Shell crosslinked nanoparticles incorporated with silver cation or degradable units for therapeutic delivery.

摘要

Nanotechnology is a multidisciplinary scientific field undergoing explosive development. One of the greatest promises of nanotechnology is in the development of new and effective medical treatments, such as nanomedicine. Many approaches are being pursued towards nanomedicine. One of the approaches is to develop nanoparticles as carriers for drug molecules to achieve enhanced bioavailability. Nanoparticles are one attractive system as nanocarriers since they have demonstrated the abilities to help the therapeutics to achieve improved solubility, increased loading capacity, and prolonged circulation time. Moreover, their polyvalency provides nanoparticles the possibility to incorporate therapeutics, imaging agents, and targeting ligands into one single formulation for more effective treatment. Various nanoparticles have been investigated for therapeutic delivery, among which shell crosslinked knedel-like (SCK) nanoparticles are one promising strategy.;SCKs are well-defined nanoparticles fabricated from the self assembly of amphiphilic block copolymers into micelles with core-shell morphologies, followed by shell crosslinking with difunctional crosslinkers. In this dissertation, as an expansion of the SCK fundamental design and preparation methodology, an amphiphilic block copolymer, poly(methyl acrylate)- b-poly(N-(acryloyloxy)succinimide-co-( N-acryloylmorpholine)) (PMA-b-P(NAS-co-NAM)), with built-in functionality was synthesized by sequential reversible addition--fragmentation chain transfer (RAFT) polymerizations and studied for convenient shell crosslinking and functionalization for facile preparation of SCKs. Then, well-defined SCKs were explored as capsules to incorporate silver species for the development of advanced antimicrobial agents, and the resulting silver-SCK complexes were evaluated in vitro for their antimicrobial efficacies.;As an ideal therapeutic carrier, the nanoparticle vehicle should also be biocompatible and bioresorbable. Two approaches were explored for the incorporation of degradability into the SCK system. An acid-labile crosslinker with a central UV-active chromophore was synthesized and used for the construction of hydrolytically-degradable SCKs with acid-sensitive crosslinks. On the other hand, a poly(lactic acid) (PLA)-based amphiphilic block copolymer was synthesized and used as a polymer precursor for the preparation of SCKs with biodegradable cores. Furthermore, SCKs, containing either degradable or non-degradable crosslinks, were investigated as carriers for the uptake and release of doxorubicin (DOX), as a model chemotherapeutic agent.