Zinc Oxide Nanocrystals for Nonresonant Nonlinear Optical Microscopy in Biology and Medicine

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Abstract
In this study, we showed that biocompatible zinc oxide (ZnO) nanocrystals (NCs) having a noncentrosymmetric structure can be used as nonresonant nonlinear optical probes for bioimaging applications in vitro by use of the second order processes of second harmonic and sum frequency generation, as well as the third order process of four wave mixing. These nonresonant processes provide advantages above and beyond traditional two photon bioimaging: (i) the probes do not photobleach; (ii) the input wavelength can be judiciously selected; and (iii) no heat is dissipated into the cells, ensuring longer cell viability and ultimately longer imaging times. ZnO NCs were synthesized in organic media by using a nonhydrolytic sol−gel process and subsequently dispersed in aqueous media using phospholipid micelles and incorporated with the biotargeting molecule folic acid (FA). Sum frequency, second harmonic, and nonresonant four wave mixing nonlinear signals from this stable dispersion of ZnO NCs, targeted to the live tumor (KB) cells, were used for imaging. Robust intracellular accumulation of the targeted (FA incorporated) ZnO nanocrystals could be observed without any indication of cytotoxicity.