxicity, oxidative stress,
deregulation of calcium homeostasis, phospholipidosis, apoptosis,
and antiproliferative eff ects, can be well predicted [64].
Despite these achievements, considerable challenges remain with
regard to the design of the toxicity assays and the cell source used.
The low proliferation rate of primary human hepatocytes makes
them less suitable for cytotoxic assessment. Furthermore, primary
human hepatocytes are phenotypically unstable under current cell
culture conditions, and de-diff erentiate rapidly. Therefore, stem cells
could be used for deriving hepatocyte cells in order to provide the
cell numbers required for toxicity screenings.

9.6 Advances in Nanomedicine for Drug

Discovery Using HCS

Nanotechnologies employ materials that have a functional
organization in at least one dimension on the nanometer scale
[65]. Many of these engineered polymeric devices are capable of
interacting with biological systems on a molecular level [66].
Great potential for their use arises from the fact that
nanotechnological applications exhibit bulk macro-scale chemical
properties that are unique to the engineered material, while not
necessarily possessed by the molecules if not arranged in a specific
fashion [67, 68]. By utilizing this trait, it is possible to develop