Shell Click-Crosslinked (SCC) Nanoparticles: A New Methodology for Synthesis and Orthogonal Functionalization Maisie J. Joralemon, ²,§ Rachel K. O’Reilly, ²,‡, ⊥ Craig J. Hawker,* ,‡,| and Karen L. Wooley* ,² Contribution from the Washington UniVersity in Saint Louis, Center for Materials InnoVation and Department of Chemistry, One Brookings DriVe, Saint Louis, Missouri 63130-4899, IBM Almaden Research Center, 650 Harry Road, San Jose, California 95120, and Materials Research Laboratory, UniVersity of California, Santa Barbara, California 93106 Received June 14, 2005; E-mail: hawker@mrl.ucsb.edu; klwooley@artsci.wustl.edu Abstract: A new methodology for the preparation of well-defined core-shell nanoparticles was developed, based upon the employment of a multifunctional crosslinker to coincidently stabilize supramolecular polymer assemblies and imbed into the shell unique chemical functionalities. Amphiphilic diblock copolymers of poly(acrylic acid)80-b-poly(styrene)90 that had been assembled into micelles and partially functionalized throughout the corona with alkynyl groups were utilized as Click-readied nanoscaffolds for the formation of shell Click-crosslinked nanoparticles (SCCs). Divergently grown dendrimers of the zero, first, second, and third generations having increasing numbers of azide terminating groups ((N 3)2-[G-0], (N3)4-[G-1], (N3)8- [G-2], and (N3)16-[G-3], respectively) were investigated as crosslinkers via Click reactions with the alkynyl groups to form covalent linkages throughout the block copolymer micelle corona, thus forming a crosslinked shell. The crosslinking reactions were characterized by 1 H NMR and IR spectroscopies, differential scanning calorimetry (DSC), and dynamic light scattering (DLS) measurements. Only the first generation dendrimer ((N 3)4-[G-1]) possessed a sufficient balance of polyvalency and water solubility to achieve crosslinking and establish a robust nanostructure. The resulting SCC was further characterized with atomic force microscopy (AFM), transmission electron microscopy (TEM), and analytical ultracentrifugation (AU). The dendritic crosslinker is important as it also allows for the incorporation of excess functionality that can undergo complementary reactions. Within the shell of this SCC the remaining azide termini of the dendrimer crosslinker were then consumed in a secondary Click reaction with an alkynyl-functionalized fluorescein to yield a fluorescently labeled SCC that was characterized with DLS, AFM, TEM, AU, UV-vis, and fluorescent measurements as a function of pH. Introduction Nature’s power to drive systems toward a desired architecture or order has been elegantly harnessed in the synthesis of self- assembled architectures. Synthetic chemistry has evolved to model such natural systems, and engineer polymer chains, such that their assembly into supramolecular architectures via non- covalent interactions has become tunable through control of the polymer composition and the physiological conditions under which assembly is conducted. 1 Architectures that have been accessed include toroids, 2 helices, 3,4 rods, 5-7 spheres, 8-10 disks, 11 vesicles, 12-14 fibers, 15-18 tubes, 19-22 and other shapes. 23,24 The ability to control self-assembly provides exciting opportuni- ties to manufacture unique materials that demonstrate properties that are not otherwise accessible. 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