Well-Defined Nanoscopic Embedded Therapeutics Nystro€m and Wooley FIGURE 1. SCKs having tailored in vivo behavior involve coupling onto polymer precursors to provide for chemical control and detailed characterization. Reprinted with permission from ref 1. Copyright 2008 American Chemical Society. equipped with poly(ethylene glycol) (PEG) grafts of different molecular weight and grafting density, combined with 64Cu radiolabels for diagnostic imaging and full BioD assessment. Importantly, the grafting of PEG chains was performed on the block copolymers prior to formation of the SCKs, to achieve accurate determination and control over the graft- ing density on the final nanostructures. It was observed that five PEG grafts per block copolymer gave a PEG spacing, D, of ca. 1 nm, capable of resisting adsorption of large and small proteins2,3 and resulting in extended blood circulation times. This approach proved to be a much more efficient route to obtaining NPs with high surface density of PEG and im- proved stealth properties, compared to a triblock copolymer of PEG-b-PAA-b-PS, even with longer PEG chain length, which is a traditional way of obtaining stealthy micellar nanostructures. The concept of targeting TNPs to specific tissue or disease of choice is the fundamental premise of creating nanome- dicines with high efficacy. The concept is not new; Paul Ehrlish postulated the magic bullet concept in the early 1900s, and it is still a highly appealing idea.4 The rationale for creating such systems is simple: targeting drugs or contrast can substantially increase the efficacy of treatment, minimize the injected dose, overcome toxicity issues, provide superior contrast (or superior local therapeutic concentrations), and allow for the intelligent design of personalized medicines specifically designed for each patient subtype. However, there are several conflicts that result from the competing effects from the use of ligands for active targeting by binding to biological receptors, including alteration of the BioD5 by hitting other targets and immunogenic responses.6 Ligand-mediated targeting of nanoparticles, or “active” targeting, utilizes biomacromolecules, such as antibodies, proteins, peptides, aptamers, or small molecular entities attached to the surface of the nanoconstruct.7 These ligands are expected to bind overexpressed or specific receptors in the tissue selected, followed often by receptor-mediated endocytosis for transport into cells. Whether the ligand targeting affects the PK or only the BioD is under debate. Studies have shown that ligand-targeted liposomes do not show a difference in the PK characteristics, but in the tumor localization (BioD). Similarly, studies have indicated that targeting NPs to a tumor has a more profound effect on the local tumor distribution, where the targeting ligand acts to distribute the NPs from the tumor stroma to an intracel- lular localization.8 Such effects are suggested to be an effect Vol. 44, No. 10 ’ 2011 ’ 969–978 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 971