The Importance of Chemistry in Creating Well-Defined Nanoscopic Embedded Therapeutics: Devices Capable of the Dual Functions of Imaging and Therapy ANDREAS M. NYSTR O€M*, † AND KAREN L. WOOLEY*, ‡ †The Swedish Medical Nanoscience Center, Department of Neuroscience, Karolinska Institutet, SE-17177 Stockholm, Sweden, and ‡Department of Chemistry, Department of Chemical Engineering, Texas A&M University, P.O. Box 30012, 3255 TAMU, College Station, Texas 77842-3012, United States RECEIVED ON MARCH 30, 2011 C O N S P E C T U S N which polymer building blocks are proving anomedicine is a rapidly evolving field, for useful for the construction of sophisticated devices that provide enhanced diagnostic imaging and treatment of disease, known as theranostics. These well-defined nanoscopic objects have high loading capacities, can protect embedded thera- peutic cargo, and offer control over the conditions and rates of release. Theranostics also offer ex- ternal surface area for the conjugation of ligands to impart stealth characteristics and/or direct their interactions with biological receptors and provide a framework for conjugation of imaging agents to track delivery to diseased site(s). The nanoscopic dimensions allow for extensive biological circulation. The incorporation of such multiple functions is complicated, requiring exquisite chemical control during production and rigorous characterization studies to confirm the compositions, structures, properties, and performance. We are particularly interested in the study of nanoscopic objects designed for treatment of lung infections and acute lung injury, urinary tract infections, and cancer. This Account highlights our work over several years to tune the assembly of unique nanostructures. We provide examples of how the composition, structure, dimensions, and morphology of theranostic devices can tune their performance as drug delivery agents for the treatment of infectious diseases and cancer. The evolution of nanostructured materials from relatively simple overall shapes and internal morphologies to those of increasing complexity is driving the development of synthetic methodologies for the preparation of increasingly complex nanomedicine devices. Our nanomedicine devices are derived from macromolecules that have well-defined compositions, structures, and topologies, which provide a framework for their programmed assembly into nanostructures with controlled sizes, shapes, and morphologies. The inclusion of functional units within selective compartments/domains allows us to create (multi)functional materials. We employ combinations of controlled radical and ring-opening polymerizations, chemical transformations, and supramolecular assembly to construct such materials as functional entities. The use of multifunctional monomers with selective polymerization chemistries affords regiochemically functionalized polymers. Further supramolecular assembly processes in water with further chemical transformations provide discrete nanoscopic objects within aqueous solutions. This approach echoes processes in nature, whereby small molecules (amino acids, nucleic acids, saccharides) are linked into polymers (proteins, DNA/RNA, polysaccharides, respectively) and then those polymers fold into three-dimensional conformations that can lead to nanoscopic functional entities. Introduction Well-defined nanoscopic objects that can be embedded therapeutic cargo with high capacity for loading and control over the conditions and rates of release, while also offering with therapeutics have great potential to protect the external surface area for conjugation of ligands to impart Published on the Web 06/15/2011 www.pubs.acs.org/accounts 10.1021/ar200097k & 2011 American Chemical Society Vol. 44, No. 10 ’ 2011 ’ 969–978 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 969