Developing New Methodologies for Crosslinked Polymeric Nanostructure Syntheses, Chemoselective Modifications, and Applications as Imaging and Delivery Agents

The overall emphasis of this dissertation research includes the syntheses of amphiphilic block copolymers bearing functional groups through controlled radical polymerization techniques, followed by the aqueous assembly of these block copolymer precursors to construct polymeric nanostructures with different sizes and morphologies. Further chemical modification of the nanostructures afforded functional crosslinked nano-objects with reporting probes for imaging and biocompatible stealth materials for tuning the in vivo fate of nanostructures. Amphiphilic block copolymers poly(acrylic acid)-block-polystyrene: PAA-b-PS) with well-defined structures were prepared through nitroxide-mediated radical polymerization: NMP). Using novel pre-functionalization strategies, these block copolymer precursors were functionalized with DOTA for chelating 64Cu and were then assembled into micelles and crosslinked throughout the micelle shell domain to afford the shell crosslinked nanoparticles: SCKs), containing large numbers of effective DOTAs per particle for 64Cu radiolabeling These 64Cu-complexed nanoparticles showed impressive specific activities: ca. 400 μCi μg-1), which suggest that they will serve as highly sensitive in vivo positron emission tomography: PET) tracers at low administering doses. The pre-grafting strategy was further extended to accomplish SCKs with variable biodistributions. PAA-b-PS amphiphilic block copolymers were modified with varying numbers of poly(ethylene oxide): PEO) chains, together with DOTA, before assembling into block copolymer micelles and crosslinking throughout the micellar shell regions. After chelation of 64Cu tracers, the in vivo fate of PEGylated SCKs was evaluated by means of biodistribution experiments and PET imaging. The blood retention of PEGylated-SCKs exhibited tunabilities, depending on the mPEG grafting density and the nanoparticle surface properties. Various bi-functional pyrazine-based chromophores were used as crosslinkers to probe directly their incorporation efficiencies into the shells of block copolymer micelles, which further determined the actual crosslinking extents ─ a critical factor for developing SCKs as PET imaging agents. The micelles were made to carry poly(N-acryloxysuccinimide): PNAS) as pre-installed amine-reactive functionalities along amphiphilic triblock copolymer precursors: PEO-b-PNAS-b-PS) prepared through reversible addition-fragmentation chain transfer: RAFT) radical polymerizations. The incorporation/crosslinking efficiencies were dependent upon the type of crosslinker and the applied stoichiometries. The intrinsic reactivity of aldehyde motivated the developments of well-defined polymers having reactive carbonyl side chain substituents. Amphiphilic block copolymers bearing poly(4-vinyl benzaldehyde): PVBA) block segments with controlled molecular weights and low polydispersities were obtained through RAFT polymerizations and assembled into polymeric vesicles and micelles. The vesicles were crosslinked and functionalized with fluorescent molecules through chemoselectively-reductive amination and were shown to display interesting in vitro cell association behaviors. The micelles were modified with near-infrared fluorescent dyes and crosslinked with diamino crosslinkers, each via reductive amination, to prepare robust nanoparticles with optimized luminescent characteristics for in vivo optical imaging