Well-Defined Nanoscopic Embedded Therapeutics Nystro€m and Wooley Imaging Modalities Positron emission tomography is a highly sensitive imaging modality, with which we have had great success in tracking SCKs in vivo. As with the PEGylation of SCKs, it was found that conjugation of chelators for the PET-active radionu- clides was best performed onto the polymer precursors to allow for efficient coupling and accurate quantification and characterization studies to be performed.25 Earlier attempts to couple chelators and perform radiolabeling onto pre- established SCKs experienced difficulties.26 The advantages of nanoparticles for PET imaging applications has already been reviewed.27 We have also begun developments of SCKs toward optical imaging modalities.28,29 Magnetic resonance imaging (MRI) is powerful in its ability to visualize soft tissues. Nanoparticles for MRI include both T1 (positive contrast) based agents, such as NPs containing rare earth metals, Gd3þ, and others, as relaxation aids, or super- paramagnetic NPs, such as SPIONs for T2 (negative contrast) weighted imaging. Apart from these standard MRI applica- tions, NPs for T1 imaging of other natural isotopes such as 19F, 31P, 13C, 14N, and others have been developed. Of these isotopes, 19F nuclei are attractive due to the lack of background in normal tissue (only low levels in teeth and bone), good biocompatibility, sensitive chemical shift, high gyromagnetic ratio, and high natural abundance. We have explored the use of nanoscale 19F-MRI agents capable of both chemotherapeu- tic delivery and 19F-MRI either in the form of hyperbranched polymer micelles30,31 or SCKs.32 Fluorinated hyperbranched polymer micelles were initially investigated, since it was hypo- thesized that the multicompartmental amphiphilic structure of the polymer scaffold would allow sufficient mobility for the fluorinated component to achieve beneficial relaxation kinetics for imaging while also providing nanoscopic compartments for chemotherapeutic loading via hydrophobic interactions. We found that this design strategy indeed produced nanopar- ticles with one narrow 19F signal and much better T1 and slightly better T2 relaxation times for imaging applications compared to perfluorocrown ether (PFCE).31 In vitro evaluation indicated low toxicity and good biocompatibility of the NP itself, but the absolute fluorine concentration was too low for in vivo imaging.30 To overcome the limitations in fluorine con- centration that the hyperbranched fluoropolymer system ex- perienced, we also explored fluorinated SCKs, as these structures have shown high loading capacities for hydrophobic chemotherapeutics.33,34 SCKs with fluorinated hydrophobic cores were further loaded with PFCEs having 15 chemically equivalent fluorine atoms. Despite the high fluorine 974 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 969–978 ’ 2011 ’ Vol. 44, No. 10 concentration, unfortunately, it was found that the hydropho- bic core restricted the mobility of the PFCE to such an extent that the signal was not detectable without plasticizing the core. Therapeutic Cargo SCKs have been investigated as carriers of therapeutics directed against three main applications: cancer,33 35 in- fectious diseases,22 and acute lung injury. In drug delivery applications, SCKs are attractive candidates due to their stability, high loading capacity, and the broad tunability of composition, structure, dimension and morphology. Our interest has been to craft the SCK to optimize drug loading capacity and control the release kinetics. The amphiphilic core shell morphology is taken advantage of, and we have performed studies that have involved packaging of thera- peutics in the core, at the core shell interface and in the shell, while tuning the compositions, properties, and dimen- sions of each. In one case, we probed effects of amorphous versus semicrystalline core domains, with the intention being to trap doxorubicin, an anthracycline antibiotic and a very common chemotherapeutic agent used in the treatment of many cancer types, within the semicrystalline core at room temperature and promote their release at physiological temperature.33,35 We found that high loading concentra- tions (20% w/w) of doxorubicin in SCKs could be achieved with both amorphous and crystalline nanoparticle cores, due to the combined favorable hydrophobic and π π inter- actions for doxorubicin with the cores and ionic interactions with the SCK shells. The drug-loaded SCKs were found to kill U87 cancer cells via apoptosis in vitro, while no negative effect on cell viability was found from the SCKs themselves. We also conducted an in-depth study of the effects of the particle dimensions, including overall diameter, core diameter, and shell thickness, on the drug release kinetics. Effects of the nanoparticle composition were held constant, by employing SCKs constructed from a single type of amphiphilic diblock copolymer (Figure 3). A series of four SCK nanoparticle samples, ranging in number-average hydrodynamic diameter from 14 to 30 nm, was prepared from four block copolymers having different relative block lengths and absolute degrees of polymerization. Their shell-to-core volume ratio showed im- pact on the rates and extents of release of DOX, with the volume occupied by the poly(acrylic acid) shell relative to the volume occupied by the polystyrene core correlating inversely with the diffusion-based release of DOX.