Well-Defined Nanoscopic Embedded Therapeutics Nystro€m and Wooley FIGURE 3. SCKs as carriers of doxorubicin, with the ability to tune the compositions and dimensions of the core and shell domains independently. Reprinted with permission from ref 34. Copyright Elsevier 2011. FIGURE 4. Loading of silver-based antimicrobial agents within the shell or core shell interface of SCK nanoparticles. Reprinted with permission from ref 22. Copyright Royal Society of Chemistry 2010. We have also investigated the SCK scaffold for the delivery of silver-based antimicrobial agents, which are of interest for treating bacterial infections in the lung and bladder. Silver-based agents are interesting as antibacterial therapeutics because toxicity to human tissues is low and bacteria rarely develop resistance against silver-based agents. The SCKs were either loaded with Agþ within the framework of the poly(acrylic acid) shell or silver carbene complexes that were expected to reside near the core shell interface (Figure 4). The SCKs were found to have high loading capability and sustained release of the silver agents over the course of several days. These silver-containing SCKs were found to be effective inhibitors of infection in vitro against urinary isolates of Escherichia coli and respiratory isolates of Pseudomonas aeruginosa. Using nature as a guide, SCKs have been prepared as synthetic analogs of histones,36 of ca. 10 nm diameter and carrying positive surface charge character, and studied for their ability to package nucleic acid-based materials (plasmid DNA, oligoDNA, peptide nucleic acids, siRNA).36 39 Ultimately, the interest is in the delivery of nucleic acids for molecular recognition of mRNA overexpressed in sites of acute lung injury, to allow for diagnostic imaging and/or therapy. A current target is the mRNA of inducible nitric oxide synthase; however, much work remains to advance from promising in vitro cell transfection results to a working system in vivo. Degradability For SCKs described so far, degradability has not been re- garded as the primary objective, mainly because the phy- siochemical, in vitro, and in vivo studies have been time- consuming, and a rapidly degradable NP system would pose challenges with study prior to the disintegration of the controlled morphology. However, to successfully utilize nanoparticle constructs for therapeutic delivery in the clinic, clearance of the NP or its building blocks must be assured, while also avoiding toxic effects from the particles and degradation products. The metabolic fate of the nanoparti- cle and the single and multiple dose toxicity must be investigated, along with many other factors such as clear- ance routes. For SCKs, both degradability of the cross-links stabilizing the micelles40 and the polymer scaffold used for construc- tion have been studied.41 Creating pH-degradable cross- links in the nanostructure is an interesting design feature that would allow degradability to be easily incorporated in any SCK construct, and result in the rapid disassembly of the nanoparticle. Provided that the constituent building blocks are small enough to allow for renal clearance, accumulation of the nanoparticle or its components can be avoided. To Vol. 44, No. 10 ’ 2011 ’ 969–978 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 975