Design and Development of Intricate Nanomedical Devices through Compositional, Dimensional and Structural Control

摘要

Nanomedicine, the medical application of nanotechnology, uses nanoscale objects that exist at the interface between small molecule and the macroscopic world for medical diagnosis and treatment. One of the healthcare applications of nanomedicine is drug delivery: the development of nanoscale objects to improve therapeutics' bioavailability and pharmacokinetics. Shell crosslinked knedel-like nanoparticles (SCKs), that are self assembled from amphiphilic block copolymers into polymeric micelles and then further stabilized with crosslinkers isolated throughout the peripheral shell layer, have been investigated for drug delivery applications that take advantage of their core-shell morphology and tunable surface chemistry. SCKs are attractive nanocarriers because the cores of the SCKs are used for sequestering and protecting guests. The readily adjustable shell crosslinking density allows for gating of the guest transport into and out of the core domain, while retaining the structural integrity of the SCKs. Moreover, the highly functionalizable shell surface provides opportunity for incorporation of targeting ligands for enhanced therapeutic delivery.The optimization of nanoparticle size, surface chemistry, composition, structure, and morphology has been pursued towards maximization of the SCKs' therapeutic efficacy. With distinctively different dimensions, compositions and structures of the core and shell domains of SCKs, and an ability to modify each independently, probing the effects of each is one of the major foci of this dissertation. Utilization of a living radical polymerization technique, reversible addition-fragmentation chain transfer (RAFT) polymerization, has allowed for facile manipulation of the block lengths of the polymer precursors and thus resulted in various dimensions of the nanoparticles. SCKs constructed from poly(acrylic acid)-b-polystyrene (PAA-b-PS) with various chain lengths, have been investigated on the loading and release of doxorubicin (DOX). The effect of PEGylation on paclitaxel (PTX) loaded SCKs on the cell internalization and killing was investigated. Apart from chemotherapies, the SCKs were explored as antimicrobial agents by incorporating silver species. Conjugation of the SCK surface with a protein adhesin through amidation chemistry to promote epithelial cell targeting and internalization was developed. Nanoscale assemblies with complex morphologies constructed from a linear triblock copolymer was investigated. Furthermore, a highly multifunctional nanodevice for imaging and drug delivery functionalized with a chelator for radio-labeling, polyethylene glycol (PEG) for improved biodistribution, targeting ligands, a chromophore and a therapeutic agent was evaluated in vivo as active-targeted delivery of therapeutics.