Well-Defined Nanoscopic Embedded Therapeutics Nystro€m and Wooley FIGURE 5. SCKs containing degradable cross-links. Reprinted with permission from ref 40. Copyright 2008 American Chemical Society. demonstrate hydrolytic cleavage of degradable cross-links, a self-reporting cross-linking system was utilized, having a UV vis reporter unit that was released upon hydrolysis of acetal linkages (Figure 5). This system allowed for real-time monitoring of the degradation process in vitro via quantifi- cation of the released 4-methoxy-1-naphthaldehyde. It was found that the half-life of the neat cross-linker at pH 7.4 was 29 h and that incorporation of the cross-linker in the SCK nanostructure reduced the half-life to ca. 1.5 h; at pH 5.0, the half-life dropped to 13 min. The rapid acceleration of hydro- lysis in the SCK shell suggests use in vivo for both therapeutic delivery and diagnostic imaging, as localization in diseased tissue should occur within a few circulation passes (seconds to minutes), followed by degradation of cross-links to release therapeutics and clear the background NP in circulation. Furthermore, the decreased half-life under acidic conditions will promote accelerated degradation and release in cells or tumor environment. Further, degradability of the polymer building blocks can be advantageous for nanoparticles that are com- posed of larger polymer chains, or for applications where complete degradation of the NP systems is desired.41 43 Conclusions/Outlook The primary advantage of theranostics is that they are not limited to therapy or imaging, but allow for combinations, to 976 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 969–978 ’ 2011 ’ Vol. 44, No. 10 give coincident diagnostic information plus delivery of ther- apeutics. Nanoscopic objects serve as scaffolds that have the optimum, intermediate size between the molecular level and microscopic materials, to provide domains for high capacities of therapeutic loading and sites for labeling, while also having high surface areas for the presentation of targeting ligands. Although imaging of the nanoscopic de- vice and delivery of a molecular therapeutic does not offer dual tracking of each independently, having information about the conditions under which the therapeutic is released and the ability to monitor the nanostructure gives some indication of the theranostic benefit. However, if each is labeled separately or if the nanoscopic diagnostic agent is the therapeutic, then dual tracking is built in. This result occurs with labeled protein or antibody therapeutics, but could also be made to be true, for instance, if synthetic nanomaterials could be advanced to the point of offering therapeutic benefit directly, by triggering biological responses without the need for release of small molecule therapeutics. We are particularly interested in studying hierarchically as- sembled nanomaterials that have complex structures and functions,44,45 and can trigger unique biological responses or carry multiple diagnostic and therapeutic payloads. This material is based upon work supported by the National Heart, Lung and Blood Institute of the National Institutes of