Figure 3.

(A) Schematic representation of the following conceptst: (i) internalization of nanoparticles by cells can lead to the down-regulation of proteins, including thymidylate synthase (TS), important for DNA damage repair response; ii. due to the down-regulation of TS, the conversion of dUMP to dTMP is inhibited; iii. subsequently, when the DNA is subjected to insult by ionizing radiation causing doublestrand breaks; and iv. the normally effective homologous recombination pathway for repairing DSB’s in S-phase cells is also inhibited, leading to a biological mechanism of radiosensitization. (B) A cross-correlative methodology developed provides a three-dimensional data set to compare cell populations and sub-populations with regard to nanoparticle dose−response at the single-cell level. Correlating biological markers imaged with laser scanning confocal microscopy with elemental content from synchrotron X-ray fluorescence microscopy for cell populations provides statistically significant, descriptive analysis of cell populations with regard to biological response for a quantified number of nanoparticles. For example, only cells with comparable numbers of nanoparticles are compared, or only cells in a certain phase are compared. The population behavior can be described by fitting functions and any individual cell from a population can be characterized by its biological markers coupled with its nanoparticle content (67).